EGFR、Ras及CEA蛋白在食管癌、胃癌和大肠癌表达的研究
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摘要
背景与目的：消化道肿瘤是我国常见的恶性肿瘤之一,其中又以食管癌、胃癌和大肠癌最为常见。在肿瘤的发生机制上,一方面此三者同作为消化道的肿瘤,同受到来自饮食、生活习惯、环境因素及遗传易感性等各种致癌因素的作用,在肿瘤的发生过程中具有相似的机制；另一方面此三者又处于消化道不同的部位,其解剖学结构和生理功能均又有所不同,这决定了致癌因素的种类和性质不完全相同,作用方式及影响程度亦各有差别和侧重,在肿瘤的发生机制上又具有差异性的环节。这种生理功能、部位、阶段及刺激因素上的相似性与差异性,决定了多种基因各有侧重地参与了食管癌、胃癌、大肠癌的发生过程。近年来表皮生长因子受体(epidermal growth factor receptor,EGFR)、原癌基因ras (Proto-oncogene ras, Ras)与癌胚抗原(carcinoembryonic antigen, CEA)蛋白在消化道肿瘤发生发展中的作用受到广泛关注,针对EGFR、Ras蛋白的药物靶向治疗也取得了一定的进展。本研究采用免疫组化方法,通过检测食管癌、胃癌和大肠癌组织中EGFR、Ras及CEA蛋白的表达情况,结合它们与临床病理特征的关系,旨从蛋白水平探讨三种蛋白在消化道不同部位肿瘤发生中的作用侧重,以及它们与肿瘤发生、进展、分化的关系,以期找到指示消化道肿瘤临床病理特征的可靠分子指标。并通过分析比较EGFR、Ras和CEA蛋白在不同部位肿瘤组织中表达的差异,为靶向药物治疗肿瘤寻找较为敏感的靶点。
方法：收集经手术切除且病理证实的食管癌21例、胃癌81例及大肠癌124例,获得完整临床及随访资料,所有标本取得前患者均未接受化学药物或放射线治疗。应用免疫组化方法检测EGFR、Ras及CEA蛋白在食管癌、胃癌及大肠癌组织中的表达情况,分析这三种蛋白表达与临床病理间的关系,所得结果在SPSS 11.5软件中进行统计学分析。
结果：1.EGFR蛋白在胃癌组表达率明显高于大肠癌组,统计学分析有显著性差异(P<0.05); Ras蛋白在食管癌和胃癌组表达率明显高于大肠癌组,统计学分析有显著性差异(P<0.05); CEA蛋白在食管癌组表达率明显低于大肠癌组,统计学分析有显著性差异(P<0.05)。
2.EGFR、Ras与CEA蛋白表达与临床病理特征之间的关系
(1)食管癌组EGFR、Ras与CEA蛋白表达与患者性别、年龄、肿瘤部位、分化程度、浸润深度及有无淋巴结转移组间均无显著性差异(P>0.05)。
(2)胃癌组中,EGFR蛋白在低分化组表达率明显高于高中分化组,统计学分析有显著性差异(P<0.05); Ras蛋白在浸润深度超出浆膜层组表达率明显高于未超出浆膜外组,统计学分析有显著性差异(P<0.05); CEA蛋白在有远处转移组明显高于无远处转移组,统计学分析有显著性差异(P<0.05)。余与性别、年龄、分化程度、浸润深度、有无淋巴结转移及有无远处转移组间均无显著性差异(P>0.05)。
(3)大肠癌组中,EGFR蛋白在浸润深度未超出浆膜层组表达率明显高于超出浆膜外组,有显著性差异(P<0.05); Ras蛋白在浸润深度未超出浆膜层组表达率明显高于超出浆膜外组,有显著性差异(P<0.05)；余与患者性别、年龄、部位、分化程度、浸润深度及有无淋巴结转移组间均无显著性差异(P>0.05)。
3.EGFR、Ras与CEA蛋白表达的相关性
(1)食管癌EGFR与CEA蛋白的表达呈正相关(r=0.552, P<0.05); EGFR与Ras蛋白、CEA与Ras蛋白的表达均无明显相关性(P>0.05)。
(2)胃癌EGFR与CEA蛋白的表达呈正相关(r=0.457, P<0.05), Ras与CEA蛋白的表达呈正相关(r=0.220, P<0.05);EGFR与Ras蛋白的表达无明显相关性(P>0.05)。
(3)大肠癌EGFR与Ras蛋白的表达呈正相关(r=0.452, P<0.05);EGFR与CEA蛋白,Ras与CEA蛋白的表达均无明显相关性(P>0.05)。
结论：1. EGFR、Ras与CEA蛋白在食管癌、胃癌与大肠癌中均有不同程度的表达,提示此三种蛋白在消化道肿瘤的发生发展中都起了一定的作用。
2. EGFR蛋白在骨癌、Ras蛋白在食管癌、CEA蛋白在大肠癌中表达最高,提示EGFR蛋白与胃癌、Ras蛋白与食管癌、CEA蛋白与大肠癌关系似乎更为密切,采用药物靶向治疗肿瘤,可以选择与此肿瘤关系较密切的蛋白作为药物靶点,以期获得较为理想的治疗效果。
3.胃癌组织中EGFR蛋白的表达与肿瘤分化程度可能成负相关,Ras蛋白的表达与肿瘤浸润深度可能成正相关,CEA蛋白的表达与肿瘤远处转移可能呈正相关。
4.食管癌及胃癌组织中EGFR与CEA蛋白表达成正相关,胃癌组织中Ras与CEA蛋白表达成正相关,大肠癌组织中EGFR与Ras蛋白表达成正相关,提示此三种蛋白在消化道肿瘤的发生发展过程中可能起了协同作用。
Background and Objective:Digestive carcinoma, especially esopha-geal cancer, gastric cancer and colorectal cancer, is most common in our country. Many factors and genes are related to their carcinogenesis. As carcinomas in alimentary canal, esophageal cancer, gastric cancer and colorectal cancer are all influenced by similar factors such as diet, habits and customs, environment and hereditary predisposition. On the other hand, these three carcinomas lie in different locations in alimentary canal, with different anatomical structure and different physiological function.This fact determins that these risk factors have distinctions in kind and character. In recent years, EGFR(epidermal growth factor receptor), Ras (Proto-oncogene ras) and CEA(carcinoembryonic antigen) protein were paid much attention to carcinomas genesis. Targeted therapy aimed at EGFR and Ras protein has been researched in recent years. By analyzing the expression of EGFR, Ras and CEA protein in esophageal cancer, gastric cancer and colorectal cancer, and their relationship with clinicopathological parameters, this project investigated the different roles of these three proteins in gastrointestinal cancer. By analyzing the different expression of EGFR, Ras and CEA protein in esophageal cancer, gastric cancer and colorectal cancer, this project intend to find targets for targeted therapy.
Methods:Surgically resected and pathologically proved cases of esophageal cancer, gastric cancer and colorectal cancer were collected. Information related to patiens'gender, age, tumor location, histological type and pathological stage were recorded. Complete clinical information were obtained in this study. None of these patients received either radiocherapy or chemocherapy before the surgery. The specimen cases were immunostainde to observe the expression of EGFR, Ras and CEA in esophageal cancer, gastric cancer cells and colorectal cancer cells. All the results were statistically analyzed with SPSS 11.5 software package.
Results:1.The positive expression rate of EGFR in gastric cancer group was obviously higher than colorectal cancer group(P<0.05). The positive rate of Ras expression in esophageal cancer group and gastric cancer group was obviously higher than colorectal cancer group(P<0.05). The positive rates of CEA expression in esophageal cancer group were obviously lower than colorectal cancer group(P<0.05).
2.The relationship between EGFR, Ras and CEA protein expression and clinical characteristics.
(1) In esophageal cancer group, the positive expression rate of EGFR, Ras and CEA have no obvious relationship with patiens'gender, age, tumour location, differention degree, depth of invasion and lymph node metastasis (P>0.05).
(2)In gastric cancer, the positive rate of EGFR protein expression in poor differentiation group was higher than well-moderate differentiation group(P<0.05); the positive expression rates of Ras in penetrated subserous layer group was higher than infiltrated to subserous layer group(P<0.05); the positive expression rate of CEA in distant metastasis group was higher than without distant metastasis group(P<0.05).
(3)In colorectal cancer, the positive rate of EGFR protein expression in infiltrated to subserous layer group was higher than penetrated subserous layer group(P<0.05); the positive rate of Ras protein expression in infiltrated to subserous layer group was higher than penetrated subserous layer group(P<0.05).
3.The correlation between EGFR, Ras and CEA protein expression.
(1)In esophageal cancer, EGFR protein expression was positively correlated with CEA protein expression(r=0.552, P<0.05). There was no significant correlation between EGFR and Ras expression(P>0.05), and the same as CEA and Ras expression.
(2)In gastric cancer, EGFR protein expression was positively corre- lated with CEA protein expression(r=0.457, P<0.05); Ras protein expres-sion is positively correlated with CEA protein expression(r=0.220, P<0.05). There was no significant correlation between EGFR and Ras expression (P>0.05).
(3)In colorectal cancer, EGFR protein expression was positively correlation with Ras protein expression(r=0.452, P<0.05). There was no significant correlation between EGFR and Ras expression(P>0.05), and the same as CEA and Ras expression.
Conclusions:1.The EGFR, Ras and CEA protein all have expression more or less in esophageal cancer, gastric cancer and colorectal cancer group. These three protein may play a part in carcinogenesis.
2.EGFR protein expression in gastric cancer, Ras protein expression in esophageal cancer and CEA protein expression in colorectal cancer were much higher than the other. The protein may be choosed as target for targeted therapy.
3.In gastric cancer the expression of EGFR protein has negative correlation to cell differentiation, the expression of Ras protein has positive correlation to depth of invasion, and the expression of CEA protein has positive correlation to distant metastasis.
4.EGFR and CEA protein expression has a close relationship in esophageal cancer and gastric cancer. Ras and CEA protein expression has a close relationship in gastric cancer. EGFR and Ras protein expression has a close relationship in colorectal cancer. These three protein may cooperate with each other in carcinogenesis.
方法：收集经手术切除且病理证实的食管癌21例、胃癌81例及大肠癌124例,获得完整临床及随访资料,所有标本取得前患者均未接受化学药物或放射线治疗。应用免疫组化方法检测EGFR、Ras及CEA蛋白在食管癌、胃癌及大肠癌组织中的表达情况,分析这三种蛋白表达与临床病理间的关系,所得结果在SPSS 11.5软件中进行统计学分析。
结果：1.EGFR蛋白在胃癌组表达率明显高于大肠癌组,统计学分析有显著性差异(P<0.05); Ras蛋白在食管癌和胃癌组表达率明显高于大肠癌组,统计学分析有显著性差异(P<0.05); CEA蛋白在食管癌组表达率明显低于大肠癌组,统计学分析有显著性差异(P<0.05)。
2.EGFR、Ras与CEA蛋白表达与临床病理特征之间的关系
(1)食管癌组EGFR、Ras与CEA蛋白表达与患者性别、年龄、肿瘤部位、分化程度、浸润深度及有无淋巴结转移组间均无显著性差异(P>0.05)。
(2)胃癌组中,EGFR蛋白在低分化组表达率明显高于高中分化组,统计学分析有显著性差异(P<0.05); Ras蛋白在浸润深度超出浆膜层组表达率明显高于未超出浆膜外组,统计学分析有显著性差异(P<0.05); CEA蛋白在有远处转移组明显高于无远处转移组,统计学分析有显著性差异(P<0.05)。余与性别、年龄、分化程度、浸润深度、有无淋巴结转移及有无远处转移组间均无显著性差异(P>0.05)。
(3)大肠癌组中,EGFR蛋白在浸润深度未超出浆膜层组表达率明显高于超出浆膜外组,有显著性差异(P<0.05); Ras蛋白在浸润深度未超出浆膜层组表达率明显高于超出浆膜外组,有显著性差异(P<0.05)；余与患者性别、年龄、部位、分化程度、浸润深度及有无淋巴结转移组间均无显著性差异(P>0.05)。
3.EGFR、Ras与CEA蛋白表达的相关性
(1)食管癌EGFR与CEA蛋白的表达呈正相关(r=0.552, P<0.05); EGFR与Ras蛋白、CEA与Ras蛋白的表达均无明显相关性(P>0.05)。
(2)胃癌EGFR与CEA蛋白的表达呈正相关(r=0.457, P<0.05), Ras与CEA蛋白的表达呈正相关(r=0.220, P<0.05);EGFR与Ras蛋白的表达无明显相关性(P>0.05)。
(3)大肠癌EGFR与Ras蛋白的表达呈正相关(r=0.452, P<0.05);EGFR与CEA蛋白,Ras与CEA蛋白的表达均无明显相关性(P>0.05)。
结论：1. EGFR、Ras与CEA蛋白在食管癌、胃癌与大肠癌中均有不同程度的表达,提示此三种蛋白在消化道肿瘤的发生发展中都起了一定的作用。
2. EGFR蛋白在骨癌、Ras蛋白在食管癌、CEA蛋白在大肠癌中表达最高,提示EGFR蛋白与胃癌、Ras蛋白与食管癌、CEA蛋白与大肠癌关系似乎更为密切,采用药物靶向治疗肿瘤,可以选择与此肿瘤关系较密切的蛋白作为药物靶点,以期获得较为理想的治疗效果。
3.胃癌组织中EGFR蛋白的表达与肿瘤分化程度可能成负相关,Ras蛋白的表达与肿瘤浸润深度可能成正相关,CEA蛋白的表达与肿瘤远处转移可能呈正相关。
4.食管癌及胃癌组织中EGFR与CEA蛋白表达成正相关,胃癌组织中Ras与CEA蛋白表达成正相关,大肠癌组织中EGFR与Ras蛋白表达成正相关,提示此三种蛋白在消化道肿瘤的发生发展过程中可能起了协同作用。
Background and Objective:Digestive carcinoma, especially esopha-geal cancer, gastric cancer and colorectal cancer, is most common in our country. Many factors and genes are related to their carcinogenesis. As carcinomas in alimentary canal, esophageal cancer, gastric cancer and colorectal cancer are all influenced by similar factors such as diet, habits and customs, environment and hereditary predisposition. On the other hand, these three carcinomas lie in different locations in alimentary canal, with different anatomical structure and different physiological function.This fact determins that these risk factors have distinctions in kind and character. In recent years, EGFR(epidermal growth factor receptor), Ras (Proto-oncogene ras) and CEA(carcinoembryonic antigen) protein were paid much attention to carcinomas genesis. Targeted therapy aimed at EGFR and Ras protein has been researched in recent years. By analyzing the expression of EGFR, Ras and CEA protein in esophageal cancer, gastric cancer and colorectal cancer, and their relationship with clinicopathological parameters, this project investigated the different roles of these three proteins in gastrointestinal cancer. By analyzing the different expression of EGFR, Ras and CEA protein in esophageal cancer, gastric cancer and colorectal cancer, this project intend to find targets for targeted therapy.
Methods:Surgically resected and pathologically proved cases of esophageal cancer, gastric cancer and colorectal cancer were collected. Information related to patiens'gender, age, tumor location, histological type and pathological stage were recorded. Complete clinical information were obtained in this study. None of these patients received either radiocherapy or chemocherapy before the surgery. The specimen cases were immunostainde to observe the expression of EGFR, Ras and CEA in esophageal cancer, gastric cancer cells and colorectal cancer cells. All the results were statistically analyzed with SPSS 11.5 software package.
Results:1.The positive expression rate of EGFR in gastric cancer group was obviously higher than colorectal cancer group(P<0.05). The positive rate of Ras expression in esophageal cancer group and gastric cancer group was obviously higher than colorectal cancer group(P<0.05). The positive rates of CEA expression in esophageal cancer group were obviously lower than colorectal cancer group(P<0.05).
2.The relationship between EGFR, Ras and CEA protein expression and clinical characteristics.
(1) In esophageal cancer group, the positive expression rate of EGFR, Ras and CEA have no obvious relationship with patiens'gender, age, tumour location, differention degree, depth of invasion and lymph node metastasis (P>0.05).
(2)In gastric cancer, the positive rate of EGFR protein expression in poor differentiation group was higher than well-moderate differentiation group(P<0.05); the positive expression rates of Ras in penetrated subserous layer group was higher than infiltrated to subserous layer group(P<0.05); the positive expression rate of CEA in distant metastasis group was higher than without distant metastasis group(P<0.05).
(3)In colorectal cancer, the positive rate of EGFR protein expression in infiltrated to subserous layer group was higher than penetrated subserous layer group(P<0.05); the positive rate of Ras protein expression in infiltrated to subserous layer group was higher than penetrated subserous layer group(P<0.05).
3.The correlation between EGFR, Ras and CEA protein expression.
(1)In esophageal cancer, EGFR protein expression was positively correlated with CEA protein expression(r=0.552, P<0.05). There was no significant correlation between EGFR and Ras expression(P>0.05), and the same as CEA and Ras expression.
(2)In gastric cancer, EGFR protein expression was positively corre- lated with CEA protein expression(r=0.457, P<0.05); Ras protein expres-sion is positively correlated with CEA protein expression(r=0.220, P<0.05). There was no significant correlation between EGFR and Ras expression (P>0.05).
(3)In colorectal cancer, EGFR protein expression was positively correlation with Ras protein expression(r=0.452, P<0.05). There was no significant correlation between EGFR and Ras expression(P>0.05), and the same as CEA and Ras expression.
Conclusions:1.The EGFR, Ras and CEA protein all have expression more or less in esophageal cancer, gastric cancer and colorectal cancer group. These three protein may play a part in carcinogenesis.
2.EGFR protein expression in gastric cancer, Ras protein expression in esophageal cancer and CEA protein expression in colorectal cancer were much higher than the other. The protein may be choosed as target for targeted therapy.
3.In gastric cancer the expression of EGFR protein has negative correlation to cell differentiation, the expression of Ras protein has positive correlation to depth of invasion, and the expression of CEA protein has positive correlation to distant metastasis.
4.EGFR and CEA protein expression has a close relationship in esophageal cancer and gastric cancer. Ras and CEA protein expression has a close relationship in gastric cancer. EGFR and Ras protein expression has a close relationship in colorectal cancer. These three protein may cooperate with each other in carcinogenesis.
引文
1.任占平,黄键辉,石喆,等.癌基因蛋白cyclinDl, p21ras在大肠癌和腺瘤组织中的表达[J].临床与实验病理学杂志,1999,15(1)：49-51.
2.赵华,冯大作,雷三林.大肠癌及癌旁粘膜中P21, P185, PCNA的表达[J].中国普通外科杂志,2000,4(9)：39-43.
3. Bazley LA, Gullick WJ. The epidermal growth factor receptor family[J]. Endocr Relat Cancer,2005,12(1):17-27.
4. Yarden Y. The EGFR family and its ligands in human cancer:signalling mecha-nisms and therapeutic opportunities[J]. Eur J Cancer,2001,37:S3-8.
5.刘宝全,范圣第.EGFR信号转导机制及靶向治疗[J].大连民族学院学报,2008,10(1)：13.
6. Wells A. EGF receptor[J]. Int J Biochem Cell Biol,1999,31(6):637-643.
7.廖小金.表皮生长因子结构和生物学效应[J].海峡药学,2006,18(5)：15.
8.宋丹,方秀斌.表皮生长因子的研究进展[J].解剖科学进展,2002,8(4)：339-340.
9.何太平,严卫红.Ras信号转导通路[J].国外医学临床生物化学与检验学分册,2004,25(1)：75.
10. Sebastian S, Settleman J, Reshkin SJ, et al. The complexity of targeting EGFR signalling in cancer:from expression to turnover[J].Biochim Biophys Acta,2006, 1766(1):120-139.
11. Hubbard SR, Miller WT. Receptor tyrosine kinases:mechanisms of activation and signaling[J]. Current Opinion in Cell Biology,2007,19(2):1 17-123.
12.Dawson JP, Berger MB, LN CC, et al. Epidermal growth factor receptor dimerization and activation require ligand-induced conformational changes in the dimer interface[J]. Molecular and Cellular Biology,2005,25(17):7734-7742.
13. Denning MF, Dlugosz AA, Cheng C, et al. Cross-talk between epidermal growth factor receptor and protein kinase C during calcium-induced differentiation of keratinocytes[J]. Exp Dermatol,2000,9:192-199.
14. Ono M, Kuwano M. Molecular mechanisms of epidermal growth factor receptor (EGFR) activation and response to gefitinib and other EGFR-targeting drugs[J]. Clin Cancer Res,2006,12(15):7242-7251.
15.Olayioye MA, Neve RM, Lane HA, et al. The ErbB signaling network:receptor heterodimerization in development and cancer[J]. The EMBO journal,2000,19 (13):3159-3167.
16. Chen P, Xie H, Sekar MC, et al. Epidermal growth factor receptor-mediated cell motility:phospholipase C activity is required, but mitogen-activated protein kinase activity is not sufficient for induced cell movement[J]. J Cell Biol,1994, 127(3):847-857.
17. Thomas SM, Coppelli FM, Wells A, et al. Epidermal gowth factor receptor-stimulated activation of phospholipase Cgamma-1 promotes invasion of head and neck squamous cell carcinoma[J]. Cancer Research,2003,63(17):5629-5635.
18.Calo V, Migliavacca M, Bazan V, et al. STAT proteins:from normal control of cellular events to tumorigenesis[J]. J Cell Physiol,2003,197(2):157-168.
19.Chin YE, Kitagawa M, Kuida K, et al. Activation of the STAT signaling pathway can cause expression of caspase 1 and apoptosis[J]. Mol Cell Biol,1997,17(9): 5328-5337.
20. Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib [J]. N Engl J Med,2004,350(21):2129-2139.
21.Paez JG, Janne PA, Lee JC, et al. EGFR mutations in lung cancer:correlation with clinical response to gefitinib therapy[J]. Science,2004,304(5676):1497-1500.
22. Kosaka T, Yatabe Y, Endoh H, et al. Analysis of epidermal growth factor receptor gene mutation in patients with non-small cell lung cancer and acquired resistance to gefitinib[J]. Clin Cancer Res,2006,12(19):5764-5769.
23. Pao W, Miller VA, Politi KA, et al. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain[J]. PLoS Med,2005,2(3):73.
24. Sasaki H, Shimizu S, Endo K, et al. EGFR and erbB2 mutation status in Japanese lung cancer patients[J]. Int J Cancer,2006,118(1):180-184.
25.董纯刚,黄进肃,黄建,等.肺癌靶向治疗进展和我国肺癌的EGFR基因突变的概况[J].肿瘤,2005,25(6)：625-634.
26.呼闯营,贺彩峰.TGF-α和EGFR在Barrett食管和食管腺癌的表达[J].世界华人消化杂志,2006,14(9)：879-883.
27. Salomon DS, Brandt R, Ciardiello F, et al. Epidermal growth factor-related peptides and their receptors in human malignancies[J]. Crit Rev Oncol Hematol, 1995,19(3):183-232.
28.翟洪涛,张齐联,翟晓梅,等.内镜超声、表皮生长因子受体,转化生长因子p-1受 体检查在大肠癌诊断中的价值[J].中华消化内镜杂志,2000,17(3)：1 37-140.
29. Sihto H, Puputti M, Pulli L, et al. Epidermal growth factor receptor domain II, IV, and kinase domain mutations in human solid tumors[J]. J Mol Med,2005,83 (12): 976-983.
30. Moscatello DK, Holgado-Madruga M, Emlet DR, et al. Constitutive activation of phosphatidylinositol 3-kinase by a naturally occurring mutant epidermal growth factor receptor[J]. J Biol Chem,1998,273(1):200-206.
31.刘国龙,张万岱,于宋刚,等.大肠癌组织中表皮生长因子受体的定量检测[J].胃肠病学和肝病学杂志,1994,3(4)：250-251.
32.冯作化.医学分子生物学.人民卫生出版社,2005,8,第1版.
33. Shiozaki H, Kadowaki T, Doki Y, et al. Effect of epidermal growth factor on cadherin-mediated adhesion in a human oesophageal cancer cell line[J]. Br J Cancer,1995,71(2):250-258.
34. Gerdes AM, Nielsen O, Mohr U, et al. Correlation between molecular genetic analyses and immunohistochemical evaluation of the epidermal growth factor receptor and p185HER2[J]. Anticancer Res,1998,18(4A):2529-2534.
35. Asano H, Toyooka S, Tokumo M, et al. Detection of EGFR gene mutation in lung cancer by mutant-enriched polymerase chain reaction assay[J]. Clin Cancer Res, 2006,12(1):43-48.
36. Saltz LB, Meropol NJ, Loehrer PJSr, et al. Phase Ⅱ trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor[J]. J Clin Oncol,2004,22(7):1201-1208.
37. Caponigro F, Basile M, Rosa V, et al. New drugs in cancer therapy, National Tumor Institute, Naples,17-18 June 2004[J]. Auticancer Drugs,2005,16(2):211-221.
38.吴东升,李明峰.大肠癌的靶向治疗[J].实用癌症杂志,2006,21(6)：654-655.
39. Shigematsu H, Takahashi T, Nomura M, et al. Somatic mutations of the HER2 kinase domain in lung adenocarcinomas[J]. Cancer Res,2005,65(5):1642-1646.
1.王茜,景学安,李栋.食管癌危险因素流行病学研究进展[J].泰山医学院学报,2007,28(12)：999-1002.
2.徐飚,王建明.胃癌流行病学研究[J].中华肿瘤防治杂志,2006,13(1)：1-7.
3.王双双,关景明,范玉晶.大肠癌发病的相关因素[J].世界华人消化杂志,2005,13(14)：534-536.
4.许良中,杨文涛.免疫组织化学反应结果的判断[J].中国癌症杂志,1996,6(4)：229-231.
5. Yarden Y. The EGFR family and its ligands in human cancer:signalling mecha-nisms and therapeutic opportunities[J]. Eur J Cancer,2001,37:3-8.
6.呼闯营,贺彩峰.TGF-α和EGFR在Barrett食管和食管腺癌的表达[J].世界华人消化杂志,2006；14(9)：879-883.
7.詹启敏主编,分子肿瘤学[M].第一版北京：人民卫生出版社,2005,71-72.
8. Yarden Y. The EGFR family and its ligands in human cancer. Signalling mechanisms and therapeutic opportunities[J]. Eur J Cancer,2001,37(4):3-8.
9.朱人敏,张予蜀.ras癌基因和大肠癌关系的研究[J].江苏医药,1 997,23(2)：103-104.
10. Maxwell P. Carcinoembryonic antigen:cell adhesion molecule and useful diagnostic marker[J]. Br J Biomed Sci,1999,56(3):209-214.
11. Hammarstrom S. The carcinoembryonic antigen(CEA)family:structures,suggested functions and expression in normal and malignant tissues[J]. Semin Cancer Biol, 1999,9(2):67-81.
12.Scorilas A, Chiang PM, Katsaros D, et al. Molecular characterization of a new gene, CEAL1, encoding for a carcinoembryonic antigen-like protein with a highly conserved domain of eukaryotic translation initiation factors[J]. Gene, 2003,310(5):79-89.
13.Eidelman FJ, Fuks A, Demarte L, et al. Human carcinoembryonic antigen,an intercellular adhesion molecule,blocks fusion and differentiation of rat myoblasts [J]. J Cell Biol,1993,123(2):467-475.
14. Kammerer R, von Kleist S. The cacinoembryonic antigen (CEA) modulates effector-target cell interaction by binding to activated lymphocytes[J]. Int J Cancer,1996,68(4):457-463.
15.何穗,李登清,李绍杰,等.CEA,CA199和CA724联合检测在结直肠癌诊断中的应 用[J].中国现代医学杂志,2004,14(18)：79-80.
16.李洪胜,王远东,谭小军,等.EGFR及E.cadherin表达与食管癌转移的关系[J].肿瘤研究与临床,2005,17(3)：175-177.
17.丁明杰,丁蔚,银德仁,等.表皮生长因子及其受体在食管癌中的表达[J].解剖学报,1999,30(1)：73-77.
18.于观贞,陈颖,潘军,等.ANXA1和EGFR在胃癌中的表达及与预后关系的研究[J].临床肿瘤学杂志,2008,13(8)：691-694.
19.朱曰林,张一楚,王瑞年,等.C.erbB.2和EGFR在胃癌中表达的研究[J].中国肿瘤临床,1996,23(12)：855-859.
20.吕洋,陈薇,赵坡.结直肠癌组织EGFR基因表达及其与临床意义的研究[J].中国肿瘤防治杂志,2008,15(3)：206-210.
21.侍立志,王兆春.EGF.EGFR和PCNA表达与大肠癌临床病理学特征及关系[J].中国普通外科杂志,2004,13(4)：253-256.
22.李建,赵治国,周琦,等.Ras蛋白在食管癌与癌前病变组织中的表达[J].中国肿瘤临床与康复,1 999；6(1)：1 1-1 2.
23.冯新海,刘琨,王忠华,等.P21 ras在食管鳞癌中表达的意义[J].临床与实验病理学杂志,1998,14(15)：516.
24.杜少陵,黄文斌,彭敦发,等.胃癌p53,p21 ras,nm23／NDPK基因表达及意义[J].临床与实验病理学杂志,1999,1 5(3)：215.
25.周戎二,陈力.胃癌组织中p53,C-erb β一2和Ras的表达及其临床意义[J].浙江医学,2008,30(1)：14-16,29.
26.赵华,冯大作,雷三林.大肠癌及癌旁粘膜中p21,p185,PCNA的表达及意义[J].中国普通外科杂志,2000,9(4)：321-325.
27.孙哲,高鹤立.P21 ras.P16在大肠癌中的表达及临床意义[J].世界华人消化杂志,2001,9(12)：1399-1403.
28.张宝玉,黄晓红,洪丰,等.CEA的表达与食管癌预后的关系[J].济宁医学院学报,2001,24(2)：47.
29.张惠忠,李海刚,黄洪铮,等.食管鳞癌细胞粘附分子的表达及其临床意义[J].癌症,1999,18增刊：52-55.
30.敖洪峰.胃腺癌中c-erbB一2,CEA,p53,E-cadherin,Ki一67,Bax的表达及其临床病理意义.2009,硕士学位论文.
31.张伟,唐仁泉,张宇,等.p53,CEA在胃黏膜上皮内瘤变及胃癌中的表达及其意义[J].中国厂矿医学,2009,22(4)：399-400.
32.陈子华,葛杰,陈志康.CDX2和CEA在人结肠癌组织中的表达及意义[J].中国现 代医学杂志,2008,18(14)：1991-1994.
33.何震宇,史传兵,闻浩,等.CEA, p53, Ki-67, GST-π在大肠癌组织表达及其相关性研究[J].肿瘤学杂志,2008,14(7)：575-577.
34. Wilkinson NW, Black JD, Roukhadze E, et al. Epidermal growth factor receptor expression correlates with histologic grade in resected esophageal adeno-carcinoma[J]. J Gastrointest Surg,2004,8(4):448-453.
35.陈海霞,武培敬,许艳梅,等.CD44v6, EGFR及nm23-H1基因蛋白在食管鳞癌组织中的表达及意义[J].肿瘤防治研究,2003,30(5)：388-390.
36. Tsugawa K, Yonemura Y, Hirono Y, et al. Amplification of the c-met, c-erbB-2 and epidermal growth factor receptor gene in human gastric cancers:correlation to clinical features[J]. Oncology,1998,55(5):475-481.
37.樊平,邹赛英,赵海华.EGFR和EGFRvⅢ在胃癌中的表达及意义[J].现代生物医学进展,2009,9(16)：3112-3114.
38. Goldstein NS, Armin M. Epidermal growth factor receptor immunohistochemical reactivity in patients with American Joint Committee on Cancer Stage IV colon adenocarcinoma:implications for a standardized scoring system[J]. Cancer,2001, 92(5):1331-1346.
39. Baretton GB, Aust DE. Intraepithelial neoplasia in ulcerative colitis:on the way to more diagnostic confidence[J]. Verh Dtsch Ges Pathol,2007,91:126-134.
40. Aoyagi K, Kohfuji K, Yano S, et al. Evaluation of the epidermal growth factor receptor (EGFR) and c-erbB-2 in superspreading-type and penetrating-type gastric carcinoma[J]. Kurume Med J,2001,48(3):197-200.
41. Garcia I, Vizoso F, Andicoechea A, et al. Clinical significance of epidermal growth factor receptor content in gastric cancer[J]. Int J Biol Markers,2001,16(3): 183-188.
42. Bos JL. Ras oncogenes in human cancer:a review[J]. Cancer Res,1989,49(17): 4682-4689.
43.Barbacid M. Ras oncogenes:their role in neoplasia[J]. Eur J Clin Invest,1990,20 (3):225-235.
44. Rak J, Mitsuhashi L, Bayko L, et al. Mutant ras oncogenes upregulate VEGF/VPF expression:implications for induction and inhibition of tumor angiogenesis[J]. Cancer Res,1995,55(20):4575-4580.
45.李健,牛正先,王立东.食管癌分子生物学的研究[J].世界华人消化杂志,1997,5(3)：189-191.
46. Galiana C, Fusco A, Martel N, et al. Possible role of activated ras genes in human esophageal carcinogenesis[J]. Int J Cancer,1993,54(6):978-982.
47. Sorsdahl K, Casson AG, Troster M, et al. p53 and ras gene expression in human esophageal cancer and Barrett's epithelium:a prospective study[J]. Cancer Detect Prev,1994,18(3):179-185.
48. Ruol A, Stephens JK, Michelassi F, et al. Expression of ras oncogene p21 protein in esophageal squamous cell carcinoma[J], J Surg Onol,1990,44(3):142-145.
49. Deng GR, Liu XH, Wang JR. Correlation of mutations of oncogene C-Ha-ras at codon 12 with metastasis and survival of gastric cancer patients[J]. Oncogene Res, 1991,6(1):33-38.
50. Cameiro F, David I, Sunkel C, et al. Immunohistochemical analysis of ras oncogene p21 product in human gastric carcinomas and their adjacent mucosas[J]. Pathol Res Pract,1992,188(3):263-272.
51.Collard JG, Schijven JF, Roos E. Invasive and metastatic potential induced by ras-transfection into mouse BW5147 T-lymphoma cells[J]. Cancer Res,1987,47 (3):754-759.
52.王瑞年,朱延波,薛建元,等.胃癌浸润转移与整合蛋白,Ⅳ型胶原酶以及细胞外基质的关系[J].中华病理学杂志,1994,23(5)：278-281.
53. Ura H, Bonfil RD, Reich R, et al. Expression of type Ⅳ collagenase and procollagen genes and its correlation with the tumorigenic,invasive, and metastatic abilities of oncogene-transformed human bronchial epithelial cells[J]. Cancer Res,1989,49(16):4615-4621.
54. Algarra I, Perez M, Serrano MJ, et al. C-K-ras overexpression is characteristic for metastases derived from a methylcholanthrene-induced fibrosarcoma[J]. Invasion Metastasis,1998-1999,18(5-6):261-270.
55.张宝玉,黄晓红,洪丰,等.CEA的表达与食管癌预后的关系[J].济宁医学院学报,200 1,24(2)：47.
56.Marrelli D, Pinto E, De Stefano A, et al. Clinical utility of CEA, CA 19-9, and CA72-4 in the follow-up of patients with resectable gastric cancer[J]. Am J Surg, 2001,181(1):16-19.
57.何科基.胃肠道癌CD44v6与CEAmRNA的表达及其临床意义[J].中国肿瘤临床与康复,2003,10(6)：512-515.
58. Teixeira CR, Tanaka S, Haruma K, et al. Carcinoembryonic antigen staining patterns at the invasive tumor margin predict the malignant potential of colorectal carcinoma[J]. Oncology,1994,51(3):228-233.
59.杨振宇,崔焌辉.CD44v6, nm23-H1和CEA在大肠癌组织中的表达及其临床意义[J].浙江临床医学,2008,10(6)：744-745.
60.肖接承.胃癌患者血清CEA在预后因素中的意义[J].国外医学.外科学分册,1999,26(2)：120-121.
61.Kitadai Y, Radinsky R, Bucana CD, et al. Regulation of Carcinoembryonic antigen expression in human colon carcinoma cells by the organ micro-environment[J]. Am J Pathol,1996,149(4):1157-1166.
62. Jessup JM, Petrick AT, Toth CA, et al. Carcinoembryonic antigen:enhancement of liver colonisation through retention of human colorectal carcinoma cells[J], Br J Cancer,1993,67(3):464-470.
63. Scartozzi M, Bearzi I, Berardi R, et al. Epidermal growth factor receptor (EGFR) downstream signalling pathway in primary colorectal tumours and related metastatic sites:optimising EGFR-targeted treatment options[J]. British Journal of Cancer,2007,97(1):92-97.
2.赵华,冯大作,雷三林.大肠癌及癌旁粘膜中P21, P185, PCNA的表达[J].中国普通外科杂志,2000,4(9)：39-43.
3. Bazley LA, Gullick WJ. The epidermal growth factor receptor family[J]. Endocr Relat Cancer,2005,12(1):17-27.
4. Yarden Y. The EGFR family and its ligands in human cancer:signalling mecha-nisms and therapeutic opportunities[J]. Eur J Cancer,2001,37:S3-8.
5.刘宝全,范圣第.EGFR信号转导机制及靶向治疗[J].大连民族学院学报,2008,10(1)：13.
6. Wells A. EGF receptor[J]. Int J Biochem Cell Biol,1999,31(6):637-643.
7.廖小金.表皮生长因子结构和生物学效应[J].海峡药学,2006,18(5)：15.
8.宋丹,方秀斌.表皮生长因子的研究进展[J].解剖科学进展,2002,8(4)：339-340.
9.何太平,严卫红.Ras信号转导通路[J].国外医学临床生物化学与检验学分册,2004,25(1)：75.
10. Sebastian S, Settleman J, Reshkin SJ, et al. The complexity of targeting EGFR signalling in cancer:from expression to turnover[J].Biochim Biophys Acta,2006, 1766(1):120-139.
11. Hubbard SR, Miller WT. Receptor tyrosine kinases:mechanisms of activation and signaling[J]. Current Opinion in Cell Biology,2007,19(2):1 17-123.
12.Dawson JP, Berger MB, LN CC, et al. Epidermal growth factor receptor dimerization and activation require ligand-induced conformational changes in the dimer interface[J]. Molecular and Cellular Biology,2005,25(17):7734-7742.
13. Denning MF, Dlugosz AA, Cheng C, et al. Cross-talk between epidermal growth factor receptor and protein kinase C during calcium-induced differentiation of keratinocytes[J]. Exp Dermatol,2000,9:192-199.
14. Ono M, Kuwano M. Molecular mechanisms of epidermal growth factor receptor (EGFR) activation and response to gefitinib and other EGFR-targeting drugs[J]. Clin Cancer Res,2006,12(15):7242-7251.
15.Olayioye MA, Neve RM, Lane HA, et al. The ErbB signaling network:receptor heterodimerization in development and cancer[J]. The EMBO journal,2000,19 (13):3159-3167.
16. Chen P, Xie H, Sekar MC, et al. Epidermal growth factor receptor-mediated cell motility:phospholipase C activity is required, but mitogen-activated protein kinase activity is not sufficient for induced cell movement[J]. J Cell Biol,1994, 127(3):847-857.
17. Thomas SM, Coppelli FM, Wells A, et al. Epidermal gowth factor receptor-stimulated activation of phospholipase Cgamma-1 promotes invasion of head and neck squamous cell carcinoma[J]. Cancer Research,2003,63(17):5629-5635.
18.Calo V, Migliavacca M, Bazan V, et al. STAT proteins:from normal control of cellular events to tumorigenesis[J]. J Cell Physiol,2003,197(2):157-168.
19.Chin YE, Kitagawa M, Kuida K, et al. Activation of the STAT signaling pathway can cause expression of caspase 1 and apoptosis[J]. Mol Cell Biol,1997,17(9): 5328-5337.
20. Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib [J]. N Engl J Med,2004,350(21):2129-2139.
21.Paez JG, Janne PA, Lee JC, et al. EGFR mutations in lung cancer:correlation with clinical response to gefitinib therapy[J]. Science,2004,304(5676):1497-1500.
22. Kosaka T, Yatabe Y, Endoh H, et al. Analysis of epidermal growth factor receptor gene mutation in patients with non-small cell lung cancer and acquired resistance to gefitinib[J]. Clin Cancer Res,2006,12(19):5764-5769.
23. Pao W, Miller VA, Politi KA, et al. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain[J]. PLoS Med,2005,2(3):73.
24. Sasaki H, Shimizu S, Endo K, et al. EGFR and erbB2 mutation status in Japanese lung cancer patients[J]. Int J Cancer,2006,118(1):180-184.
25.董纯刚,黄进肃,黄建,等.肺癌靶向治疗进展和我国肺癌的EGFR基因突变的概况[J].肿瘤,2005,25(6)：625-634.
26.呼闯营,贺彩峰.TGF-α和EGFR在Barrett食管和食管腺癌的表达[J].世界华人消化杂志,2006,14(9)：879-883.
27. Salomon DS, Brandt R, Ciardiello F, et al. Epidermal growth factor-related peptides and their receptors in human malignancies[J]. Crit Rev Oncol Hematol, 1995,19(3):183-232.
28.翟洪涛,张齐联,翟晓梅,等.内镜超声、表皮生长因子受体,转化生长因子p-1受 体检查在大肠癌诊断中的价值[J].中华消化内镜杂志,2000,17(3)：1 37-140.
29. Sihto H, Puputti M, Pulli L, et al. Epidermal growth factor receptor domain II, IV, and kinase domain mutations in human solid tumors[J]. J Mol Med,2005,83 (12): 976-983.
30. Moscatello DK, Holgado-Madruga M, Emlet DR, et al. Constitutive activation of phosphatidylinositol 3-kinase by a naturally occurring mutant epidermal growth factor receptor[J]. J Biol Chem,1998,273(1):200-206.
31.刘国龙,张万岱,于宋刚,等.大肠癌组织中表皮生长因子受体的定量检测[J].胃肠病学和肝病学杂志,1994,3(4)：250-251.
32.冯作化.医学分子生物学.人民卫生出版社,2005,8,第1版.
33. Shiozaki H, Kadowaki T, Doki Y, et al. Effect of epidermal growth factor on cadherin-mediated adhesion in a human oesophageal cancer cell line[J]. Br J Cancer,1995,71(2):250-258.
34. Gerdes AM, Nielsen O, Mohr U, et al. Correlation between molecular genetic analyses and immunohistochemical evaluation of the epidermal growth factor receptor and p185HER2[J]. Anticancer Res,1998,18(4A):2529-2534.
35. Asano H, Toyooka S, Tokumo M, et al. Detection of EGFR gene mutation in lung cancer by mutant-enriched polymerase chain reaction assay[J]. Clin Cancer Res, 2006,12(1):43-48.
36. Saltz LB, Meropol NJ, Loehrer PJSr, et al. Phase Ⅱ trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor[J]. J Clin Oncol,2004,22(7):1201-1208.
37. Caponigro F, Basile M, Rosa V, et al. New drugs in cancer therapy, National Tumor Institute, Naples,17-18 June 2004[J]. Auticancer Drugs,2005,16(2):211-221.
38.吴东升,李明峰.大肠癌的靶向治疗[J].实用癌症杂志,2006,21(6)：654-655.
39. Shigematsu H, Takahashi T, Nomura M, et al. Somatic mutations of the HER2 kinase domain in lung adenocarcinomas[J]. Cancer Res,2005,65(5):1642-1646.
1.王茜,景学安,李栋.食管癌危险因素流行病学研究进展[J].泰山医学院学报,2007,28(12)：999-1002.
2.徐飚,王建明.胃癌流行病学研究[J].中华肿瘤防治杂志,2006,13(1)：1-7.
3.王双双,关景明,范玉晶.大肠癌发病的相关因素[J].世界华人消化杂志,2005,13(14)：534-536.
4.许良中,杨文涛.免疫组织化学反应结果的判断[J].中国癌症杂志,1996,6(4)：229-231.
5. Yarden Y. The EGFR family and its ligands in human cancer:signalling mecha-nisms and therapeutic opportunities[J]. Eur J Cancer,2001,37:3-8.
6.呼闯营,贺彩峰.TGF-α和EGFR在Barrett食管和食管腺癌的表达[J].世界华人消化杂志,2006；14(9)：879-883.
7.詹启敏主编,分子肿瘤学[M].第一版北京：人民卫生出版社,2005,71-72.
8. Yarden Y. The EGFR family and its ligands in human cancer. Signalling mechanisms and therapeutic opportunities[J]. Eur J Cancer,2001,37(4):3-8.
9.朱人敏,张予蜀.ras癌基因和大肠癌关系的研究[J].江苏医药,1 997,23(2)：103-104.
10. Maxwell P. Carcinoembryonic antigen:cell adhesion molecule and useful diagnostic marker[J]. Br J Biomed Sci,1999,56(3):209-214.
11. Hammarstrom S. The carcinoembryonic antigen(CEA)family:structures,suggested functions and expression in normal and malignant tissues[J]. Semin Cancer Biol, 1999,9(2):67-81.
12.Scorilas A, Chiang PM, Katsaros D, et al. Molecular characterization of a new gene, CEAL1, encoding for a carcinoembryonic antigen-like protein with a highly conserved domain of eukaryotic translation initiation factors[J]. Gene, 2003,310(5):79-89.
13.Eidelman FJ, Fuks A, Demarte L, et al. Human carcinoembryonic antigen,an intercellular adhesion molecule,blocks fusion and differentiation of rat myoblasts [J]. J Cell Biol,1993,123(2):467-475.
14. Kammerer R, von Kleist S. The cacinoembryonic antigen (CEA) modulates effector-target cell interaction by binding to activated lymphocytes[J]. Int J Cancer,1996,68(4):457-463.
15.何穗,李登清,李绍杰,等.CEA,CA199和CA724联合检测在结直肠癌诊断中的应 用[J].中国现代医学杂志,2004,14(18)：79-80.
16.李洪胜,王远东,谭小军,等.EGFR及E.cadherin表达与食管癌转移的关系[J].肿瘤研究与临床,2005,17(3)：175-177.
17.丁明杰,丁蔚,银德仁,等.表皮生长因子及其受体在食管癌中的表达[J].解剖学报,1999,30(1)：73-77.
18.于观贞,陈颖,潘军,等.ANXA1和EGFR在胃癌中的表达及与预后关系的研究[J].临床肿瘤学杂志,2008,13(8)：691-694.
19.朱曰林,张一楚,王瑞年,等.C.erbB.2和EGFR在胃癌中表达的研究[J].中国肿瘤临床,1996,23(12)：855-859.
20.吕洋,陈薇,赵坡.结直肠癌组织EGFR基因表达及其与临床意义的研究[J].中国肿瘤防治杂志,2008,15(3)：206-210.
21.侍立志,王兆春.EGF.EGFR和PCNA表达与大肠癌临床病理学特征及关系[J].中国普通外科杂志,2004,13(4)：253-256.
22.李建,赵治国,周琦,等.Ras蛋白在食管癌与癌前病变组织中的表达[J].中国肿瘤临床与康复,1 999；6(1)：1 1-1 2.
23.冯新海,刘琨,王忠华,等.P21 ras在食管鳞癌中表达的意义[J].临床与实验病理学杂志,1998,14(15)：516.
24.杜少陵,黄文斌,彭敦发,等.胃癌p53,p21 ras,nm23／NDPK基因表达及意义[J].临床与实验病理学杂志,1999,1 5(3)：215.
25.周戎二,陈力.胃癌组织中p53,C-erb β一2和Ras的表达及其临床意义[J].浙江医学,2008,30(1)：14-16,29.
26.赵华,冯大作,雷三林.大肠癌及癌旁粘膜中p21,p185,PCNA的表达及意义[J].中国普通外科杂志,2000,9(4)：321-325.
27.孙哲,高鹤立.P21 ras.P16在大肠癌中的表达及临床意义[J].世界华人消化杂志,2001,9(12)：1399-1403.
28.张宝玉,黄晓红,洪丰,等.CEA的表达与食管癌预后的关系[J].济宁医学院学报,2001,24(2)：47.
29.张惠忠,李海刚,黄洪铮,等.食管鳞癌细胞粘附分子的表达及其临床意义[J].癌症,1999,18增刊：52-55.
30.敖洪峰.胃腺癌中c-erbB一2,CEA,p53,E-cadherin,Ki一67,Bax的表达及其临床病理意义.2009,硕士学位论文.
31.张伟,唐仁泉,张宇,等.p53,CEA在胃黏膜上皮内瘤变及胃癌中的表达及其意义[J].中国厂矿医学,2009,22(4)：399-400.
32.陈子华,葛杰,陈志康.CDX2和CEA在人结肠癌组织中的表达及意义[J].中国现 代医学杂志,2008,18(14)：1991-1994.
33.何震宇,史传兵,闻浩,等.CEA, p53, Ki-67, GST-π在大肠癌组织表达及其相关性研究[J].肿瘤学杂志,2008,14(7)：575-577.
34. Wilkinson NW, Black JD, Roukhadze E, et al. Epidermal growth factor receptor expression correlates with histologic grade in resected esophageal adeno-carcinoma[J]. J Gastrointest Surg,2004,8(4):448-453.
35.陈海霞,武培敬,许艳梅,等.CD44v6, EGFR及nm23-H1基因蛋白在食管鳞癌组织中的表达及意义[J].肿瘤防治研究,2003,30(5)：388-390.
36. Tsugawa K, Yonemura Y, Hirono Y, et al. Amplification of the c-met, c-erbB-2 and epidermal growth factor receptor gene in human gastric cancers:correlation to clinical features[J]. Oncology,1998,55(5):475-481.
37.樊平,邹赛英,赵海华.EGFR和EGFRvⅢ在胃癌中的表达及意义[J].现代生物医学进展,2009,9(16)：3112-3114.
38. Goldstein NS, Armin M. Epidermal growth factor receptor immunohistochemical reactivity in patients with American Joint Committee on Cancer Stage IV colon adenocarcinoma:implications for a standardized scoring system[J]. Cancer,2001, 92(5):1331-1346.
39. Baretton GB, Aust DE. Intraepithelial neoplasia in ulcerative colitis:on the way to more diagnostic confidence[J]. Verh Dtsch Ges Pathol,2007,91:126-134.
40. Aoyagi K, Kohfuji K, Yano S, et al. Evaluation of the epidermal growth factor receptor (EGFR) and c-erbB-2 in superspreading-type and penetrating-type gastric carcinoma[J]. Kurume Med J,2001,48(3):197-200.
41. Garcia I, Vizoso F, Andicoechea A, et al. Clinical significance of epidermal growth factor receptor content in gastric cancer[J]. Int J Biol Markers,2001,16(3): 183-188.
42. Bos JL. Ras oncogenes in human cancer:a review[J]. Cancer Res,1989,49(17): 4682-4689.
43.Barbacid M. Ras oncogenes:their role in neoplasia[J]. Eur J Clin Invest,1990,20 (3):225-235.
44. Rak J, Mitsuhashi L, Bayko L, et al. Mutant ras oncogenes upregulate VEGF/VPF expression:implications for induction and inhibition of tumor angiogenesis[J]. Cancer Res,1995,55(20):4575-4580.
45.李健,牛正先,王立东.食管癌分子生物学的研究[J].世界华人消化杂志,1997,5(3)：189-191.
46. Galiana C, Fusco A, Martel N, et al. Possible role of activated ras genes in human esophageal carcinogenesis[J]. Int J Cancer,1993,54(6):978-982.
47. Sorsdahl K, Casson AG, Troster M, et al. p53 and ras gene expression in human esophageal cancer and Barrett's epithelium:a prospective study[J]. Cancer Detect Prev,1994,18(3):179-185.
48. Ruol A, Stephens JK, Michelassi F, et al. Expression of ras oncogene p21 protein in esophageal squamous cell carcinoma[J], J Surg Onol,1990,44(3):142-145.
49. Deng GR, Liu XH, Wang JR. Correlation of mutations of oncogene C-Ha-ras at codon 12 with metastasis and survival of gastric cancer patients[J]. Oncogene Res, 1991,6(1):33-38.
50. Cameiro F, David I, Sunkel C, et al. Immunohistochemical analysis of ras oncogene p21 product in human gastric carcinomas and their adjacent mucosas[J]. Pathol Res Pract,1992,188(3):263-272.
51.Collard JG, Schijven JF, Roos E. Invasive and metastatic potential induced by ras-transfection into mouse BW5147 T-lymphoma cells[J]. Cancer Res,1987,47 (3):754-759.
52.王瑞年,朱延波,薛建元,等.胃癌浸润转移与整合蛋白,Ⅳ型胶原酶以及细胞外基质的关系[J].中华病理学杂志,1994,23(5)：278-281.
53. Ura H, Bonfil RD, Reich R, et al. Expression of type Ⅳ collagenase and procollagen genes and its correlation with the tumorigenic,invasive, and metastatic abilities of oncogene-transformed human bronchial epithelial cells[J]. Cancer Res,1989,49(16):4615-4621.
54. Algarra I, Perez M, Serrano MJ, et al. C-K-ras overexpression is characteristic for metastases derived from a methylcholanthrene-induced fibrosarcoma[J]. Invasion Metastasis,1998-1999,18(5-6):261-270.
55.张宝玉,黄晓红,洪丰,等.CEA的表达与食管癌预后的关系[J].济宁医学院学报,200 1,24(2)：47.
56.Marrelli D, Pinto E, De Stefano A, et al. Clinical utility of CEA, CA 19-9, and CA72-4 in the follow-up of patients with resectable gastric cancer[J]. Am J Surg, 2001,181(1):16-19.
57.何科基.胃肠道癌CD44v6与CEAmRNA的表达及其临床意义[J].中国肿瘤临床与康复,2003,10(6)：512-515.
58. Teixeira CR, Tanaka S, Haruma K, et al. Carcinoembryonic antigen staining patterns at the invasive tumor margin predict the malignant potential of colorectal carcinoma[J]. Oncology,1994,51(3):228-233.
59.杨振宇,崔焌辉.CD44v6, nm23-H1和CEA在大肠癌组织中的表达及其临床意义[J].浙江临床医学,2008,10(6)：744-745.
60.肖接承.胃癌患者血清CEA在预后因素中的意义[J].国外医学.外科学分册,1999,26(2)：120-121.
61.Kitadai Y, Radinsky R, Bucana CD, et al. Regulation of Carcinoembryonic antigen expression in human colon carcinoma cells by the organ micro-environment[J]. Am J Pathol,1996,149(4):1157-1166.
62. Jessup JM, Petrick AT, Toth CA, et al. Carcinoembryonic antigen:enhancement of liver colonisation through retention of human colorectal carcinoma cells[J], Br J Cancer,1993,67(3):464-470.
63. Scartozzi M, Bearzi I, Berardi R, et al. Epidermal growth factor receptor (EGFR) downstream signalling pathway in primary colorectal tumours and related metastatic sites:optimising EGFR-targeted treatment options[J]. British Journal of Cancer,2007,97(1):92-97.