胰高血糖素样肽-1及其类似物Exendin4对肝内胆管癌发生发展的作用
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摘要
肝内胆管癌（Intrahepaticcholangiocarcinoma）是起源于胆管内皮细胞的恶性肿瘤。在肝胆外科肿瘤中发病率仅次于肝细胞癌。随着生活习惯的改变，胆管癌的发病率逐年升高。在1974年至1994年的20年间，胆管癌成为上海地区发病率增长最快的肿瘤，男、女发病率分别升高了119%和124%。【1】再加上胆管癌的恶性程度高，治疗难度大，成为危害人群健康的重要因素。目前，对于胆管癌的发病机理尚不清楚。大量研究表明一些肝胆系统疾病与胆管癌的发生关系密切，如原发性硬化性胆管炎（PCS）、肝内外胆管结石、胆管腺瘤、肝脏吸虫病、先天性胆管畸形如卡洛里病（Calori’sdisease）等，ICC的其他几个重要的危险因素，如丙肝及非酒精性脂肪肝有了明显的升高。国际学术界公认长期的胆管病变，导致各种因子刺激胆管上皮引发胆管上皮细胞的过度增生继而癌变是胆管癌形成的主要原因。【2】
已有的研究表明胆管细胞增生调节与内分泌系统有着密切的联系。内分泌系统通过多种不同种类的激素对胆管细胞的增生起到很重要的调节作用，而胆管细胞增生和凋亡的失衡、恶性转变及胆管癌的产生也与内分泌系统的调节障碍有重要关系。与此相关，一些临床研究发现内分泌系统疾病特别是糖尿病亦参与胆管肿瘤的发生发展，并逐渐受到重视,近来，胡先贵等关于糖尿病是否增加胆管癌罹患的风险的Meta分析指出，肥胖、糖尿病可能是胆管癌（包括肝内胆管癌和肝外胆管癌）发病的危险因素。这些研究都表明，内分泌系统疾病与胆管系统疾病和胆管肿瘤有着重要的联系。而糖尿病作为我国的常见病和多发病，也势必对胆管肿瘤的发病率和临床治疗产生影响。然而，糖尿病和胆管癌之间关系的机理还不清楚。
胰高血糖素样肽-1（Glucagon-likepeptide-1，GLP-1）是机体神经内分泌系统中重要的一员，而且在糖尿病的治疗领域也备受关注。GLP-1是由肠道上皮L型内分泌细胞所分泌的肽类激素。由于胰腺与胆管系统的胚胎起源相近，【18】近年来，GLP-1对胆管系统的作用也逐渐受到重视。然而，目前尚没有GLP-1对于肝内胆管癌的发生、发展的研究见于报道。胆管细胞的过度增生与神经内分泌系统有着紧密的联系，而临床上肝内胆管癌的发生、发展也与糖尿病等内分泌系统疾病密不可分。而GLP-1作为在两个领域的交点，对解答肝内胆管癌发生发展的问题意义重大。目前，对于GLP-1及其类似物Exendin-4的研究主要集中在糖尿病的治疗领域，而关于其对胆管系统疾病的作用尚未引起重视，在国内外诸多文献证实神经内分泌系统和内分泌疾病对于胆管癌发生发展的影响下，我们希望探讨神经内分泌激素GLP-1及其受体在人胆管癌组织中的表达，GLP-1及其类似物Exendin-4对胆管癌细胞的作用及细胞内信号传导路线，同时利用动物模型来评价GLP-1极其类似物Exendin-4在胆管癌的治疗领域中的意义。研究结果将有助于回答：糖尿病与胆管癌之间究竟通过怎样的机理相互联系？GLP-1在胆管系统疾病中起到了什么样的作用，是否和对胰岛β细胞的作用相似？GLP-1类似物Exendin-4在治疗糖尿病的同时对胆管系统有什么影响？能否为胆管癌的治疗提供新的思路？随着糖尿病和胆管癌发病率持续升高，该课题的开展具有重要的实际意义。因此，本研究从临床资料入手，收集63例肝内胆管癌细胞的临床病例资料，分析其病历资料特点，63例患者全部接受手术切除肝内胆管癌，其平均存活时间为21.6月，中位生存时间为18个月，63例患者中糖尿病的发生率为20.6%（13/63），是胆管癌发病的独立危险因素，单因素分析结果提示，影响预后的整体因素包括肿瘤的TNM分期，肿瘤的数目，肿瘤大小，是否有门静脉癌栓，是否有血管侵犯。多因素分析提示影响预后的独立危险因素为TNM分期，以及门静脉癌栓。同时选取肝细胞癌组织、正常肝组织作为对照，分析GLP-1R在各种组织中的表达，在63例胆管癌组织中，阳性表达率为55.6%肝细胞癌中的阳性表达率为19.2%，说明，GLP-1R在胆管细胞癌中的表达明显高于肝细胞癌和正常肝组织，我们也可能得出这样的结论：GLP-1可能为肝内胆管癌的一个潜在的Mark，或者一个治疗的新靶点。基于上述情况，我们选取人肝内胆管癌细胞系HuCCT1进行进一步的实验，实验中我们发现，GLP-1及其类似物Exendin-4对于肿瘤细胞具有一定的抑制增殖、促进凋亡的作用，进一步联合化疗药物奥沙利铂共同处理肿瘤细胞，发现Exendin-4具有对化疗药物的增敏作用，其肿瘤形成减少，凋亡增多。肿瘤侵袭迁移能力下降。裸鼠种植肝内胆管癌皮下瘤，荷瘤成功后，予以Exendin-4及奥沙利铂共同处理，发现，共同处理的荷瘤小鼠肿瘤体积有明显的缩小，且其组织表达肿瘤增殖的指标也有所下降。在裸鼠肝脏种植肝内胆肝癌移植瘤，分组进行药物调控，发现经过Exendin4处理过的肝内移植瘤，其增殖能力下降，而肿瘤凋亡能力上升。
随着肥胖以及2型糖尿病患者的增多，GLP-1在这一领域的应用也逐渐增多。然而，这类药物对恶性肿瘤的影响还没有被研究透彻，受限于样本量和研究时间，我们还需要更长的时间来拿出更令人信服的证据。总之，我们的研究表明，肠促胰岛素GLP-1作为一个强有力的cAMP诱导剂，能够抑制肝内胆管癌细胞的增殖。GLPL-1水平下调也可能是引起肥胖、糖尿病患者发生肝内胆管癌的一个新的机制。
Intrahepatic cholangiocarcinoma (ICC) is a rare malignant tumor which arises from the epithelial cells of intrahepatic bile ducts (beyond the second order bile ducts), and it has a global increasing trend in recent years. ICC is the second most common primary liver malignancy after hepatocellular carcinoma (HCC), accounting for10%to15%of all primary liver cancers. From1972to1994, cholangiocarcinoma was the most rapidly increasing malignancy in Shanghai, with an increase in incidence of119%in men and124%in women. The reason for the increasing incidence of ICC is not entirely understood. Several risk factors can predispose an individual to ICC, include primary biliary cirrhosis, primary sclerosing cholangitis, hepatolithiasis, choledochal cyst disease, the use of the radiological contrast agent thorotrast, parasitic biliary infestation (Clonorchis sinensis and Opisthorchis viverrini), Calori's disease and hepatitis B. Other important risk factors for ICC, hepatitis C and nonalcoholic fatty liver disease (NAFLD), have been increasing in incidence. Recognized by the world that long-term bile duct lesions may be the main reason for the formation of cholangiocarcinoma.
Previous studies have shown that the proliferation of cholangiocytes have close link with endocrine system. Endocrine system through a variety of different hormones on the proliferation of cholangiocytes, and the imbalance between proliferation and apoptosis, malignant transformation, formation of cholangiocarcinoma has closely relationship with endocrine system. Related to this, a number of clinical studies have found endocrine system diseases, especially diabetes also participate in the development of the cholangiocarcinoma. Recently, a mata anaysis from Hu et. about whether diabetes increase the risk of choalangiocarcinoma, shows that DM may be the risk factors of cholangiocarcinoma. These studies have shown that the endocrine system disease and bile duct disease and cholangiocarcinoma has closely link. Although diabetes mellitus (DM) has been shown to be risk factors for many cancers, the associations remain inconclusive for ICC.
Glucagon like peptide1(GLP-1) is a gut-derived peptide secreted in a nutrient-dependent manner from the small intestine and stimulates glucose-dependent insulin production and secretion via specific receptors expressed on islet b cells. Similar embryonic origin of the pancreas and bile duct system, in recent years, GLP-1on the role of the bile duct system is also gradually be taken seriously. we demonstrated that activation of the GLP-1R in cholangiocytes by its selective agonist exendin-4prevents cholangiocyte apoptosis. Overall, our findings suggest that exendin-4is a molecule that is able to correct the dysregulated balance between cholangiocyte proliferation and apoptosis. Besides being relevant for the understanding of the pathophysiology of chronic cholestasis. While there is no recent study on relationship between GLP-1and intrahepatic cholangiocarcinoma. GLP-1as the intersection of the two areas, has significant meaning of the development of intrahepatic cholangiocarcinoma. Currently, the GLP-1and its analogs Exendin-4research mainly in the field of diabetes treatment, attention on diseases of the biliary system has not yet, in many domestic and international literature precisely the neuroendocrine system and endocrine diseases play an important role of the development of the cholangiocarcinoma, we hope to explore the role of neuroendocrine hormones GLP-1and its receptor expression in human cholangiocarcinoma, how the GLP-1and its analogs Exendin-4work on cholangiocarcinoma cell and intracellular signaling transmission line, while the use of animal models to evaluate the GLP-1analogue Exendin-4in significance in the field of treatment of cholangiocarcinoma extremely.
Therefore, in our study63cases of intrahepatic cholangiocarcinoma who were underwent a surgical resection of intrahepatic cholangiocarcinoma, the average survival time of21.6months, the medianthe survival time of18months, among the63cases,13cases have been diagnosis of DM, diabetes is associated with an increased risk for ICC, for the univariate analysis results suggest that, overall prognostic factors including TNM stage, tumor number, tumor size, and portal vein thrombosis, multivariate analysis prompted an independent risk factor affecting the prognosis for TNM staging, as well as the number of tumors. Select hepatocellular carcinoma, normal liver tissue as a control, GLP-1R expression in various tissues, These results suggest that GLP-1R expression in cholangiocarcinoma was significantly higher than that of hepatocellular carcinoma and normal liver tissue, We may also conclude that:GLP-1may be a potential Mark for intrahepatic cholangiocarcinoma, or a treatment of a new target. We found that GLP-1and its analogs Exendin-4tumor cells with a certain degree of inhibition of proliferation, promote apoptosis, further combination chemotherapy drug oxaliplatin with tumor cells, we found that Exendin-4has a sensitizing effect of chemotherapy drugs, it can make tumor formation decreased, and apoptosis increased.
With the increase in obesity and type2diabetes, GLP-1in this field of application is also gradually increasing. However, the impact of these drugs on malignant tumors has not been studied thoroughly, however, due to the limited of the sample size and study time, we also need a longer time to come up with more convincing evidence. In conclusion, our study shows that the incretin GLP-1as a strong cAMP inducer, can inhibit the proliferation of intrahepatic cholangiocarcinoma cells. Down regulation of the GLP-1may cause obesity, diabetes patients with a new mechanism of intrahepatic cholangiocarcinoma.
已有的研究表明胆管细胞增生调节与内分泌系统有着密切的联系。内分泌系统通过多种不同种类的激素对胆管细胞的增生起到很重要的调节作用，而胆管细胞增生和凋亡的失衡、恶性转变及胆管癌的产生也与内分泌系统的调节障碍有重要关系。与此相关，一些临床研究发现内分泌系统疾病特别是糖尿病亦参与胆管肿瘤的发生发展，并逐渐受到重视,近来，胡先贵等关于糖尿病是否增加胆管癌罹患的风险的Meta分析指出，肥胖、糖尿病可能是胆管癌（包括肝内胆管癌和肝外胆管癌）发病的危险因素。这些研究都表明，内分泌系统疾病与胆管系统疾病和胆管肿瘤有着重要的联系。而糖尿病作为我国的常见病和多发病，也势必对胆管肿瘤的发病率和临床治疗产生影响。然而，糖尿病和胆管癌之间关系的机理还不清楚。
胰高血糖素样肽-1（Glucagon-likepeptide-1，GLP-1）是机体神经内分泌系统中重要的一员，而且在糖尿病的治疗领域也备受关注。GLP-1是由肠道上皮L型内分泌细胞所分泌的肽类激素。由于胰腺与胆管系统的胚胎起源相近，【18】近年来，GLP-1对胆管系统的作用也逐渐受到重视。然而，目前尚没有GLP-1对于肝内胆管癌的发生、发展的研究见于报道。胆管细胞的过度增生与神经内分泌系统有着紧密的联系，而临床上肝内胆管癌的发生、发展也与糖尿病等内分泌系统疾病密不可分。而GLP-1作为在两个领域的交点，对解答肝内胆管癌发生发展的问题意义重大。目前，对于GLP-1及其类似物Exendin-4的研究主要集中在糖尿病的治疗领域，而关于其对胆管系统疾病的作用尚未引起重视，在国内外诸多文献证实神经内分泌系统和内分泌疾病对于胆管癌发生发展的影响下，我们希望探讨神经内分泌激素GLP-1及其受体在人胆管癌组织中的表达，GLP-1及其类似物Exendin-4对胆管癌细胞的作用及细胞内信号传导路线，同时利用动物模型来评价GLP-1极其类似物Exendin-4在胆管癌的治疗领域中的意义。研究结果将有助于回答：糖尿病与胆管癌之间究竟通过怎样的机理相互联系？GLP-1在胆管系统疾病中起到了什么样的作用，是否和对胰岛β细胞的作用相似？GLP-1类似物Exendin-4在治疗糖尿病的同时对胆管系统有什么影响？能否为胆管癌的治疗提供新的思路？随着糖尿病和胆管癌发病率持续升高，该课题的开展具有重要的实际意义。因此，本研究从临床资料入手，收集63例肝内胆管癌细胞的临床病例资料，分析其病历资料特点，63例患者全部接受手术切除肝内胆管癌，其平均存活时间为21.6月，中位生存时间为18个月，63例患者中糖尿病的发生率为20.6%（13/63），是胆管癌发病的独立危险因素，单因素分析结果提示，影响预后的整体因素包括肿瘤的TNM分期，肿瘤的数目，肿瘤大小，是否有门静脉癌栓，是否有血管侵犯。多因素分析提示影响预后的独立危险因素为TNM分期，以及门静脉癌栓。同时选取肝细胞癌组织、正常肝组织作为对照，分析GLP-1R在各种组织中的表达，在63例胆管癌组织中，阳性表达率为55.6%肝细胞癌中的阳性表达率为19.2%，说明，GLP-1R在胆管细胞癌中的表达明显高于肝细胞癌和正常肝组织，我们也可能得出这样的结论：GLP-1可能为肝内胆管癌的一个潜在的Mark，或者一个治疗的新靶点。基于上述情况，我们选取人肝内胆管癌细胞系HuCCT1进行进一步的实验，实验中我们发现，GLP-1及其类似物Exendin-4对于肿瘤细胞具有一定的抑制增殖、促进凋亡的作用，进一步联合化疗药物奥沙利铂共同处理肿瘤细胞，发现Exendin-4具有对化疗药物的增敏作用，其肿瘤形成减少，凋亡增多。肿瘤侵袭迁移能力下降。裸鼠种植肝内胆管癌皮下瘤，荷瘤成功后，予以Exendin-4及奥沙利铂共同处理，发现，共同处理的荷瘤小鼠肿瘤体积有明显的缩小，且其组织表达肿瘤增殖的指标也有所下降。在裸鼠肝脏种植肝内胆肝癌移植瘤，分组进行药物调控，发现经过Exendin4处理过的肝内移植瘤，其增殖能力下降，而肿瘤凋亡能力上升。
随着肥胖以及2型糖尿病患者的增多，GLP-1在这一领域的应用也逐渐增多。然而，这类药物对恶性肿瘤的影响还没有被研究透彻，受限于样本量和研究时间，我们还需要更长的时间来拿出更令人信服的证据。总之，我们的研究表明，肠促胰岛素GLP-1作为一个强有力的cAMP诱导剂，能够抑制肝内胆管癌细胞的增殖。GLPL-1水平下调也可能是引起肥胖、糖尿病患者发生肝内胆管癌的一个新的机制。
Intrahepatic cholangiocarcinoma (ICC) is a rare malignant tumor which arises from the epithelial cells of intrahepatic bile ducts (beyond the second order bile ducts), and it has a global increasing trend in recent years. ICC is the second most common primary liver malignancy after hepatocellular carcinoma (HCC), accounting for10%to15%of all primary liver cancers. From1972to1994, cholangiocarcinoma was the most rapidly increasing malignancy in Shanghai, with an increase in incidence of119%in men and124%in women. The reason for the increasing incidence of ICC is not entirely understood. Several risk factors can predispose an individual to ICC, include primary biliary cirrhosis, primary sclerosing cholangitis, hepatolithiasis, choledochal cyst disease, the use of the radiological contrast agent thorotrast, parasitic biliary infestation (Clonorchis sinensis and Opisthorchis viverrini), Calori's disease and hepatitis B. Other important risk factors for ICC, hepatitis C and nonalcoholic fatty liver disease (NAFLD), have been increasing in incidence. Recognized by the world that long-term bile duct lesions may be the main reason for the formation of cholangiocarcinoma.
Previous studies have shown that the proliferation of cholangiocytes have close link with endocrine system. Endocrine system through a variety of different hormones on the proliferation of cholangiocytes, and the imbalance between proliferation and apoptosis, malignant transformation, formation of cholangiocarcinoma has closely relationship with endocrine system. Related to this, a number of clinical studies have found endocrine system diseases, especially diabetes also participate in the development of the cholangiocarcinoma. Recently, a mata anaysis from Hu et. about whether diabetes increase the risk of choalangiocarcinoma, shows that DM may be the risk factors of cholangiocarcinoma. These studies have shown that the endocrine system disease and bile duct disease and cholangiocarcinoma has closely link. Although diabetes mellitus (DM) has been shown to be risk factors for many cancers, the associations remain inconclusive for ICC.
Glucagon like peptide1(GLP-1) is a gut-derived peptide secreted in a nutrient-dependent manner from the small intestine and stimulates glucose-dependent insulin production and secretion via specific receptors expressed on islet b cells. Similar embryonic origin of the pancreas and bile duct system, in recent years, GLP-1on the role of the bile duct system is also gradually be taken seriously. we demonstrated that activation of the GLP-1R in cholangiocytes by its selective agonist exendin-4prevents cholangiocyte apoptosis. Overall, our findings suggest that exendin-4is a molecule that is able to correct the dysregulated balance between cholangiocyte proliferation and apoptosis. Besides being relevant for the understanding of the pathophysiology of chronic cholestasis. While there is no recent study on relationship between GLP-1and intrahepatic cholangiocarcinoma. GLP-1as the intersection of the two areas, has significant meaning of the development of intrahepatic cholangiocarcinoma. Currently, the GLP-1and its analogs Exendin-4research mainly in the field of diabetes treatment, attention on diseases of the biliary system has not yet, in many domestic and international literature precisely the neuroendocrine system and endocrine diseases play an important role of the development of the cholangiocarcinoma, we hope to explore the role of neuroendocrine hormones GLP-1and its receptor expression in human cholangiocarcinoma, how the GLP-1and its analogs Exendin-4work on cholangiocarcinoma cell and intracellular signaling transmission line, while the use of animal models to evaluate the GLP-1analogue Exendin-4in significance in the field of treatment of cholangiocarcinoma extremely.
Therefore, in our study63cases of intrahepatic cholangiocarcinoma who were underwent a surgical resection of intrahepatic cholangiocarcinoma, the average survival time of21.6months, the medianthe survival time of18months, among the63cases,13cases have been diagnosis of DM, diabetes is associated with an increased risk for ICC, for the univariate analysis results suggest that, overall prognostic factors including TNM stage, tumor number, tumor size, and portal vein thrombosis, multivariate analysis prompted an independent risk factor affecting the prognosis for TNM staging, as well as the number of tumors. Select hepatocellular carcinoma, normal liver tissue as a control, GLP-1R expression in various tissues, These results suggest that GLP-1R expression in cholangiocarcinoma was significantly higher than that of hepatocellular carcinoma and normal liver tissue, We may also conclude that:GLP-1may be a potential Mark for intrahepatic cholangiocarcinoma, or a treatment of a new target. We found that GLP-1and its analogs Exendin-4tumor cells with a certain degree of inhibition of proliferation, promote apoptosis, further combination chemotherapy drug oxaliplatin with tumor cells, we found that Exendin-4has a sensitizing effect of chemotherapy drugs, it can make tumor formation decreased, and apoptosis increased.
With the increase in obesity and type2diabetes, GLP-1in this field of application is also gradually increasing. However, the impact of these drugs on malignant tumors has not been studied thoroughly, however, due to the limited of the sample size and study time, we also need a longer time to come up with more convincing evidence. In conclusion, our study shows that the incretin GLP-1as a strong cAMP inducer, can inhibit the proliferation of intrahepatic cholangiocarcinoma cells. Down regulation of the GLP-1may cause obesity, diabetes patients with a new mechanism of intrahepatic cholangiocarcinoma.
引文
1. Lacey JV Jr, Susan SD, Louise AB. Recent trends in breastcancer incidence and mortality. Environ Mol Mutagen,2002,39:82-88
2. Wolf I, Sadetzki S, Catane R, Karasik A, Kaufman B. Diabetes mellitus and breast cancer. Lancet Oncol,2005,6:103-111
3. Eliassen AH, Tworoger SS, Mantzoros CS, Pollak MN, Hankinson SE. Circulating insulin and C-peptide levels and risk of breast cancer among predominately premenopausal women. Cancer Epidemiol Biomarkers Prev,2007,16:161-164
4. Schernhammer ES, Holly JM, Pollak MN, Hankinson SE. Circulating levels of insulin-like growth factors, their binding proteins, and breast cancer risk. Cancer Epidemiol Biomarkers Prev,2005,14:699-704
5. Wolf I, Sadetzki S, Gluck I, Oberman B, Ben-David M, Papa MZ, Catane R, Kaufman B. Association between diabetes mellitus and adverse characteristics of breast cancer at presentation. Eur J Cancer,2006,42:1077-1082
6. Yee D. Targeting insulin-like growth factor pathways. Br J Cancer,2006,94:465-468
7. Baggio LL, Drucker DJ. Biology of incretins:GLP-1and GIP. Gastroenterology,2007,132:2131-2157
8. Dufayet de la Tour D, Halvorsen T, Demeterco C, Tyrberg B, Itkin-Ansari P, Loy M, Yoo S-J, Hao E, Bossie S, Levine F.β-Cell differentiation from a human pancreatic cell line in vitro and in vivo. Mol Endocrinol,2001,15:476-483
9. Holst JJ, Vilsboll T, Deacon CF. The incretin system and its role in type2diabetes mellitus. Mol Cell Endocrinol,2009,297:127-136
10. Idris I, Patiag D, Gray S, Donnelly R. Exendin-4increases insulin sensitivity via a PI-3-kinase-dependent mechanism:contrasting effects of GLP-1. Biochem Pharmacol,2002,63:993-996
11. Lee YS, Shin S, Shigihara T, Hahm E, Liu MJ, Han J, Yoon JW, Jun HS. Glucagon-like peptide-1gene therapy in obesediabetic mice results in long-term cure of diabetes by improving insulin sensitivity and reducing hepatic gluconeogenesis. Diabetes,2007,56:1671-1679
12. Eng J, Kleinman W, Singh L, Singh G, Raufman J. Isolation and characterization of exendin-4, an exendin-3analogue,from Heloderma suspectum venom. Further evidence for an exendin receptor on dispersed acini from guinea pig pancreas. J Biol Chem,1992,267:7402-7405
13. Rai A, Singh G, Raffaniello R, Eng J, Raufman JP. Actionsof Helodermatidae venom peptides and mammalian glucagonlike peptides on gastric chief cells. Am J Physiol Gastrointest Liver Physiol,1993,265:G118-G125
14. Drucker DJ, Buse JB, Taylor K, Kendall DM, Trautmann M, Zhuang D, Porter L. Exenatide once weekly versus twice daily for the treatment of type2diabetes:a randomised, openlabel, non-inferiority study. Lancet,2008,372:1240-1250
15. Kim D, MacConell L, Zhuang D, Kothare PA, Trautmann M, Fineman M, Taylor K. Effects of once-weekly dosing of a long-acting release Formulation of exenatide on glucose control and body weight in subjects with type2diabetes. Diabetes Care,2007,30:1487-1493
16. Koehler JA, Drucker DJ. Activation of glucagon-like peptide-1receptor signaling does not modify the growth or apoptosis of human pancreatic cancer cells. Diabetes,2006,55:1369-1379
17. Elashoff M, Matveyenko AV, Gier B, Elashoff R, Butler PC. Pancreatitis, pancreatic and thyroid cancer with glucagonlikepeptide-1-based therapies. Gastroenterol ogy
18. Berdichevsky F, Alford D, D'Souza B, Taylor-Papadimitriou J. Branching morphogenesis of human mammary epithelialcells in collagen gels. J Cell Sci,1994,107:3557-3568
19. Sapir T, Shternhall K, Meivar-Levy I, Blumenfeld T, Cohen H, Skutelsky E, Eventov-Friedman S, Barshack I, Goldberg I, PriChen S et al. Cell-replacement therapy for diabetes:generating functional insulin-producing tissue from adult human liver cells. Proc Natl Acad Sci USA,2005,102:7964-7969
20. Wolf I, Levanon-Cohen S, Bose S, Ligumsky H, Sredni B, Kanety H, Kuro-o M, Karlan B, Kaufman B, Koeffler HP et al. Klotho:a tumor suppressor and a modulator of the IGF-1and FGF pathways in human breast cancer. Oncogene,2008,27:7094-7105
21. Wolf I, O'Kelly J, Rubinek T, Tong M, Nguyen A, Lin BT, Tai H-H, Karlan BY, Koeffler HP.15-Hydroxyprostaglandin dehydrogenase is a tumor suppressor of human breast cancer. Cancer Res,2006,66:7818-7823
22. Wolf I, Bose S, Williamson EA, Miller CW, Karlan BY, Koeffler HP. FOXA1: growth inhibitor and a favorable prognostic factor in human breast cancer. Int J Cancer,2007,120:1013-1022
23. Montrose-Rafizadeh C, Egan J, Roth J. Incretin hormones regulate glucose-dependent insulin secretion in RIN1046-38cells:mechanisms of action. Endocrinology,1994,135:589-594
24. Drucker DJ, Nauck MA. The incretin system:glucagonlike peptide-1receptor agonists and dipeptidyl peptidase-4inhibitors in type2diabetes. Lancet,2006,368:1696-1705
25. Lacroix M, Leclercq G. Relevance of breast cancer cell lines as models for breast tumours:an update. Breast Cancer Res Treat,2004,83:249-289
26. Calebiro D, Nikolaev VO, Persani L, Lohse MJ. Signaling by internalized G-protein-coupled receptors. Trends Pharmacol Sci,2010,31:221-228
27. Chahrzad Montrose-Rafizadeh HY, Wang Yihong, Roth Jesse, Montrose Marshall H, Adams Lisa G. Novel signal transduction and peptide specificity of glucagon-like peptide receptor in3T3-L1adipocytes. J Cel Physiol,1997,172:275-283
28. Villanueva-Penacarrillo ML, Delgado E, Trapote MA, Alcantara A, Clemente F, Luque MA, Perea A, Valverde I. Glucagon-like peptide-1binding to rat hepatic membranes. J Endocrinol,1995,146:183-189
29. Yang H, Egan JM, Wang Y, Moyes CD, Roth J, Montrose MH, Montrose-Rafizadeh C. GLP-1action in L6myotubes is via a receptor different from the pancreatic GLP-1receptor. Am J Physiol,1998,275:C675-C683
30. Tagliaferri P, Katsaros D, Clair T, Ally S, Tortora G, Neckers L, Rubalcava B, Parandoosh Z, Chang Y-a, Revankar GR et al. Synergistic inhibition of growth of breast and colon human cancer cell lines by site-selective cyclic AMP analogues. Cancer Res,1988,48:1642-1650
31. Ahn Y-H, Jung JM, Hong SH.8-Chloro-cyclic AMP induced growth inhibition and apoptosis is mediated by p38mitogen-activated protein kinase activation in HL60cells. Cancer Res,2005,65:4896-4901
32. Tru mper J, Ross D, Jahr H, Brendel MD, Goke R, Horsch D. The Rap-B-Raf signalling pathway is activated by glucose and glucagon-like peptide-1in human islet cells. Diabetologia,2005,48:1534-1540
33. Li Y, Tweedie D, Mattson MP, Holloway HW, Greig NH. Enhancing the GLP-1receptor signaling pathway leads to proliferation and neuroprotection in human neuroblastoma cells. J Neurochem,2010,113:1621-1631
34. Korner A, Pazaitou-Panayiotou K, Kelesidis T, Kelesidis I, Williams CJ, Kaprara A, Bullen J, Neuwirth A, Tseleni S, Mitsiades N et al. Total and high-molecular-weight adiponectin in breast cancer:in vitro and in vivo studies. J Clin Endocrinol Metab,2007,92:1041-1048
35. Novosyadlyy R, Lann DE, Vijayakumar A, Rowzee A, Lazzarino DA, Fierz Y, Carboni JM, Gottardis MM, Pennisi PA, Molinolo A et al. Insulin-mediated acceleration of breast cancer development and progression in a nonobese model of type2diabetes. Cancer Res,2010,70:741-751
36. Vilsboll T, Krarup T, Deacon CF, Madsbad S, Holst JJ. Reduced postprandial concentrations of intact biologically active glucagon-like peptide1in type2diabetic patients. Diabetes,2001,50:609-613
37. Toft-Nielsen M-B, Damholt MB, Madsbad S, Hilsted LM, Hughes TE, Michelsen BK, Holst JJ. Determinants of the impaired secretion of glucagon-like peptide-1in type2diabetic patients. J Clin Endocrinol Metab,2001,86:3717-3723
38. Kjems LL, Holst JJ, Volund A, Madsbad S. The influence of GLP-1on glucose-stimulated insulin secretion. Diabetes,2003,52:380-386
39. Carr RD, Larsen MO, Jelic K, Lindgren O, Vikman J, Holst JJ, Deacon CF, Ahren B. Secretion and dipeptidyl peptidase-4-mediated metabolism of incretin hormones after a mixed meal or glucose ingestion in obese compared to lean, nondiabetic men. J Clin Endocrinol Metab,2009,95(2):872-878
40.Coopman K, Huang Y, Johnston N, Bradley SJ, Wilkinson GF, agonist glucagon-like peptide-1(GLP-1)-(7-36) amide and the small-molecule ago-allosteric agent "Compound2" at the GLP-1receptor. J Pharmacol Exp Ther,2008,334:795-808
41. Widmann C, Dolci W, Thorens B. Internalization and homologous desensitization of the GLP-1receptor depend on phosphorylation of the receptor carboxyl tail at the same three sites. Mol Endocrinol,1997,11:1094-1102
42. Tomas E, Habener JF. Insulin-like actions of glucagon-like peptide-1:a dual receptor hypothesis. Trends Endocrinol Metab,2009,21:59-67
43. Tomas E, Stanojevic V, Habener JF. GLP-1(9-36) amide metabolite suppression of glucose production in isolated mouse hepatocytes. Horm Metab Res,2010,42:657-662
44. Aviv V, Meivar-Levy I, Rachmut IH, Rubinek T, Mor E, Ferber S. Exendin-4promotes liver cell proliferation and enhances the PDX-1-induced liver to pancreas transdifferentiation process. J Biol Chem,2009,284:33509-33520
45. GGt Holz, Leech CA, Habener JF. Activation of a cAMP regulated Ca(2?)-signaling pathway in pancreatic beta-cells by the insulinotropic hormone glucagon-like peptide-1. J Biol Chem,1995,270:17749-17757
46. Srivastava RK, Srivastava AR, Cho-Chung YS. Synergistic effects of8-Cl-cAMP and retinoic acids in the inhibition of growth and induction of apoptosis in ovarian cancer cells:induction of retinoic acid receptor b. Mol Cell Biochem,2000,204:1-9
47. Vuc'ic'V, Nic'iforovic'A, Adz'ic'M, Radojc'ic'M, Ruz'dijic'S. The combination of gamma ionizing radiation and8-Cl-cAMP induces synergistic cell growth inhibition and induction ofapoptosis in human prostate cancer cells. Invest New Drugs,2008,26:309-17
48. Stork PJS, Schmitt JM. Crosstalk between cAMP and MAP kinase signaling in the regulation of cell proliferation. Trends Cell Biol,2002,12:258-66
49. Zhang Z, Xin S-M, Wu G-X, Zhang W-B, Ma L, Pei G. Endogenous d-opioid and ORL1receptors couple to phosphorylation and activation of p38MAPK in NG108-15cells and this is regulated by protein kinase A and protein kinase C. J Neurochem,1999,73:1502-1509
50. Zhen X, Uryu K, Wang H-Y, Friedman E. D1dopamine receptor agonists mediate activation of p38mitogen-activated protein kinase and c-Jun amino-terminal kinase by a protein kinase A-dependent mechanism in SK-N-MC human neuroblastoma cells. Mol Pharmacol,1998,54:453-458
51. Quoyer J, Longuet C, Broca C, Linck N, Costes S, Varin E, Bockaert Jl, Bertrand G, Sp Dalle. GLP-1mediates antiapoptotic effect by phosphorylating Bad through a b-arrestin1-mediated ERK1/2activation in pancreatic b-cells. J Biol Chem,2010,285:1989-2002
52Ann W.Hsing, Mingdong Zhang et al. Hepatitis B and C virus infection and the risk of biliary tract cancer:a population-based study in china. Int J Cancer2008,122:1849-1853
53.Alpini G, Lenzi R,Sarkozi L, Tavoloni N. J Clin Invest,1988;81:569-578
54Domenico Alvaro, Maria Grazia Mancino, Shannon Glaser et al. Proliferating cholangiocyes:a neuroendocrine compartment in the diseased liver. Gastroenterology2007,132:415-431
55Tan CK, Podila PV, Taylor GE et al. Human cholangiocarcinomas express somatostatin receptorsandrespond to somatostatin with growth inhibition. Gastroenterology1995;108:1908-1916.
56Onori P, Wise C, Gaudio E, Francis H et al. Secretin inhibites cholangiocarcinoma growth via dysregulation of the cAMP-dependent sigaling mechanisms of secretin receptor. Int J Cancer,2010,127(1):43-54
57. Gene D.Lesage, Luca Marucci, Domenico Alvaro et al. Insulin inhibits secretin-induced ductal secretion by activation of PKC alpha and inhibition of PKC activity. Hepatology,2002,36(3):641-51
58. Wei jing, Gang Jing, Xuyu Zhou, et al. Diabetes mellitus and increased risk of cholangiocarcinoma:a meta-analysis European Journal of Cancer Prevention2012,21:24-31
59. Hagai Ligumsky, Ido Wolf, Shira Israeli et, al The peptide-hormone glucagon-like peptide-1activates cAMP and inhibits growth of breast cancer cells. Breast Cancer Res Treat.2012Apr,132(2):449-61
1. Lazaridis KN, Gores GJ. Cholangiocarcinoma. Gastroenterology2005;128(6):1655-67.
2. Vauthey JN, Blumgart LH. Recent advances in the management of cholangiocarcinomas. Semin Liver Dis1994;14(2):109-14.
3. Carpizo DR, D'Angelica M. Management and extent of resection for intrahepatic cholangiocarcinoma. Surg Oncol Clin N Am2009;18(2):289-305, viii-ix.
4. Aljiffry M, Abdulelah A, Walsh M, et al. Evidence-based approach to cholangiocarcinoma:a systematic review of the current literature. J Am Coll Surg2009;208(1):134-47.
5. Patel T. Worldwide trends in mortality from biliary tract malignancies. BMC Cancer2002;2:10.
6. Shaib YH, Davila JA, McGlynn K, et al. Rising incidence of intrahepatic cholangiocarcinoma in the United States:a true increase? J Hepatol2004;40(3):472-7.
7. Taylor-Robinson SD, Foster GR, Arora S, et al. Increase in primary liver cancer in the UK,1979-94. Lancet1997;350(9085):1142-3.
8. Kato I, Kuroishi T, Tominaga S. Descriptive epidemiology of subsites of cancers of the liver, biliary tract and pancreas in Japan. Jpn J Clin Oncol1990;20(3):232-7.
9. Welzel TM, McGlynn KA, Hsing AW, et al. Impact of classification of hilar cholangiocarcinomas (Klatskin tumors) on the incidence of intra-and extrahepatic cholangiocarcinoma in the United States. J Natl Cancer Inst2006;98(12):873-5.
10. El-Serag HB, Engels EA, Landgren O, et al. Risk of hepatobiliary and pancreatic cancers after hepatitis C virus infection:a population-based study of U.S. veterans. Hepatology2009;49(1):116-23.
11. Shaib YH, El-Serag HB, Davila JA, et al. Risk factors of intrahepatic cholangiocarcinoma troenterology2005;128(3):620-6.
12. Donato F, Gelatti U, Tagger A, et al. Intrahepatic cholangiocarcinoma and hepatitis C and B virus infection, alcohol intake, and hepatolithiasis:a case-control study in Italy. Cancer Causes Control2001;12(10):959-64.
13. Kobayashi M, Ikeda K, Saitoh S, et al. Incidence of primary cholangiocellular carcinoma of the liver in Japanese patients with hepatitis C virus-related cirrhosis. Cancer2000;88(11):2471-7.
14. Welzel TM, Graubard BI, El-Serag HB, et al. Risk factors for intrahepatic and extrahepatic cholangiocarcinoma in the United States:a population-based case-control study. Clin Gastroenterol Hepatol2007;5(10):1221-8.
15. Patel T. Increasing incidence and mortality of primary intrahepatic cholangiocarcinoma in the United States. Hepatology2001;33(6):1353-7.
16. Nathan H, Pawlik TM, Wolfgang CL, et al. Trends in survival after surgery for cholangiocarcinoma:a30-year population-based SEER database analysis. J Gastrointest Surg2007;11(11):1488-96[discussion:1496-7].
17. Patel AH, Harnois DM, Klee GG, et al. The utility of CA19-9in the diagnoses of cholangiocarcinoma in patients without primary sclerosing cholangitis. Am J Gastroenterol2000;95(1):204-7.
18. Tamandl D, Herberger B, Gruenberger B, et al. Influence of hepatic resection margin on recurrence and survival in intrahepatic cholangiocarcinoma. Ann Surg Oncol2008;15(10):2787-94.
19. Yamasaki S. Intrahepatic cholangiocarcinoma:macroscopic type and stage classification. J Hepatobiliary Pancreat Surg2003;10(4):288-91.
20. Chung YE, Kim MJ, Park YN, et al. Varying appearances of cholangiocarcinoma: radiologic-pathologic correlation. Radiographics2009;29(3):683-700.
21. Manfredi R, Barbaro B, Masselli G, et al. Magnetic resonance imaging of cholangiocarcinoma. Semin Liver Dis2004;24(2):155-64.
22. Chen LD, Xu HX, Xie XY, et al. Enhancement patterns of intrahepatic cholangiocarcinoma:comparison between contrast-enhanced ultrasound and contrastenhanced CT. Br J Radiol2008;81(971):881-9.
23. Miller G, Schwartz LH, D'Angelica M. The use of imaging in the diagnosis and staging of hepatobiliary malignancies. Surg Oncol Clin N Am2007;16(2):343-68.
24. Maetani Y, Itoh K, Watanabe C, et al. MR imaging of intrahepatic cholangiocarcinoma with pathologic correlation. AJR Am J Roentgenol2001;176(6):1499-507.
25. Anderson CD, Rice MH, Pinson CW, et al. Fluorodeoxyglucose PET imaging in the evaluation of gallbladder carcinom a and cholangiocarcinoma. J Gastrointest Surg2004;8(1):90-7.
26. Kim YJ, Yun M, Lee WJ, et al. Usefulness of18F-FDG PET in intrahepatic cholangiocarcinoma. Eur J Nucl Med Mol Imaging2003;30(11):1467-72.
27. Corvera CU, Blumgart LH, Akhurst T, et al.18F-fluorodeoxyglucose positron emission tomography influences management decisions in patients with biliary cancer. J Am Coll Surg2008;206(1):57-65.
28. Petrowsky H, Wildbrett P, Husarik DB, et al. Impact of integrated positron emission tomography and computed tomography on staging and management of gallbladder cancer and cholangiocarcinoma. J Hepatol2006;45(1):43-50.
29. Goere D, Wagholikar GD, Pessaux P, et al. Utility of staging laparoscopy in subsets of biliary cancers:laparoscopy is a powerful diagnostic tool in patients with intrahepatic and gallbladder carcinoma. Surg Endosc2006;20(5):721-5.
30. Weber SM, Jarnagin WR, Klimstra D, et al. Intrahepatic cholangiocarcinoma: resectability, recurrence pattern, and outcomes. J Am Coll Surg2001;193(4):384-91.
31. Tan JC, Coburn NG, Baxter NN, et al. Surgical management of intrahepatic cholangiocarcinoma-a population-based study. Ann Surg Oncol2008;15(2):600-8.
32. Sotiropoulos GC, Bockhorn M, Sgourakis G, et al. RO liver resections for primary malignant liver tumors in the noncirrhotic liver:a diagnosis-related analysis. Dig Dis Sci2009;54(4):887-94.
33. Endo I, Gonen M, Yopp AC, et al. Intrahepatic cholangiocarcinoma:rising requency, improved survival, and determinants of outcome after resection. Ann Surg2008;248(1):84-96.
34. Konstadoulakis MM, Roayaie S, Gomatos IP, et al. Fifteen-year, single-center experience with the surgical management of intrahepatic cholangiocarcinoma: operative results and long-term outcome. Surgery2008;143(3):366-74.
35. Lang H, Sotiropoulos GC, Sgourakis G, et al. Operations for intrahepatic cholangiocarcinoma:single-institution experience of158patients. J Am Coll Surg2009;208(2):218-28.
36. Nakagohri T, Kinoshita T, Konishi M, et al. Surgical outcome and prognostic factors in intrahepatic cholangiocarcinoma. World J Surg2008;32(12):2675-80.
37. Shimada K, Sano T, Nara S, et al. Therapeutic value of lymph node dissection during hepatectomy in patients with intrahepatic cholangiocellular carcinoma with negative lymph node involvement. Surgery2009;145(4):411-6.
38. Nathan H, Cameron JL, Choti MA, et al. The volume-outcomes effect in hepatopancreato-biliary surgery:hospital versus surgeon contributions and specificity of the relationship. J Am Coll Surg2009;208(4):528-38.
39. Nakagawa T, Kamiyama T, Kurauchi N, et al. Number of lymph node metastases is a significant prognostic factor in intrahepatic cholangiocarcinoma. World J Surg2005;29(6):728-33.
40. Nathan H, Aloia TA, Vauthey JN, et al. A proposed staging system for intrahepatic cholangiocarcinoma. Ann Surg Oncol2009;16(1):14-22.
41. Choi SB, Kim KS, Choi JY, et al. The prognosis and survival outcome of intrahepatic cholangiocarcinoma following surgical resection:association of lymph node metastasis and lymph node dissection with survival. Ann Surg Oncol2009;16(11):3048-56.
42. Okabayashi T, Yamamoto J, Kosuge T, et al. A new staging system for massforming intrahepatic cholangiocarcinoma:analysis of preoperative and postoperative variables. Cancer2001;92(9):2374-83.
43. Greene F, Page D, Flemming I, et al. AJCC cancer staging manual.6th edition. New York:Springer-Verlag;2002.
44. Ikeda K, Saitoh S, Koida I, et al. A multivariate analysis of risk factors for hepatocellular carcinogenesis:a prospective observation of795patients with viral and alcoholic cirrhosis. Hepatology1993;18(1):47-53.
45. Inoue K, Makuuchi M, Takayama T, et al. Long-term survival and prognostic factors in the surgical treatment of mass-forming type cholangiocarcinoma. Surgery2000;127(5):498-505.
46. Parkin DM, Srivatanakul P, Khlat M, et al. Liver cancer in Thailand. I. A casecontrol study of cholangiocarcinoma. Int J Cancer1991;48(3):323-8.
47. Srivatanakul P, Parkin DM, Jiang YZ, et al. The role of infection by Opisthorchis viverrini, hepatitis B virus, and aflatoxin exposure in the etiology of liver cancer in Thailand. A correlation study. Cancer1991;68(11):2411-7.
48. Srivatanakul P, Parkin DM, Khlat M, et al. Liver cancer in Thailand. Ⅱ. A casecontrol study of hepatocellular carcinoma. Int J Cancer1991;48(3):329-32.
49. Ohtsuka M, Ito H, Kimura F, et al. Results of surgical treatment for intrahepatic cholangiocarcinoma and clinicopathological factors influencing survival. Br J Surg2002;89(12):1525-31.
50. Paik KY, Jung JC, Heo JS, et al. What prognostic factors are important for resected intrahepatic cholangiocarcinoma? J Gastroenterol Hepatol2008;23(5):766-70.
51. Uenishi T, Kubo S, Yamazaki O, et al. Indications for surgical treatment of intrahepatic cholangiocarcinoma with lymph node metastases. J Hepatobiliary Pancreat Surg2008;15(4):417-22.
52. Shimada M, Yamashita Y, Aishima S, et al. Value of lymph node dissection during resection of intrahepatic cholangiocarcinoma. Br J Surg2001;88(11):1463-6.
53. Edge S, Byrd D, Compton C, et al. AJCC cancer staging manual.7th edition. New York:Springer-Verlag;2010.
54. Weimann A, Varnholt H, Schlitt HJ, et al. Retrospective analysis of prognostic factors after liver resection and transplantation for cholangiocellular carcinoma. Br J Surg2000;87(9):1182-7.
55. Suzuki S, Sakaguchi T, Yokoi Y, et al. Clinicopathological prognostic factors and impact of surgical treatment of mass-forming intrahepatic cholangiocarcinoma. World J Surg2002;26(6):687-93.
56. Tamandl D, Kaczirek K, Gruenberger B, et al. Lymph node ratio after curative surgery for intrahepatic cholangiocarcinoma. Br J Surg2009;96(8):919-25.57.
57. Asakura H, Ohtsuka M, Ito H, et al. Long-term survival after extended surgical resection of intrahepatic cholangiocarcinoma with extensive lymph node metastasis. Hepatogastroenterology2005;52(63):722-4.
58. Murakami Y, Yokoyama T, Takesue Y, et al. Long-term survival of peripheral intrahepatic cholangiocarcinoma with metastasis to the para-aortic lymph nodes. Surgery2000;127(1):105-6.
59. DeOliveira ML, Cunningham SC, Cameron JL, et al. Cholangiocarcinoma: thirtyone-year experience with564patients at a single institution. Ann Surg2007;245(5):755-62.
60. Jan YY, Yeh CN, Yeh TS, et al. Clinicopathological factors predicting long-term overall survival after hepatectomy for peripheral cholangiocarcinoma. World J Surg2005;29(7):894-8.
61. Guglielmi A, Ruzzenente A, cAMPagnaro T, et al. Intrahepatic cholangiocarcinoma:prognostic factors after surgical resection. World J Surg2009;33(6):1247-54.
62. Bodingbauer M, Tamandl D, Schmid K, et al. Size of surgical margin does not influence recurrence rates after curative liver resection for colorectal cancer liver metastases. Br J Surg2007;94(9):1133-8.
63. Yamamoto M, Takasaki K, Otsubo T, et al. Recurrence after surgical resection of intrahepatic cholangiocarcinoma. J Hepatobiliary Pancreat Surg2001;8(2):154-7.
64. Chou FF, Sheen-Chen SM, Chen YS, et al. Surgical treatment of cholangiocarcinoma. Hepatogastroenterology1997;44(15):760-5.
65. Eckel F, Schmid RM. Chemotherapy in advanced biliary tract carcinoma:a pooled analysis of clinical trials. Br J Cancer2007;96(6):896-902.
66. Huitzil-Melendez FD, O'Reilly EM, Duffy A, et al. Indications for neoadjuvant, adjuvant, and palliative chemotherapy in the treatment of biliary tract cancers. Surg Oncol Clin N Am2009;18(2):361-79, x.
67. Hezel AF, Zhu AX. Systemic therapy for biliary tract cancers. Oncologist2008;13(4):415-23.
68. Verderame F, Russo A, Di Leo R, et al. Gemcitabine and oxaliplatin combination chemotherapy in advanced biliary tract cancers. Ann Oncol2006;17(Suppl7):vii,68-72.
69. Valle J, Wasan H, Palmer DH, et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med2010;362(14):1273-81.
70. Bengala C, Bertolini F, Malavasi N, et al. Sorafenib in patients with advanced biliary tract carcinoma:a phase Ⅱ trial. Br J Cancer2010;102(1):68-72.
71. Zhu AX, Meyerhardt JA, Blaszkowsky LS, et al. Efficacy and safety of gemcitabine, oxaliplatin, and bevacizumab in advanced biliary-tract cancers and correlation of changes in18-fluorodeoxyglucose PET with clinical outcome:a phase2study. Lancet Oncol2010;11(1):48-54.
72. Malka D, Trarbach T, Fartoux L, et al. A multicenter, randomized phase Ⅱ trial of gemcitabine and oxaliplatin (GEMOX) alone or in combination with biweekly cetuximab in the first-line treatment of advanced biliary cancer:interim analysis of the BINGO trial [abstract:4520]. J Clin Oncol2009;27(Suppl):15s.
73. Philip PA, Mahoney MR, Allmer C, et al. Phase Ⅱ study of erlotinib in patients with advanced biliary cancer. J Clin Oncol2006;24(19):3069-74.
74. Ramanathan RK, Belani CP, Singh DA, et al. A phase Ⅱ study of lapatinib in patients with advanced biliary tree and hepatocellular cancer. Cancer Chemother Pharmacol2009;64(4):777-83.
75. Shinohara ET, Mitra N, Guo M, et al. Radiation therapy is associated with improved survival in the adjuvant and definitive treatment of intrahepatic cholangiocarcinoma. Int J Radiat Oncol Biol Phys2008;72(5):1495-501.
76. Zeng ZC, Tang ZY, Fan J, et al. Consideration of the role of radiotherapy for unresectable intrahepatic cholangiocarcinoma:a retrospective analysis of75patients. Cancer J2006;12(2):113-22.
77. Kemeny NE, Niedzwiecki D, Hollis DR, et al. Hepatic arterial infusion versus systemic therapy for hepatic metastases from colorectal cancer:a randomized trial of efficacy, quality of life, and molecular markers (CALGB9481). J Clin Oncol2006;24(9):1395-403.
78. Cantore M, Mambrini A, Fiorentini G, et al. Phase Ⅱ study of hepatic intraarterial epirubicin and cisplatin, with systemic5-fluorouracil in patients with unresectable biliary tract tumors. Cancer2005;103(7):1402-7.
79. Jarnagin WR, Schwartz LH, Gultekin DH, et al. Regional chemotherapy for unresectable primary liver cancer:results of a phase Ⅱ clinical trial and assessment of DCE-MRI as a biomarker of survival. Ann Oncol2009;20(9):1589-95.
80. Shitara K, Ikami I, Munakata M, et al. Hepatic arterial infusion of mitomycin C with degradable starch microspheres for unresectable intrahepatic cholangiocarcinoma. Clin Oncol (R Coll Radiol)2008;20(3):241-6.
81. Tanaka N, Yamakado K, Nakatsuka A, et al. Arterial chemoinfusion therapy through an implanted port system for patients with unresectable intrahepatic cholangiocarcinoma-initial experience. Eur J Radiol2002;41(1):42-8.
82. Llovet JM, Real MI, Montana X, et al. Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma:a randomised controlled trial. Lancet2002;359(9319):1734-9.
83. Lo CM, Ngan H, Tso WK, et al. Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma. Hepatology2002;35(5):1164-71.
84. Gusani NJ, Balaa FK, Steel JL, et al. Treatment of unresectable cholangiocarcinoma with gemcitabine-based transcatheter arterial chemoembolization (TACE):a single-institution experience. J Gastrointest Surg2008;12(1):129-37.
85. Burger I, Hong K, Schulick R, et al. Transcatheter arterial chemoembolization in unresectable cholangiocarcinoma:initial experience in a single institution. J Vasc Interv Radiol2005;16(3):353-61.
1. Alpini G, Prall RT, LaRusso NF. The pathobiology of biliary epithelia. In:Arias IM, Boyer JL, Chisari FV, Fausto N, Jakoby W, Schachter D, Shafritz DA, eds. The liver:biology and pathobiology.4th ed. Philadelphia, PA:Lippincott Williams&Wilkins;2001:421-435.
2. Kanno N, LeSage G, Glaser S, Alvaro D, Alpini G. Functional heterogeneity of the intrahepatic biliary epithelium. Hepatology2000;31:555-561.
3. Roskams TA, Theise ND, Balabaud C, Bhagat G, Bhathal PS, Bioulac-Sage P, Brunt EM, Crawford JM, Crosby HA, Desmet V, Finegold MJ, Geller SA, Gouw AS, Hytiroglou P, Knisely AS, Kojiro M, Lefkowitch JH, Nakanuma Y, Olynyk JK, Park
YN, Portmann B, Saxena R, Scheuer PJ, Strain AJ, Thung SN, Wanless IR, West AB. Nomenclature of the finer branches of the biliary tree:canals, ductules, and ductular reactions in human livers. Hepatology2004;39:1739-1745.
4. Hering E. Ueber den Bau der Wirbelthierleber. Arch Mikrosk Anat1867;3:88-114.
5. Theise ND, Saxena R, Portmann BC, Thung SN, Yee H, Chiriboga L, Kumar A, Crawford JM. The canals of Hering and hepatic stem cells in humans. Hepatology1999;30:1425-1433.
6. Crawford JM. Normal and abnormal development of the biliary tree. In:Alpini G, Alvaro D, LeSage G, Marzioni M, LaRusso NF, eds. The pathophysiology of biliary epithelia. Georgetown, TX:Landes Biosciences;2004:1-13.
7. Saxena R, Theise ND, Crawford JM. Microanatomy of the human liver:exploring the hidden interfaces. Hepatology1999;30:1339-1346.
8. Reilly FD, McCuskey PA, McCuskey RS. Intrahepatic distribution of nerves in the rat. Anat Rec1978;191:55-68.
9. McCuskey RS. Anatomy of efferent hepatic nerves. Anat Rec A Discov Mol Cell Evol Biol2004;280:821-826.
10. Berthoud HR. Anatomy and function of sensory hepatic nerves. Anat Rec A Discov Mol Cell Evol Biol2004;280:827-835.11. el-Salhy M, Stenling R, Grimelius L. Peptidergic innervation and endocrine cells in the human liver. Scand J Gastroenterol1993;28:809-815.
12. Goehler LE, Sternini C, Brecha NC. Calcitonin gene-related peptide immunoreactivity in the biliary pathway and liver of the guinea-pig:distribution and colocalization with substance P. Cell Tissue Res1988;253:145-150.
13. Inoue N, Hirata K, Yamada M, Hamamori Y, Matsuda Y, Akita H, Yokoyama M. Lysophosphatidylcholine inhibits bradykinin-induced phosphoinositide hydrolysis and calcium transients in cultured bovine aortic endothelial cells. Circ Res1992;71:1410-1421.
14. Burt AD, Tiniakos D, MacSween RN, Griffiths MR, Wisse E, Polak JM. Localization of adrenergic and neuropeptide tyrosine-containing nerves in the mammalian liver. Hepatology1989;9:839-845.
15. Schultzberg M, Dalsgaard CJ. Enteric origin of bombesin immunoreactive fibres in the rat coeliac-superior mesenteric ganglion. Brain Res1983;269:190-195.
16. Barbaro B, Glaser S, Francis H, Taffetani S, Marzioni M, LeSage G, Alpini G. Nerve regulation of cholangiocyte functions. In:Alpini G, Alvaro D, LeSage G, Marzioni M, LaRusso NF, eds. The pathophysiology of biliary epithelia. Georgetown, TX:Landes Biosciences;2004:199-209.
17. Gaudio E, Onori P, Pannarale L, Alvaro D. Hepatic microcirculation and peribiliary plexus in experimental biliary cirrhosis:a morphological study. Gastroenterology1996;111:1118-1824.
18. Gaudio E, Onori P, Franchitto A, Sferra R, Vetuschi A, Morini S, Alpini G, Alvaro D. Vascularization of the intrahepatic biliary tree and its role in the regulation of cholangiocyte growth. In:Alpini G, Alvaro D, LeSage G, Marzioni M, LaRusso NF, eds. The pathophysiology of biliary epithelia. Georgetown, TX:Landes Biosciences;2004:41-45.
19. LeSage G, Glaser S, Gubba S, Robertson WE, Phinizy JL, Lasater J, Rodgers RE, Alpini G. Regrowth of the rat biliary tree after70%partial hepatectomy is coupled to increased secretin-induced ductal secretion. Gastroenterology1996;111:1633-1644.
20. Schaffner F, Popper H. Electron microscopic studies of normal and proliferated bile ductules. Am J Pathol1961;38:393-410.
21. Demetris AJ. Participation of cytokines and growth factors in biliary cell proliferation and mito-inhibition during ductular reaction. In:Alpini G, Alvaro D, LeSage G, Marzioni M, LaRusso NF, eds. The pathophysiology of biliary epithelia. Georgetown, TX:Landes Biosciences;2004:167-182.
22. Tadlock L, Yamagiwa Y, Hawker J, Marienfeld C, Patel T. Transforming growth factor-beta inhibition of proteasomal activity:a potential mechanism of growth arrest. Am J Physiol Cell Physiol2003;285:C277-C285.
23. Harnois DM, Que FG, Celli A, LaRusso NF, Gores GJ. Bel-2is overexpressed and alters the threshold for apoptosis in a cholangiocarcinoma cell line. Hepatology 1997;26:884-890.
24. Okaro AC, Deery AR, Hutchins RR, Davidson BR. The expression of antiapoptotic proteins Bcl-2, Bcl-X(L), and Mcl-1in benign, dysplastic, and malignant biliary epithelium. J Clin Pathol2001;54:927-932.
25. Masyuk AI, Splinter PL, Masyuk TV, Stroope AJ, LaRusso NF. Cholangiocyte cilia act as sensory organelles affecting the intracellular signaling pathways. FASEB J2005;19:A148.
26. Alpini G, Glaser S, Ueno Y, Pham L, Podila PV, Caligiuri A, LeSage G, LaRusso NF. Heterogeneity of the proliferative capacity of rat cholangiocytes after bile duct ligation. Am J Physiol Gastrointest Liver Physiol1998;274:G767-G775.
27. Glaser S, Benedetti A, Marucci L, Alvaro D, Baiocchi L, Kanno N, Caligiuri A, Phinizy JL, Chowdhury U, Papa E, LeSage G, Alpini G. Gastrin inhibits cholangiocyte growth in bile duct-ligated rats by interaction with cholecystokinin-B/Gastrin receptors via D-myoinositol1,4,5-triphosphate-, Ca(2)-, and protein kinase C alphadependent mechanisms. Hepatology2000;32:17-25.
28. Glaser S, Alvaro D, Ueno Y, Francis H, Marzioni M, Phinizy JL, Baumann B, Mancino MG, Venter J, LeSage G, Alpini G. Gastrin reverses established cholangiocyte proliferation and enhanced secretin-stimulated ductal secretion of BDL rats by activation of apoptosis through increased expression of Ca2-dependent PKC isoforms. Liver Int2003;23:78-88.
29. Francis H, Glaser S, Ueno Y, LeSage G, Marucci L, Benedetti A, Taffetani S, Marzioni M, Alvaro D, Venter J, Reichenbach R, Fava G, Phinizy JL, Alpini G. cAMP stimulates the secretory and proliferative capacity of the rat intrahepatic biliary epithelium through changes in the PKA/Src/MEK/ERK1/2pathway. J Hepatol2004;41:528-537.
30. LeSage G, Alvaro D, Benedetti A, Glaser S, Marucci L, Baiocchi L, Eisel W, Caligiuri A, Phinizy JL, Rodgers R, Francis H, Alpini G. Cholinergic system modulates growth, apoptosis, and secretion of cholangiocytes from bile duct-ligated rats. Gastroenterology1999;117:191-199.
31. Sand TE, Thoresen GH, Refsnes M, Christoffersen T. Growthregulatory effects of glucagon, insulin, and epidermal growthfactor in cultured hepatocytes. Temporal aspects and evidence for bidirectional control by cAMP. Dig Dis Sci1992;37:84-92.
32. Alvaro D, Gigliozzi A, Attili AF. Regulation and deregulation of cholangiocyte proliferation. J Hepatol2000;33:333-340.33. Desmet V, Roskams T, Van Eyken P. Pathology of the biliary tree in cholestasis:ductular reaction. In:Manns MP, Boyer JL, Jansen PLM, Reichen J, eds. Cholestatic liver diseases. New York:Kluwer Academic Publishers;1998:143-154.
34. Roskams T, Van den Oord JJ, De Vos R, Desmet VJ. Neuroendocrine features of reactive bile ductules in cholestatic liver disease. Am J Pathol1990;137:1019-1025.
35. Desmet V, Roskams T, Van Eyken P. Ductular reaction in the liver. Pathol Res Pract1995;191:513-524.
36. Popper H, Kent G, Stein R. Ductular reaction in the liver in hepatic injury. J Mt Sinai Hosp1957;24:551-556.
37. Lazaridis KN, Strazzabosco M, LaRusso NF. The cholangiopathies:disorders of biliary epithelia. Gastroenterology2004;127:1565-1577.
38. Alpini G, Lenzi R, Sarkozi L, Tavoloni N. Biliary physiology in rats with bile ductular cell hyperplasia. Evidence for a secretory function of proliferated bile ductules. J Clin Invest1988;81:569-578.
39. LeSage G, Glaser S, Ueno Y, Alvaro D, Baiocchi L, Kanno N, Phinizy JL, Francis H, Alpini G. Regression of cholangiocyte proliferation after cessation of ANIT feeding is coupled with increased apoptosis. Am J Physiol Gastrointest Liver Physiol2001;281:G182-G190.
40. Vacanti JP, Folkman J. Bile duct enlargement by infusion of L-proline:potential significance in biliary atresia. J Pediatr Surg1979;14:814-848.
41. Alpini G, Glaser S, Ueno Y, Rodgers R, Phinizy JL, Francis H, Baiocchi L, Holcomb LA, Caligiuri A, LeSage G. Bile acid feeding induces cholangiocyte proliferation and secretion:evidence for bile acid-regulated ductal secretion. Gastroenterology1999;116:179-186.
42. Palmer RH, Ruban Z. Production of bile duct hyperplasia and gallstones by lithocholic acid. J Clin Invest1966;45:1255-1267.
43. Masyuk TV, Masyuk AI, Ritman EL, LaRusso NF. Three-dimensional reconstruction of the rat intrahepatic biliary tree:physiological implications. In: Alpini G, Alvaro D, LeSage G, Marzioni M, LaRusso NF, eds. The pathophysiology of biliary epithelia. Georgetown, TX:Landes Biosciences;2004:60-67.
44. Masyuk TV, Ritman EL, LaRusso NF. Quantitative assessment of the rat intrahepatic biliary system by three-dimensional reconstruction. Am J Pathol2001;158:2079-2088.
45. Slott PA, Liu MH, Tavoloni N. Origin, pattern, and mechanism of bile duct proliferation following biliary obstruction in the rat. Gastroenterology1990;99:466-477.
46. Grisham JW. A morphologic study of deoxyribonucleic acid synthesis and cell proliferation in regenerating rat liver; autoradiography with thymidine-H3. Cancer Res1962;22:842-849.
47. James J, Lygidakis NJ, van Eyken P, Tanka AK, Bosch KS, Ramaekers FC, Desmer V. Application of keratin immunocytochemistry and Sirius red staining in evaluating intrahepatic changes with acute extrahepatic cholestasis due to hepatic duct carcinoma. Hepatogastroenterology1989;36:151-155.
48. Omori M, Evarts RP, Omori N, Hu Z, Marsden ER, Thorgeirsson SS. Expression of alpha-fetoprotein and stem cell factor/c-kit system in bile duct ligated young rats. Hepatology1997;25:1115-1122.
49. Miller DJ, Keeton DG, Webber BL, Pathol FF, Saunders SJ. Jaundice in severe bacterial infection. Gastroenterology1976;71:94-97.
50. Celli A, Que FG. Dysregulation of apoptosis in the cholangiopathies and cholangiocarcinoma. Semin Liver Dis1998;18:177-185.
51. Desmet VJ. Current problems in diagnosis of biliary disease and cholestasis. Semin Liver Dis1986;6:233-245.
52. Fausto N, Webber EM. Liver regeneration. In:Arias IM, Boyer JL, Fausto N, Jakoby WB, Schachter D, Shafritz DA, eds. The liver:biology and pathobiology.3rd ed. New York:Raven,1994:1059-1084.
53. Wegmann R, Corcos V, Caroli J. Histoenzymologie des ductules biliaires chez l'embryon humain normal et au tours des cirrhoses humaines. Arch Mal Appar Dig1967;54:215-228.
54. Kuhlmann WD, Wurster K. Correlation of histology and alpha1-fetoprotein resurgence in rat liver regeneration after experimental injury by galactosamine. Virchows Archiv A, Pathol Anat Histol1980;387:47-57.
55. LeSage G, Benedetti A, Glaser S, Marucci L, Tretjak Z, Caligiuri A, Rodgers R, Phinizy JL, Baiocchi L, Francis H, Lasater J, Ugili L, Alpini G. Acute carbon tetrachloride feeding selectively damages large, but not small, cholangiocytes from normal rat liver. Hepatology1999;29:307-319.
56. LeSage G, Glaser S, Marucci L, Benedetti A, Phinizy JL, Rodgers R, Caligiuri A, Papa E, Tretjak Z, Jezequel AM, Holcomb LA, Alpini G. Acute carbon tetrachloride feeding induces damage of large but not small cholangiocytes from BDL rat liver. Am J Physiol Gastrointest Liver Physiol1999;276:G1289-G1301.
57. Nagore N, Howe S, Boxer L, Scheuer PJ. Liver cell rosettes:structural differences in cholestasis and hepatitis. Liver1989;9:43-51.
58. Knowles DM, Wolff M. Focal nodular hyperplasia of the liver:a clinicopathologic study and review of the literature. Hum Pathol1976;7:533-545.
59. Yamada S, Howe S, Scheuer PJ. Three-dimensional reconstruction of biliary pathways in primary biliary cirrhosis:a computerassisted study. J Pathol1987;152:317-323.
60. Crosby HA, Hubscher S, Fabris L, Joplin R, Sell S, Kelly D, Strain AJ. Immunolocalization of putative human liver progenitor cells in livers from patients with end-stage primary biliary cirrhosis and sclerosing cholangitis using the monoclonal antibody OV-6. Am J Pathol1998;152:771-779.
61. De Vos R, Desmet V. Ultrastructural characteristics of novel epithelial cell types identified in human pathologic liver specimens with chronic ductular reaction. Am J Pathol1992;140:1441-1450.
62. Tan J, Hytiroglou P, Wieczorek R, Park YN, Thung SN, Arias B, Theise ND. Immunohistochemical evidence for hepatic progenitor cells in liver diseases. Liver 2002;22:365-373.
63. Roskams T. Progenitor cell involvement in cirrhotic human liver diseases:from controversy to consensus. J Hepatol2003;39:431-434.64. Lunz JG,3rd, Tsuji H, Nozaki I, Murase N, Demetris AJ. An inhibitor of cyclin-dependent kinase, stress-induced p21Waf-1/Cip-1, mediates hepatocyte mito-inhibition during the evolution of cirrhosis. Hepatology2005;41:1262-1271.
65. Clouston AD, Powell EE, Walsh MJ, Richardson MM, Demetris AJ, Jonsson JR. Fibrosis correlates with a ductular reaction in hepatitis C:roles of impaired replication, progenitor cells and steatosis. Hepatology2005;41:809-818.
66. Ren P, Silberg DG, Sirica AE. Expression of an intestine-specific transcription factor (CDX1) in intestinal metaplasia and in subsequently developed intestinal type of cholangiocarcinoma in rat liver. Am J Pathol2000;156:621-627.
67. Lowes KN, Brennan BA, Yeoh GC, Olynyk JK. Oval cell numbers in human chronic liver diseases are directly related to disease severity. Am J Pathol1999;154:537-541.
68. Petropoulos CJ, Yaswen P, Panzica M, Fausto N. Cell lineages in liver carcinogenesis:possible clues from studies of the distribution of alpha-fetoprotein RNA sequences in cell populations isolated from normal, regenerating, and preneoplastic rat livers. Cancer Res1985;45:5762-5768.
69. Sirica AE, Cihla HP. Isolation and partial characterizations of oval and hyperplastic bile ductular cell-enriched populations from the livers of carcinogen and noncarcinogen-treated rats. Cancer Res1984;44:3454-3466.
70. Farber E. Similarities in the sequence of early histological changes induced in the liver of the rat by ethionine,2-acetylamino-fluorene, and3'-methyl-4-dimethylaminoazobenzene. Cancer Res1956;16:142-148.
71. Roskams T, Cassiman D, De Vos R, Libbrecht L. Neuroregulation of the neuroendocrine compartment of the liver. Anat Rec A Discov Mol Cell Evol Biol2004;280:910-923.
72. Yang S, Koteish A, Lin H, Huang J, Roskams T, Dawson V, Diehl AM. Oval cells compensate for damage and replicative senescence of mature hepatocytes in mice with fatty liver disease. Hepatology2004;39:403-411.
73. Roskams T, Desmet V. Ductular reaction and its diagnostic significance. Semin Diagn Pathol1998;15:259-269.
74. Haque S, Haruna Y, Saito K, Nalesnik MA, Atillasoy E, Thung SN, Gerber MA. Identification of bipotential progenitor cells in human liver regeneration. Lab Invest1996;75:699-705.
75. Roskams TA, Libbrecht L, Desmet VJ. Progenitor cells in diseased human liver. Semin Liver Dis2003;23:385-396.
76. Ros JE, Roskams TA, Geuken M, Havinga R, Splinter PL, Petersen BE, LaRusso NF, van der Kolk DM, Kuipers F, Faber KN, Muller M, Jansen PL. ATP binding cassette transporter gene expression in rat liver progenitor cells. Gut2003;52:1060-1067.
77. Roskams T, De Vos R, Van Eyken P, Myazaki H, Van Damme B, Desmet V. Hepatic OV-6expression in human liver disease and rat experiments:evidence for hepatic progenitor cells in man. J Hepatol1998;29:455-463.
78. Alvaro D, Invernizzi P, Onori P, Franchitto A, De Santis A, Crosignani A, Sferra R, Ginanni-Corradini S, Mancino MG, Maggioni M, Attili AF, Podda M, Gaudio E. Estrogen receptors in cholangiocytes and the progression of primary biliary cirrhosis. J Hepatol2004;41:905-912.
79. Harada K, Furubo S, Ozaki S, Hiramatsu K, Sudo Y, Nakanuma Y. Increased expression of WAF1in intrahepatic bile ducts in primary biliary cirrhosis relates to apoptosis. J Hepatol2001;34:500-506.
80. Tinmouth J, Lee M, Wanless IR, Tsui FW, Inman R, Heathcote EJ. Apoptosis of biliary epithelial cells in primary biliary cirrhosis and primary sclerosing cholangitis. Liver2002;22:228-234.
2. Wolf I, Sadetzki S, Catane R, Karasik A, Kaufman B. Diabetes mellitus and breast cancer. Lancet Oncol,2005,6:103-111
3. Eliassen AH, Tworoger SS, Mantzoros CS, Pollak MN, Hankinson SE. Circulating insulin and C-peptide levels and risk of breast cancer among predominately premenopausal women. Cancer Epidemiol Biomarkers Prev,2007,16:161-164
4. Schernhammer ES, Holly JM, Pollak MN, Hankinson SE. Circulating levels of insulin-like growth factors, their binding proteins, and breast cancer risk. Cancer Epidemiol Biomarkers Prev,2005,14:699-704
5. Wolf I, Sadetzki S, Gluck I, Oberman B, Ben-David M, Papa MZ, Catane R, Kaufman B. Association between diabetes mellitus and adverse characteristics of breast cancer at presentation. Eur J Cancer,2006,42:1077-1082
6. Yee D. Targeting insulin-like growth factor pathways. Br J Cancer,2006,94:465-468
7. Baggio LL, Drucker DJ. Biology of incretins:GLP-1and GIP. Gastroenterology,2007,132:2131-2157
8. Dufayet de la Tour D, Halvorsen T, Demeterco C, Tyrberg B, Itkin-Ansari P, Loy M, Yoo S-J, Hao E, Bossie S, Levine F.β-Cell differentiation from a human pancreatic cell line in vitro and in vivo. Mol Endocrinol,2001,15:476-483
9. Holst JJ, Vilsboll T, Deacon CF. The incretin system and its role in type2diabetes mellitus. Mol Cell Endocrinol,2009,297:127-136
10. Idris I, Patiag D, Gray S, Donnelly R. Exendin-4increases insulin sensitivity via a PI-3-kinase-dependent mechanism:contrasting effects of GLP-1. Biochem Pharmacol,2002,63:993-996
11. Lee YS, Shin S, Shigihara T, Hahm E, Liu MJ, Han J, Yoon JW, Jun HS. Glucagon-like peptide-1gene therapy in obesediabetic mice results in long-term cure of diabetes by improving insulin sensitivity and reducing hepatic gluconeogenesis. Diabetes,2007,56:1671-1679
12. Eng J, Kleinman W, Singh L, Singh G, Raufman J. Isolation and characterization of exendin-4, an exendin-3analogue,from Heloderma suspectum venom. Further evidence for an exendin receptor on dispersed acini from guinea pig pancreas. J Biol Chem,1992,267:7402-7405
13. Rai A, Singh G, Raffaniello R, Eng J, Raufman JP. Actionsof Helodermatidae venom peptides and mammalian glucagonlike peptides on gastric chief cells. Am J Physiol Gastrointest Liver Physiol,1993,265:G118-G125
14. Drucker DJ, Buse JB, Taylor K, Kendall DM, Trautmann M, Zhuang D, Porter L. Exenatide once weekly versus twice daily for the treatment of type2diabetes:a randomised, openlabel, non-inferiority study. Lancet,2008,372:1240-1250
15. Kim D, MacConell L, Zhuang D, Kothare PA, Trautmann M, Fineman M, Taylor K. Effects of once-weekly dosing of a long-acting release Formulation of exenatide on glucose control and body weight in subjects with type2diabetes. Diabetes Care,2007,30:1487-1493
16. Koehler JA, Drucker DJ. Activation of glucagon-like peptide-1receptor signaling does not modify the growth or apoptosis of human pancreatic cancer cells. Diabetes,2006,55:1369-1379
17. Elashoff M, Matveyenko AV, Gier B, Elashoff R, Butler PC. Pancreatitis, pancreatic and thyroid cancer with glucagonlikepeptide-1-based therapies. Gastroenterol ogy
18. Berdichevsky F, Alford D, D'Souza B, Taylor-Papadimitriou J. Branching morphogenesis of human mammary epithelialcells in collagen gels. J Cell Sci,1994,107:3557-3568
19. Sapir T, Shternhall K, Meivar-Levy I, Blumenfeld T, Cohen H, Skutelsky E, Eventov-Friedman S, Barshack I, Goldberg I, PriChen S et al. Cell-replacement therapy for diabetes:generating functional insulin-producing tissue from adult human liver cells. Proc Natl Acad Sci USA,2005,102:7964-7969
20. Wolf I, Levanon-Cohen S, Bose S, Ligumsky H, Sredni B, Kanety H, Kuro-o M, Karlan B, Kaufman B, Koeffler HP et al. Klotho:a tumor suppressor and a modulator of the IGF-1and FGF pathways in human breast cancer. Oncogene,2008,27:7094-7105
21. Wolf I, O'Kelly J, Rubinek T, Tong M, Nguyen A, Lin BT, Tai H-H, Karlan BY, Koeffler HP.15-Hydroxyprostaglandin dehydrogenase is a tumor suppressor of human breast cancer. Cancer Res,2006,66:7818-7823
22. Wolf I, Bose S, Williamson EA, Miller CW, Karlan BY, Koeffler HP. FOXA1: growth inhibitor and a favorable prognostic factor in human breast cancer. Int J Cancer,2007,120:1013-1022
23. Montrose-Rafizadeh C, Egan J, Roth J. Incretin hormones regulate glucose-dependent insulin secretion in RIN1046-38cells:mechanisms of action. Endocrinology,1994,135:589-594
24. Drucker DJ, Nauck MA. The incretin system:glucagonlike peptide-1receptor agonists and dipeptidyl peptidase-4inhibitors in type2diabetes. Lancet,2006,368:1696-1705
25. Lacroix M, Leclercq G. Relevance of breast cancer cell lines as models for breast tumours:an update. Breast Cancer Res Treat,2004,83:249-289
26. Calebiro D, Nikolaev VO, Persani L, Lohse MJ. Signaling by internalized G-protein-coupled receptors. Trends Pharmacol Sci,2010,31:221-228
27. Chahrzad Montrose-Rafizadeh HY, Wang Yihong, Roth Jesse, Montrose Marshall H, Adams Lisa G. Novel signal transduction and peptide specificity of glucagon-like peptide receptor in3T3-L1adipocytes. J Cel Physiol,1997,172:275-283
28. Villanueva-Penacarrillo ML, Delgado E, Trapote MA, Alcantara A, Clemente F, Luque MA, Perea A, Valverde I. Glucagon-like peptide-1binding to rat hepatic membranes. J Endocrinol,1995,146:183-189
29. Yang H, Egan JM, Wang Y, Moyes CD, Roth J, Montrose MH, Montrose-Rafizadeh C. GLP-1action in L6myotubes is via a receptor different from the pancreatic GLP-1receptor. Am J Physiol,1998,275:C675-C683
30. Tagliaferri P, Katsaros D, Clair T, Ally S, Tortora G, Neckers L, Rubalcava B, Parandoosh Z, Chang Y-a, Revankar GR et al. Synergistic inhibition of growth of breast and colon human cancer cell lines by site-selective cyclic AMP analogues. Cancer Res,1988,48:1642-1650
31. Ahn Y-H, Jung JM, Hong SH.8-Chloro-cyclic AMP induced growth inhibition and apoptosis is mediated by p38mitogen-activated protein kinase activation in HL60cells. Cancer Res,2005,65:4896-4901
32. Tru mper J, Ross D, Jahr H, Brendel MD, Goke R, Horsch D. The Rap-B-Raf signalling pathway is activated by glucose and glucagon-like peptide-1in human islet cells. Diabetologia,2005,48:1534-1540
33. Li Y, Tweedie D, Mattson MP, Holloway HW, Greig NH. Enhancing the GLP-1receptor signaling pathway leads to proliferation and neuroprotection in human neuroblastoma cells. J Neurochem,2010,113:1621-1631
34. Korner A, Pazaitou-Panayiotou K, Kelesidis T, Kelesidis I, Williams CJ, Kaprara A, Bullen J, Neuwirth A, Tseleni S, Mitsiades N et al. Total and high-molecular-weight adiponectin in breast cancer:in vitro and in vivo studies. J Clin Endocrinol Metab,2007,92:1041-1048
35. Novosyadlyy R, Lann DE, Vijayakumar A, Rowzee A, Lazzarino DA, Fierz Y, Carboni JM, Gottardis MM, Pennisi PA, Molinolo A et al. Insulin-mediated acceleration of breast cancer development and progression in a nonobese model of type2diabetes. Cancer Res,2010,70:741-751
36. Vilsboll T, Krarup T, Deacon CF, Madsbad S, Holst JJ. Reduced postprandial concentrations of intact biologically active glucagon-like peptide1in type2diabetic patients. Diabetes,2001,50:609-613
37. Toft-Nielsen M-B, Damholt MB, Madsbad S, Hilsted LM, Hughes TE, Michelsen BK, Holst JJ. Determinants of the impaired secretion of glucagon-like peptide-1in type2diabetic patients. J Clin Endocrinol Metab,2001,86:3717-3723
38. Kjems LL, Holst JJ, Volund A, Madsbad S. The influence of GLP-1on glucose-stimulated insulin secretion. Diabetes,2003,52:380-386
39. Carr RD, Larsen MO, Jelic K, Lindgren O, Vikman J, Holst JJ, Deacon CF, Ahren B. Secretion and dipeptidyl peptidase-4-mediated metabolism of incretin hormones after a mixed meal or glucose ingestion in obese compared to lean, nondiabetic men. J Clin Endocrinol Metab,2009,95(2):872-878
40.Coopman K, Huang Y, Johnston N, Bradley SJ, Wilkinson GF, agonist glucagon-like peptide-1(GLP-1)-(7-36) amide and the small-molecule ago-allosteric agent "Compound2" at the GLP-1receptor. J Pharmacol Exp Ther,2008,334:795-808
41. Widmann C, Dolci W, Thorens B. Internalization and homologous desensitization of the GLP-1receptor depend on phosphorylation of the receptor carboxyl tail at the same three sites. Mol Endocrinol,1997,11:1094-1102
42. Tomas E, Habener JF. Insulin-like actions of glucagon-like peptide-1:a dual receptor hypothesis. Trends Endocrinol Metab,2009,21:59-67
43. Tomas E, Stanojevic V, Habener JF. GLP-1(9-36) amide metabolite suppression of glucose production in isolated mouse hepatocytes. Horm Metab Res,2010,42:657-662
44. Aviv V, Meivar-Levy I, Rachmut IH, Rubinek T, Mor E, Ferber S. Exendin-4promotes liver cell proliferation and enhances the PDX-1-induced liver to pancreas transdifferentiation process. J Biol Chem,2009,284:33509-33520
45. GGt Holz, Leech CA, Habener JF. Activation of a cAMP regulated Ca(2?)-signaling pathway in pancreatic beta-cells by the insulinotropic hormone glucagon-like peptide-1. J Biol Chem,1995,270:17749-17757
46. Srivastava RK, Srivastava AR, Cho-Chung YS. Synergistic effects of8-Cl-cAMP and retinoic acids in the inhibition of growth and induction of apoptosis in ovarian cancer cells:induction of retinoic acid receptor b. Mol Cell Biochem,2000,204:1-9
47. Vuc'ic'V, Nic'iforovic'A, Adz'ic'M, Radojc'ic'M, Ruz'dijic'S. The combination of gamma ionizing radiation and8-Cl-cAMP induces synergistic cell growth inhibition and induction ofapoptosis in human prostate cancer cells. Invest New Drugs,2008,26:309-17
48. Stork PJS, Schmitt JM. Crosstalk between cAMP and MAP kinase signaling in the regulation of cell proliferation. Trends Cell Biol,2002,12:258-66
49. Zhang Z, Xin S-M, Wu G-X, Zhang W-B, Ma L, Pei G. Endogenous d-opioid and ORL1receptors couple to phosphorylation and activation of p38MAPK in NG108-15cells and this is regulated by protein kinase A and protein kinase C. J Neurochem,1999,73:1502-1509
50. Zhen X, Uryu K, Wang H-Y, Friedman E. D1dopamine receptor agonists mediate activation of p38mitogen-activated protein kinase and c-Jun amino-terminal kinase by a protein kinase A-dependent mechanism in SK-N-MC human neuroblastoma cells. Mol Pharmacol,1998,54:453-458
51. Quoyer J, Longuet C, Broca C, Linck N, Costes S, Varin E, Bockaert Jl, Bertrand G, Sp Dalle. GLP-1mediates antiapoptotic effect by phosphorylating Bad through a b-arrestin1-mediated ERK1/2activation in pancreatic b-cells. J Biol Chem,2010,285:1989-2002
52Ann W.Hsing, Mingdong Zhang et al. Hepatitis B and C virus infection and the risk of biliary tract cancer:a population-based study in china. Int J Cancer2008,122:1849-1853
53.Alpini G, Lenzi R,Sarkozi L, Tavoloni N. J Clin Invest,1988;81:569-578
54Domenico Alvaro, Maria Grazia Mancino, Shannon Glaser et al. Proliferating cholangiocyes:a neuroendocrine compartment in the diseased liver. Gastroenterology2007,132:415-431
55Tan CK, Podila PV, Taylor GE et al. Human cholangiocarcinomas express somatostatin receptorsandrespond to somatostatin with growth inhibition. Gastroenterology1995;108:1908-1916.
56Onori P, Wise C, Gaudio E, Francis H et al. Secretin inhibites cholangiocarcinoma growth via dysregulation of the cAMP-dependent sigaling mechanisms of secretin receptor. Int J Cancer,2010,127(1):43-54
57. Gene D.Lesage, Luca Marucci, Domenico Alvaro et al. Insulin inhibits secretin-induced ductal secretion by activation of PKC alpha and inhibition of PKC activity. Hepatology,2002,36(3):641-51
58. Wei jing, Gang Jing, Xuyu Zhou, et al. Diabetes mellitus and increased risk of cholangiocarcinoma:a meta-analysis European Journal of Cancer Prevention2012,21:24-31
59. Hagai Ligumsky, Ido Wolf, Shira Israeli et, al The peptide-hormone glucagon-like peptide-1activates cAMP and inhibits growth of breast cancer cells. Breast Cancer Res Treat.2012Apr,132(2):449-61
1. Lazaridis KN, Gores GJ. Cholangiocarcinoma. Gastroenterology2005;128(6):1655-67.
2. Vauthey JN, Blumgart LH. Recent advances in the management of cholangiocarcinomas. Semin Liver Dis1994;14(2):109-14.
3. Carpizo DR, D'Angelica M. Management and extent of resection for intrahepatic cholangiocarcinoma. Surg Oncol Clin N Am2009;18(2):289-305, viii-ix.
4. Aljiffry M, Abdulelah A, Walsh M, et al. Evidence-based approach to cholangiocarcinoma:a systematic review of the current literature. J Am Coll Surg2009;208(1):134-47.
5. Patel T. Worldwide trends in mortality from biliary tract malignancies. BMC Cancer2002;2:10.
6. Shaib YH, Davila JA, McGlynn K, et al. Rising incidence of intrahepatic cholangiocarcinoma in the United States:a true increase? J Hepatol2004;40(3):472-7.
7. Taylor-Robinson SD, Foster GR, Arora S, et al. Increase in primary liver cancer in the UK,1979-94. Lancet1997;350(9085):1142-3.
8. Kato I, Kuroishi T, Tominaga S. Descriptive epidemiology of subsites of cancers of the liver, biliary tract and pancreas in Japan. Jpn J Clin Oncol1990;20(3):232-7.
9. Welzel TM, McGlynn KA, Hsing AW, et al. Impact of classification of hilar cholangiocarcinomas (Klatskin tumors) on the incidence of intra-and extrahepatic cholangiocarcinoma in the United States. J Natl Cancer Inst2006;98(12):873-5.
10. El-Serag HB, Engels EA, Landgren O, et al. Risk of hepatobiliary and pancreatic cancers after hepatitis C virus infection:a population-based study of U.S. veterans. Hepatology2009;49(1):116-23.
11. Shaib YH, El-Serag HB, Davila JA, et al. Risk factors of intrahepatic cholangiocarcinoma troenterology2005;128(3):620-6.
12. Donato F, Gelatti U, Tagger A, et al. Intrahepatic cholangiocarcinoma and hepatitis C and B virus infection, alcohol intake, and hepatolithiasis:a case-control study in Italy. Cancer Causes Control2001;12(10):959-64.
13. Kobayashi M, Ikeda K, Saitoh S, et al. Incidence of primary cholangiocellular carcinoma of the liver in Japanese patients with hepatitis C virus-related cirrhosis. Cancer2000;88(11):2471-7.
14. Welzel TM, Graubard BI, El-Serag HB, et al. Risk factors for intrahepatic and extrahepatic cholangiocarcinoma in the United States:a population-based case-control study. Clin Gastroenterol Hepatol2007;5(10):1221-8.
15. Patel T. Increasing incidence and mortality of primary intrahepatic cholangiocarcinoma in the United States. Hepatology2001;33(6):1353-7.
16. Nathan H, Pawlik TM, Wolfgang CL, et al. Trends in survival after surgery for cholangiocarcinoma:a30-year population-based SEER database analysis. J Gastrointest Surg2007;11(11):1488-96[discussion:1496-7].
17. Patel AH, Harnois DM, Klee GG, et al. The utility of CA19-9in the diagnoses of cholangiocarcinoma in patients without primary sclerosing cholangitis. Am J Gastroenterol2000;95(1):204-7.
18. Tamandl D, Herberger B, Gruenberger B, et al. Influence of hepatic resection margin on recurrence and survival in intrahepatic cholangiocarcinoma. Ann Surg Oncol2008;15(10):2787-94.
19. Yamasaki S. Intrahepatic cholangiocarcinoma:macroscopic type and stage classification. J Hepatobiliary Pancreat Surg2003;10(4):288-91.
20. Chung YE, Kim MJ, Park YN, et al. Varying appearances of cholangiocarcinoma: radiologic-pathologic correlation. Radiographics2009;29(3):683-700.
21. Manfredi R, Barbaro B, Masselli G, et al. Magnetic resonance imaging of cholangiocarcinoma. Semin Liver Dis2004;24(2):155-64.
22. Chen LD, Xu HX, Xie XY, et al. Enhancement patterns of intrahepatic cholangiocarcinoma:comparison between contrast-enhanced ultrasound and contrastenhanced CT. Br J Radiol2008;81(971):881-9.
23. Miller G, Schwartz LH, D'Angelica M. The use of imaging in the diagnosis and staging of hepatobiliary malignancies. Surg Oncol Clin N Am2007;16(2):343-68.
24. Maetani Y, Itoh K, Watanabe C, et al. MR imaging of intrahepatic cholangiocarcinoma with pathologic correlation. AJR Am J Roentgenol2001;176(6):1499-507.
25. Anderson CD, Rice MH, Pinson CW, et al. Fluorodeoxyglucose PET imaging in the evaluation of gallbladder carcinom a and cholangiocarcinoma. J Gastrointest Surg2004;8(1):90-7.
26. Kim YJ, Yun M, Lee WJ, et al. Usefulness of18F-FDG PET in intrahepatic cholangiocarcinoma. Eur J Nucl Med Mol Imaging2003;30(11):1467-72.
27. Corvera CU, Blumgart LH, Akhurst T, et al.18F-fluorodeoxyglucose positron emission tomography influences management decisions in patients with biliary cancer. J Am Coll Surg2008;206(1):57-65.
28. Petrowsky H, Wildbrett P, Husarik DB, et al. Impact of integrated positron emission tomography and computed tomography on staging and management of gallbladder cancer and cholangiocarcinoma. J Hepatol2006;45(1):43-50.
29. Goere D, Wagholikar GD, Pessaux P, et al. Utility of staging laparoscopy in subsets of biliary cancers:laparoscopy is a powerful diagnostic tool in patients with intrahepatic and gallbladder carcinoma. Surg Endosc2006;20(5):721-5.
30. Weber SM, Jarnagin WR, Klimstra D, et al. Intrahepatic cholangiocarcinoma: resectability, recurrence pattern, and outcomes. J Am Coll Surg2001;193(4):384-91.
31. Tan JC, Coburn NG, Baxter NN, et al. Surgical management of intrahepatic cholangiocarcinoma-a population-based study. Ann Surg Oncol2008;15(2):600-8.
32. Sotiropoulos GC, Bockhorn M, Sgourakis G, et al. RO liver resections for primary malignant liver tumors in the noncirrhotic liver:a diagnosis-related analysis. Dig Dis Sci2009;54(4):887-94.
33. Endo I, Gonen M, Yopp AC, et al. Intrahepatic cholangiocarcinoma:rising requency, improved survival, and determinants of outcome after resection. Ann Surg2008;248(1):84-96.
34. Konstadoulakis MM, Roayaie S, Gomatos IP, et al. Fifteen-year, single-center experience with the surgical management of intrahepatic cholangiocarcinoma: operative results and long-term outcome. Surgery2008;143(3):366-74.
35. Lang H, Sotiropoulos GC, Sgourakis G, et al. Operations for intrahepatic cholangiocarcinoma:single-institution experience of158patients. J Am Coll Surg2009;208(2):218-28.
36. Nakagohri T, Kinoshita T, Konishi M, et al. Surgical outcome and prognostic factors in intrahepatic cholangiocarcinoma. World J Surg2008;32(12):2675-80.
37. Shimada K, Sano T, Nara S, et al. Therapeutic value of lymph node dissection during hepatectomy in patients with intrahepatic cholangiocellular carcinoma with negative lymph node involvement. Surgery2009;145(4):411-6.
38. Nathan H, Cameron JL, Choti MA, et al. The volume-outcomes effect in hepatopancreato-biliary surgery:hospital versus surgeon contributions and specificity of the relationship. J Am Coll Surg2009;208(4):528-38.
39. Nakagawa T, Kamiyama T, Kurauchi N, et al. Number of lymph node metastases is a significant prognostic factor in intrahepatic cholangiocarcinoma. World J Surg2005;29(6):728-33.
40. Nathan H, Aloia TA, Vauthey JN, et al. A proposed staging system for intrahepatic cholangiocarcinoma. Ann Surg Oncol2009;16(1):14-22.
41. Choi SB, Kim KS, Choi JY, et al. The prognosis and survival outcome of intrahepatic cholangiocarcinoma following surgical resection:association of lymph node metastasis and lymph node dissection with survival. Ann Surg Oncol2009;16(11):3048-56.
42. Okabayashi T, Yamamoto J, Kosuge T, et al. A new staging system for massforming intrahepatic cholangiocarcinoma:analysis of preoperative and postoperative variables. Cancer2001;92(9):2374-83.
43. Greene F, Page D, Flemming I, et al. AJCC cancer staging manual.6th edition. New York:Springer-Verlag;2002.
44. Ikeda K, Saitoh S, Koida I, et al. A multivariate analysis of risk factors for hepatocellular carcinogenesis:a prospective observation of795patients with viral and alcoholic cirrhosis. Hepatology1993;18(1):47-53.
45. Inoue K, Makuuchi M, Takayama T, et al. Long-term survival and prognostic factors in the surgical treatment of mass-forming type cholangiocarcinoma. Surgery2000;127(5):498-505.
46. Parkin DM, Srivatanakul P, Khlat M, et al. Liver cancer in Thailand. I. A casecontrol study of cholangiocarcinoma. Int J Cancer1991;48(3):323-8.
47. Srivatanakul P, Parkin DM, Jiang YZ, et al. The role of infection by Opisthorchis viverrini, hepatitis B virus, and aflatoxin exposure in the etiology of liver cancer in Thailand. A correlation study. Cancer1991;68(11):2411-7.
48. Srivatanakul P, Parkin DM, Khlat M, et al. Liver cancer in Thailand. Ⅱ. A casecontrol study of hepatocellular carcinoma. Int J Cancer1991;48(3):329-32.
49. Ohtsuka M, Ito H, Kimura F, et al. Results of surgical treatment for intrahepatic cholangiocarcinoma and clinicopathological factors influencing survival. Br J Surg2002;89(12):1525-31.
50. Paik KY, Jung JC, Heo JS, et al. What prognostic factors are important for resected intrahepatic cholangiocarcinoma? J Gastroenterol Hepatol2008;23(5):766-70.
51. Uenishi T, Kubo S, Yamazaki O, et al. Indications for surgical treatment of intrahepatic cholangiocarcinoma with lymph node metastases. J Hepatobiliary Pancreat Surg2008;15(4):417-22.
52. Shimada M, Yamashita Y, Aishima S, et al. Value of lymph node dissection during resection of intrahepatic cholangiocarcinoma. Br J Surg2001;88(11):1463-6.
53. Edge S, Byrd D, Compton C, et al. AJCC cancer staging manual.7th edition. New York:Springer-Verlag;2010.
54. Weimann A, Varnholt H, Schlitt HJ, et al. Retrospective analysis of prognostic factors after liver resection and transplantation for cholangiocellular carcinoma. Br J Surg2000;87(9):1182-7.
55. Suzuki S, Sakaguchi T, Yokoi Y, et al. Clinicopathological prognostic factors and impact of surgical treatment of mass-forming intrahepatic cholangiocarcinoma. World J Surg2002;26(6):687-93.
56. Tamandl D, Kaczirek K, Gruenberger B, et al. Lymph node ratio after curative surgery for intrahepatic cholangiocarcinoma. Br J Surg2009;96(8):919-25.57.
57. Asakura H, Ohtsuka M, Ito H, et al. Long-term survival after extended surgical resection of intrahepatic cholangiocarcinoma with extensive lymph node metastasis. Hepatogastroenterology2005;52(63):722-4.
58. Murakami Y, Yokoyama T, Takesue Y, et al. Long-term survival of peripheral intrahepatic cholangiocarcinoma with metastasis to the para-aortic lymph nodes. Surgery2000;127(1):105-6.
59. DeOliveira ML, Cunningham SC, Cameron JL, et al. Cholangiocarcinoma: thirtyone-year experience with564patients at a single institution. Ann Surg2007;245(5):755-62.
60. Jan YY, Yeh CN, Yeh TS, et al. Clinicopathological factors predicting long-term overall survival after hepatectomy for peripheral cholangiocarcinoma. World J Surg2005;29(7):894-8.
61. Guglielmi A, Ruzzenente A, cAMPagnaro T, et al. Intrahepatic cholangiocarcinoma:prognostic factors after surgical resection. World J Surg2009;33(6):1247-54.
62. Bodingbauer M, Tamandl D, Schmid K, et al. Size of surgical margin does not influence recurrence rates after curative liver resection for colorectal cancer liver metastases. Br J Surg2007;94(9):1133-8.
63. Yamamoto M, Takasaki K, Otsubo T, et al. Recurrence after surgical resection of intrahepatic cholangiocarcinoma. J Hepatobiliary Pancreat Surg2001;8(2):154-7.
64. Chou FF, Sheen-Chen SM, Chen YS, et al. Surgical treatment of cholangiocarcinoma. Hepatogastroenterology1997;44(15):760-5.
65. Eckel F, Schmid RM. Chemotherapy in advanced biliary tract carcinoma:a pooled analysis of clinical trials. Br J Cancer2007;96(6):896-902.
66. Huitzil-Melendez FD, O'Reilly EM, Duffy A, et al. Indications for neoadjuvant, adjuvant, and palliative chemotherapy in the treatment of biliary tract cancers. Surg Oncol Clin N Am2009;18(2):361-79, x.
67. Hezel AF, Zhu AX. Systemic therapy for biliary tract cancers. Oncologist2008;13(4):415-23.
68. Verderame F, Russo A, Di Leo R, et al. Gemcitabine and oxaliplatin combination chemotherapy in advanced biliary tract cancers. Ann Oncol2006;17(Suppl7):vii,68-72.
69. Valle J, Wasan H, Palmer DH, et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med2010;362(14):1273-81.
70. Bengala C, Bertolini F, Malavasi N, et al. Sorafenib in patients with advanced biliary tract carcinoma:a phase Ⅱ trial. Br J Cancer2010;102(1):68-72.
71. Zhu AX, Meyerhardt JA, Blaszkowsky LS, et al. Efficacy and safety of gemcitabine, oxaliplatin, and bevacizumab in advanced biliary-tract cancers and correlation of changes in18-fluorodeoxyglucose PET with clinical outcome:a phase2study. Lancet Oncol2010;11(1):48-54.
72. Malka D, Trarbach T, Fartoux L, et al. A multicenter, randomized phase Ⅱ trial of gemcitabine and oxaliplatin (GEMOX) alone or in combination with biweekly cetuximab in the first-line treatment of advanced biliary cancer:interim analysis of the BINGO trial [abstract:4520]. J Clin Oncol2009;27(Suppl):15s.
73. Philip PA, Mahoney MR, Allmer C, et al. Phase Ⅱ study of erlotinib in patients with advanced biliary cancer. J Clin Oncol2006;24(19):3069-74.
74. Ramanathan RK, Belani CP, Singh DA, et al. A phase Ⅱ study of lapatinib in patients with advanced biliary tree and hepatocellular cancer. Cancer Chemother Pharmacol2009;64(4):777-83.
75. Shinohara ET, Mitra N, Guo M, et al. Radiation therapy is associated with improved survival in the adjuvant and definitive treatment of intrahepatic cholangiocarcinoma. Int J Radiat Oncol Biol Phys2008;72(5):1495-501.
76. Zeng ZC, Tang ZY, Fan J, et al. Consideration of the role of radiotherapy for unresectable intrahepatic cholangiocarcinoma:a retrospective analysis of75patients. Cancer J2006;12(2):113-22.
77. Kemeny NE, Niedzwiecki D, Hollis DR, et al. Hepatic arterial infusion versus systemic therapy for hepatic metastases from colorectal cancer:a randomized trial of efficacy, quality of life, and molecular markers (CALGB9481). J Clin Oncol2006;24(9):1395-403.
78. Cantore M, Mambrini A, Fiorentini G, et al. Phase Ⅱ study of hepatic intraarterial epirubicin and cisplatin, with systemic5-fluorouracil in patients with unresectable biliary tract tumors. Cancer2005;103(7):1402-7.
79. Jarnagin WR, Schwartz LH, Gultekin DH, et al. Regional chemotherapy for unresectable primary liver cancer:results of a phase Ⅱ clinical trial and assessment of DCE-MRI as a biomarker of survival. Ann Oncol2009;20(9):1589-95.
80. Shitara K, Ikami I, Munakata M, et al. Hepatic arterial infusion of mitomycin C with degradable starch microspheres for unresectable intrahepatic cholangiocarcinoma. Clin Oncol (R Coll Radiol)2008;20(3):241-6.
81. Tanaka N, Yamakado K, Nakatsuka A, et al. Arterial chemoinfusion therapy through an implanted port system for patients with unresectable intrahepatic cholangiocarcinoma-initial experience. Eur J Radiol2002;41(1):42-8.
82. Llovet JM, Real MI, Montana X, et al. Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma:a randomised controlled trial. Lancet2002;359(9319):1734-9.
83. Lo CM, Ngan H, Tso WK, et al. Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma. Hepatology2002;35(5):1164-71.
84. Gusani NJ, Balaa FK, Steel JL, et al. Treatment of unresectable cholangiocarcinoma with gemcitabine-based transcatheter arterial chemoembolization (TACE):a single-institution experience. J Gastrointest Surg2008;12(1):129-37.
85. Burger I, Hong K, Schulick R, et al. Transcatheter arterial chemoembolization in unresectable cholangiocarcinoma:initial experience in a single institution. J Vasc Interv Radiol2005;16(3):353-61.
1. Alpini G, Prall RT, LaRusso NF. The pathobiology of biliary epithelia. In:Arias IM, Boyer JL, Chisari FV, Fausto N, Jakoby W, Schachter D, Shafritz DA, eds. The liver:biology and pathobiology.4th ed. Philadelphia, PA:Lippincott Williams&Wilkins;2001:421-435.
2. Kanno N, LeSage G, Glaser S, Alvaro D, Alpini G. Functional heterogeneity of the intrahepatic biliary epithelium. Hepatology2000;31:555-561.
3. Roskams TA, Theise ND, Balabaud C, Bhagat G, Bhathal PS, Bioulac-Sage P, Brunt EM, Crawford JM, Crosby HA, Desmet V, Finegold MJ, Geller SA, Gouw AS, Hytiroglou P, Knisely AS, Kojiro M, Lefkowitch JH, Nakanuma Y, Olynyk JK, Park
YN, Portmann B, Saxena R, Scheuer PJ, Strain AJ, Thung SN, Wanless IR, West AB. Nomenclature of the finer branches of the biliary tree:canals, ductules, and ductular reactions in human livers. Hepatology2004;39:1739-1745.
4. Hering E. Ueber den Bau der Wirbelthierleber. Arch Mikrosk Anat1867;3:88-114.
5. Theise ND, Saxena R, Portmann BC, Thung SN, Yee H, Chiriboga L, Kumar A, Crawford JM. The canals of Hering and hepatic stem cells in humans. Hepatology1999;30:1425-1433.
6. Crawford JM. Normal and abnormal development of the biliary tree. In:Alpini G, Alvaro D, LeSage G, Marzioni M, LaRusso NF, eds. The pathophysiology of biliary epithelia. Georgetown, TX:Landes Biosciences;2004:1-13.
7. Saxena R, Theise ND, Crawford JM. Microanatomy of the human liver:exploring the hidden interfaces. Hepatology1999;30:1339-1346.
8. Reilly FD, McCuskey PA, McCuskey RS. Intrahepatic distribution of nerves in the rat. Anat Rec1978;191:55-68.
9. McCuskey RS. Anatomy of efferent hepatic nerves. Anat Rec A Discov Mol Cell Evol Biol2004;280:821-826.
10. Berthoud HR. Anatomy and function of sensory hepatic nerves. Anat Rec A Discov Mol Cell Evol Biol2004;280:827-835.11. el-Salhy M, Stenling R, Grimelius L. Peptidergic innervation and endocrine cells in the human liver. Scand J Gastroenterol1993;28:809-815.
12. Goehler LE, Sternini C, Brecha NC. Calcitonin gene-related peptide immunoreactivity in the biliary pathway and liver of the guinea-pig:distribution and colocalization with substance P. Cell Tissue Res1988;253:145-150.
13. Inoue N, Hirata K, Yamada M, Hamamori Y, Matsuda Y, Akita H, Yokoyama M. Lysophosphatidylcholine inhibits bradykinin-induced phosphoinositide hydrolysis and calcium transients in cultured bovine aortic endothelial cells. Circ Res1992;71:1410-1421.
14. Burt AD, Tiniakos D, MacSween RN, Griffiths MR, Wisse E, Polak JM. Localization of adrenergic and neuropeptide tyrosine-containing nerves in the mammalian liver. Hepatology1989;9:839-845.
15. Schultzberg M, Dalsgaard CJ. Enteric origin of bombesin immunoreactive fibres in the rat coeliac-superior mesenteric ganglion. Brain Res1983;269:190-195.
16. Barbaro B, Glaser S, Francis H, Taffetani S, Marzioni M, LeSage G, Alpini G. Nerve regulation of cholangiocyte functions. In:Alpini G, Alvaro D, LeSage G, Marzioni M, LaRusso NF, eds. The pathophysiology of biliary epithelia. Georgetown, TX:Landes Biosciences;2004:199-209.
17. Gaudio E, Onori P, Pannarale L, Alvaro D. Hepatic microcirculation and peribiliary plexus in experimental biliary cirrhosis:a morphological study. Gastroenterology1996;111:1118-1824.
18. Gaudio E, Onori P, Franchitto A, Sferra R, Vetuschi A, Morini S, Alpini G, Alvaro D. Vascularization of the intrahepatic biliary tree and its role in the regulation of cholangiocyte growth. In:Alpini G, Alvaro D, LeSage G, Marzioni M, LaRusso NF, eds. The pathophysiology of biliary epithelia. Georgetown, TX:Landes Biosciences;2004:41-45.
19. LeSage G, Glaser S, Gubba S, Robertson WE, Phinizy JL, Lasater J, Rodgers RE, Alpini G. Regrowth of the rat biliary tree after70%partial hepatectomy is coupled to increased secretin-induced ductal secretion. Gastroenterology1996;111:1633-1644.
20. Schaffner F, Popper H. Electron microscopic studies of normal and proliferated bile ductules. Am J Pathol1961;38:393-410.
21. Demetris AJ. Participation of cytokines and growth factors in biliary cell proliferation and mito-inhibition during ductular reaction. In:Alpini G, Alvaro D, LeSage G, Marzioni M, LaRusso NF, eds. The pathophysiology of biliary epithelia. Georgetown, TX:Landes Biosciences;2004:167-182.
22. Tadlock L, Yamagiwa Y, Hawker J, Marienfeld C, Patel T. Transforming growth factor-beta inhibition of proteasomal activity:a potential mechanism of growth arrest. Am J Physiol Cell Physiol2003;285:C277-C285.
23. Harnois DM, Que FG, Celli A, LaRusso NF, Gores GJ. Bel-2is overexpressed and alters the threshold for apoptosis in a cholangiocarcinoma cell line. Hepatology 1997;26:884-890.
24. Okaro AC, Deery AR, Hutchins RR, Davidson BR. The expression of antiapoptotic proteins Bcl-2, Bcl-X(L), and Mcl-1in benign, dysplastic, and malignant biliary epithelium. J Clin Pathol2001;54:927-932.
25. Masyuk AI, Splinter PL, Masyuk TV, Stroope AJ, LaRusso NF. Cholangiocyte cilia act as sensory organelles affecting the intracellular signaling pathways. FASEB J2005;19:A148.
26. Alpini G, Glaser S, Ueno Y, Pham L, Podila PV, Caligiuri A, LeSage G, LaRusso NF. Heterogeneity of the proliferative capacity of rat cholangiocytes after bile duct ligation. Am J Physiol Gastrointest Liver Physiol1998;274:G767-G775.
27. Glaser S, Benedetti A, Marucci L, Alvaro D, Baiocchi L, Kanno N, Caligiuri A, Phinizy JL, Chowdhury U, Papa E, LeSage G, Alpini G. Gastrin inhibits cholangiocyte growth in bile duct-ligated rats by interaction with cholecystokinin-B/Gastrin receptors via D-myoinositol1,4,5-triphosphate-, Ca(2)-, and protein kinase C alphadependent mechanisms. Hepatology2000;32:17-25.
28. Glaser S, Alvaro D, Ueno Y, Francis H, Marzioni M, Phinizy JL, Baumann B, Mancino MG, Venter J, LeSage G, Alpini G. Gastrin reverses established cholangiocyte proliferation and enhanced secretin-stimulated ductal secretion of BDL rats by activation of apoptosis through increased expression of Ca2-dependent PKC isoforms. Liver Int2003;23:78-88.
29. Francis H, Glaser S, Ueno Y, LeSage G, Marucci L, Benedetti A, Taffetani S, Marzioni M, Alvaro D, Venter J, Reichenbach R, Fava G, Phinizy JL, Alpini G. cAMP stimulates the secretory and proliferative capacity of the rat intrahepatic biliary epithelium through changes in the PKA/Src/MEK/ERK1/2pathway. J Hepatol2004;41:528-537.
30. LeSage G, Alvaro D, Benedetti A, Glaser S, Marucci L, Baiocchi L, Eisel W, Caligiuri A, Phinizy JL, Rodgers R, Francis H, Alpini G. Cholinergic system modulates growth, apoptosis, and secretion of cholangiocytes from bile duct-ligated rats. Gastroenterology1999;117:191-199.
31. Sand TE, Thoresen GH, Refsnes M, Christoffersen T. Growthregulatory effects of glucagon, insulin, and epidermal growthfactor in cultured hepatocytes. Temporal aspects and evidence for bidirectional control by cAMP. Dig Dis Sci1992;37:84-92.
32. Alvaro D, Gigliozzi A, Attili AF. Regulation and deregulation of cholangiocyte proliferation. J Hepatol2000;33:333-340.33. Desmet V, Roskams T, Van Eyken P. Pathology of the biliary tree in cholestasis:ductular reaction. In:Manns MP, Boyer JL, Jansen PLM, Reichen J, eds. Cholestatic liver diseases. New York:Kluwer Academic Publishers;1998:143-154.
34. Roskams T, Van den Oord JJ, De Vos R, Desmet VJ. Neuroendocrine features of reactive bile ductules in cholestatic liver disease. Am J Pathol1990;137:1019-1025.
35. Desmet V, Roskams T, Van Eyken P. Ductular reaction in the liver. Pathol Res Pract1995;191:513-524.
36. Popper H, Kent G, Stein R. Ductular reaction in the liver in hepatic injury. J Mt Sinai Hosp1957;24:551-556.
37. Lazaridis KN, Strazzabosco M, LaRusso NF. The cholangiopathies:disorders of biliary epithelia. Gastroenterology2004;127:1565-1577.
38. Alpini G, Lenzi R, Sarkozi L, Tavoloni N. Biliary physiology in rats with bile ductular cell hyperplasia. Evidence for a secretory function of proliferated bile ductules. J Clin Invest1988;81:569-578.
39. LeSage G, Glaser S, Ueno Y, Alvaro D, Baiocchi L, Kanno N, Phinizy JL, Francis H, Alpini G. Regression of cholangiocyte proliferation after cessation of ANIT feeding is coupled with increased apoptosis. Am J Physiol Gastrointest Liver Physiol2001;281:G182-G190.
40. Vacanti JP, Folkman J. Bile duct enlargement by infusion of L-proline:potential significance in biliary atresia. J Pediatr Surg1979;14:814-848.
41. Alpini G, Glaser S, Ueno Y, Rodgers R, Phinizy JL, Francis H, Baiocchi L, Holcomb LA, Caligiuri A, LeSage G. Bile acid feeding induces cholangiocyte proliferation and secretion:evidence for bile acid-regulated ductal secretion. Gastroenterology1999;116:179-186.
42. Palmer RH, Ruban Z. Production of bile duct hyperplasia and gallstones by lithocholic acid. J Clin Invest1966;45:1255-1267.
43. Masyuk TV, Masyuk AI, Ritman EL, LaRusso NF. Three-dimensional reconstruction of the rat intrahepatic biliary tree:physiological implications. In: Alpini G, Alvaro D, LeSage G, Marzioni M, LaRusso NF, eds. The pathophysiology of biliary epithelia. Georgetown, TX:Landes Biosciences;2004:60-67.
44. Masyuk TV, Ritman EL, LaRusso NF. Quantitative assessment of the rat intrahepatic biliary system by three-dimensional reconstruction. Am J Pathol2001;158:2079-2088.
45. Slott PA, Liu MH, Tavoloni N. Origin, pattern, and mechanism of bile duct proliferation following biliary obstruction in the rat. Gastroenterology1990;99:466-477.
46. Grisham JW. A morphologic study of deoxyribonucleic acid synthesis and cell proliferation in regenerating rat liver; autoradiography with thymidine-H3. Cancer Res1962;22:842-849.
47. James J, Lygidakis NJ, van Eyken P, Tanka AK, Bosch KS, Ramaekers FC, Desmer V. Application of keratin immunocytochemistry and Sirius red staining in evaluating intrahepatic changes with acute extrahepatic cholestasis due to hepatic duct carcinoma. Hepatogastroenterology1989;36:151-155.
48. Omori M, Evarts RP, Omori N, Hu Z, Marsden ER, Thorgeirsson SS. Expression of alpha-fetoprotein and stem cell factor/c-kit system in bile duct ligated young rats. Hepatology1997;25:1115-1122.
49. Miller DJ, Keeton DG, Webber BL, Pathol FF, Saunders SJ. Jaundice in severe bacterial infection. Gastroenterology1976;71:94-97.
50. Celli A, Que FG. Dysregulation of apoptosis in the cholangiopathies and cholangiocarcinoma. Semin Liver Dis1998;18:177-185.
51. Desmet VJ. Current problems in diagnosis of biliary disease and cholestasis. Semin Liver Dis1986;6:233-245.
52. Fausto N, Webber EM. Liver regeneration. In:Arias IM, Boyer JL, Fausto N, Jakoby WB, Schachter D, Shafritz DA, eds. The liver:biology and pathobiology.3rd ed. New York:Raven,1994:1059-1084.
53. Wegmann R, Corcos V, Caroli J. Histoenzymologie des ductules biliaires chez l'embryon humain normal et au tours des cirrhoses humaines. Arch Mal Appar Dig1967;54:215-228.
54. Kuhlmann WD, Wurster K. Correlation of histology and alpha1-fetoprotein resurgence in rat liver regeneration after experimental injury by galactosamine. Virchows Archiv A, Pathol Anat Histol1980;387:47-57.
55. LeSage G, Benedetti A, Glaser S, Marucci L, Tretjak Z, Caligiuri A, Rodgers R, Phinizy JL, Baiocchi L, Francis H, Lasater J, Ugili L, Alpini G. Acute carbon tetrachloride feeding selectively damages large, but not small, cholangiocytes from normal rat liver. Hepatology1999;29:307-319.
56. LeSage G, Glaser S, Marucci L, Benedetti A, Phinizy JL, Rodgers R, Caligiuri A, Papa E, Tretjak Z, Jezequel AM, Holcomb LA, Alpini G. Acute carbon tetrachloride feeding induces damage of large but not small cholangiocytes from BDL rat liver. Am J Physiol Gastrointest Liver Physiol1999;276:G1289-G1301.
57. Nagore N, Howe S, Boxer L, Scheuer PJ. Liver cell rosettes:structural differences in cholestasis and hepatitis. Liver1989;9:43-51.
58. Knowles DM, Wolff M. Focal nodular hyperplasia of the liver:a clinicopathologic study and review of the literature. Hum Pathol1976;7:533-545.
59. Yamada S, Howe S, Scheuer PJ. Three-dimensional reconstruction of biliary pathways in primary biliary cirrhosis:a computerassisted study. J Pathol1987;152:317-323.
60. Crosby HA, Hubscher S, Fabris L, Joplin R, Sell S, Kelly D, Strain AJ. Immunolocalization of putative human liver progenitor cells in livers from patients with end-stage primary biliary cirrhosis and sclerosing cholangitis using the monoclonal antibody OV-6. Am J Pathol1998;152:771-779.
61. De Vos R, Desmet V. Ultrastructural characteristics of novel epithelial cell types identified in human pathologic liver specimens with chronic ductular reaction. Am J Pathol1992;140:1441-1450.
62. Tan J, Hytiroglou P, Wieczorek R, Park YN, Thung SN, Arias B, Theise ND. Immunohistochemical evidence for hepatic progenitor cells in liver diseases. Liver 2002;22:365-373.
63. Roskams T. Progenitor cell involvement in cirrhotic human liver diseases:from controversy to consensus. J Hepatol2003;39:431-434.64. Lunz JG,3rd, Tsuji H, Nozaki I, Murase N, Demetris AJ. An inhibitor of cyclin-dependent kinase, stress-induced p21Waf-1/Cip-1, mediates hepatocyte mito-inhibition during the evolution of cirrhosis. Hepatology2005;41:1262-1271.
65. Clouston AD, Powell EE, Walsh MJ, Richardson MM, Demetris AJ, Jonsson JR. Fibrosis correlates with a ductular reaction in hepatitis C:roles of impaired replication, progenitor cells and steatosis. Hepatology2005;41:809-818.
66. Ren P, Silberg DG, Sirica AE. Expression of an intestine-specific transcription factor (CDX1) in intestinal metaplasia and in subsequently developed intestinal type of cholangiocarcinoma in rat liver. Am J Pathol2000;156:621-627.
67. Lowes KN, Brennan BA, Yeoh GC, Olynyk JK. Oval cell numbers in human chronic liver diseases are directly related to disease severity. Am J Pathol1999;154:537-541.
68. Petropoulos CJ, Yaswen P, Panzica M, Fausto N. Cell lineages in liver carcinogenesis:possible clues from studies of the distribution of alpha-fetoprotein RNA sequences in cell populations isolated from normal, regenerating, and preneoplastic rat livers. Cancer Res1985;45:5762-5768.
69. Sirica AE, Cihla HP. Isolation and partial characterizations of oval and hyperplastic bile ductular cell-enriched populations from the livers of carcinogen and noncarcinogen-treated rats. Cancer Res1984;44:3454-3466.
70. Farber E. Similarities in the sequence of early histological changes induced in the liver of the rat by ethionine,2-acetylamino-fluorene, and3'-methyl-4-dimethylaminoazobenzene. Cancer Res1956;16:142-148.
71. Roskams T, Cassiman D, De Vos R, Libbrecht L. Neuroregulation of the neuroendocrine compartment of the liver. Anat Rec A Discov Mol Cell Evol Biol2004;280:910-923.
72. Yang S, Koteish A, Lin H, Huang J, Roskams T, Dawson V, Diehl AM. Oval cells compensate for damage and replicative senescence of mature hepatocytes in mice with fatty liver disease. Hepatology2004;39:403-411.
73. Roskams T, Desmet V. Ductular reaction and its diagnostic significance. Semin Diagn Pathol1998;15:259-269.
74. Haque S, Haruna Y, Saito K, Nalesnik MA, Atillasoy E, Thung SN, Gerber MA. Identification of bipotential progenitor cells in human liver regeneration. Lab Invest1996;75:699-705.
75. Roskams TA, Libbrecht L, Desmet VJ. Progenitor cells in diseased human liver. Semin Liver Dis2003;23:385-396.
76. Ros JE, Roskams TA, Geuken M, Havinga R, Splinter PL, Petersen BE, LaRusso NF, van der Kolk DM, Kuipers F, Faber KN, Muller M, Jansen PL. ATP binding cassette transporter gene expression in rat liver progenitor cells. Gut2003;52:1060-1067.
77. Roskams T, De Vos R, Van Eyken P, Myazaki H, Van Damme B, Desmet V. Hepatic OV-6expression in human liver disease and rat experiments:evidence for hepatic progenitor cells in man. J Hepatol1998;29:455-463.
78. Alvaro D, Invernizzi P, Onori P, Franchitto A, De Santis A, Crosignani A, Sferra R, Ginanni-Corradini S, Mancino MG, Maggioni M, Attili AF, Podda M, Gaudio E. Estrogen receptors in cholangiocytes and the progression of primary biliary cirrhosis. J Hepatol2004;41:905-912.
79. Harada K, Furubo S, Ozaki S, Hiramatsu K, Sudo Y, Nakanuma Y. Increased expression of WAF1in intrahepatic bile ducts in primary biliary cirrhosis relates to apoptosis. J Hepatol2001;34:500-506.
80. Tinmouth J, Lee M, Wanless IR, Tsui FW, Inman R, Heathcote EJ. Apoptosis of biliary epithelial cells in primary biliary cirrhosis and primary sclerosing cholangitis. Liver2002;22:228-234.