Syndecan-1在肝细胞癌的表达及其与肿瘤转移、增殖和血管生成的相关性研究
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摘要
研究背景：
肝细胞癌(Hepatocellular carcinoma, HCC)是世界第五大恶性肿瘤,全世界肝癌患者中我国约占55%,男性发病率是女性的4-5倍。在我国农村居肿瘤相关死亡率第一位,城市肿瘤相关死亡率仅次于肺癌,居第二位。手术切除和肝移植是治愈HCC的两大手段,但长期生存取决于诊断时的分期。早期HCC患者的1、3、5年生存率分别为93.5%、70.1%和59.1%；中期HCC患者的1、3、5年生存率分别为65.3%、30.5%和23.5%；晚期HCC患者的半年、1年生存率分别为52.5%、14.7%。HCC的治疗难点在于：①大多数患者具有乙肝和肝硬化背景,常合并肝功能障碍；②发病年龄相对较低,起病隐匿,进展迅速,容易发生肝内播散和远处转移；③仅部分患者可接受手术治疗(少于20%),根治性切除率更低；④手术后复发率高。与过去30年纵向比较,由于诊断水平的提高,早期HCC确诊率增高,手术切除比例增高,非手术疗法的进步,我国HCC的生存期及生存率已获得了显著改善。但与乳腺癌、结直肠癌等横向比较,HCC总生存率低、生存期短,主要原因归结为：对于其发生、发展机制了解不够,无法进行针对性治疗,因而探寻HCC的分子机制是目前迫切的需要。HCC发生、发展和转移与细胞信号传导通路和新生血管增生异常等密切相关,其中存在多个关键性环节,是进行分子靶向治疗的理论基础和重要潜在靶点。近年来,分子靶向药物治疗HCC已成为研究热点。索拉非尼是一种口服多靶点、多激酶抑制剂,抑制肿瘤血管生成和肿瘤增殖。基于两项随机、双盲、平行对照的多中心Ⅲ期临床研究结果(SHARP和Oriental研究),索拉非尼能显著延长晚期HCC患者的总生存期和至疾病进展时间,2008年欧洲EMEA、美国FDA和我国SFDA已相继批准索拉非尼用于不能手术切除和远处转移的晚期HCC的标准治疗选择之一。
Syndecan-1是硫酸类肝素蛋白聚糖家族(Heparin-sulphate proteoglycans, HSPGs)的syndecans亚家族成员之一,表达于多种类型细胞表面,通过与肿瘤微环境(Tumor microenvironment)中间质细胞、细胞外基质成分(Extracellular matrix, ECM)、生物活性分子等相互作用,影响肿瘤细胞增殖、粘附、迁移及血管生成等过程。Syndecan-1在不同肿瘤表达水平及临床病理意义不同。有研究表明,syndecan-1表达下降与肿瘤恶性表型有关,细胞表面syndecan-1表达下降使细胞粘附减弱,转移潜力增强。然而,尽管胰腺癌及多发性骨髓瘤肿瘤细胞表面表达syndecan-1,亦容易发生远处转移。
目前关于syndecan-1与HCC相关性研究,主要从syndecan-1在HCC组织表达的临床病理意义方面阐述,可能机制报道甚少。数个研究结果显示syndecan-1表达缺失或下降与HCC分化不良、侵袭转移等恶性表型有关。但是,也有研究显示syndecan-1高表达于HCC低分化癌组织中,与上述研究的结论相互矛盾。
研究目的：
了解syndecan-1在HCC原发灶、癌旁肝组织及肝内转移灶的表达强度,探讨syndecan-1在HCC原发灶表达强度与临床病理因素的相关性,及其与肿瘤转移,增殖和血管生成的关系。
研究方法：
1.应用免疫组织化学(Immunohistochemistry, IHC)方法检测syndecan-1在HCC原发灶、癌旁肝组织和肝内转移灶的表达,血管内皮生长因子(Vascularendothelial growth factor, VEGF)、CD34-微血管密度(Microvessel density，MVD)在原发灶和肝内转移灶的表达及Ki-67在原发灶的表达。
(1)比较30例HCC原发灶、癌旁肝组织及肝内转移灶中syndecan-1表达强度的差异；
(2)分析30例HCC原发灶中syndecan-1表达强度与HCC临床病理因素(包括临床分期、肿瘤大小、分级、血清AFP水平、Child-Pugh肝功能分级、是否伴有肝硬化及癌栓)之间的关系；
(3)分析30例HCC原发灶中syndecan-1表达强度与Ki-67增殖指数之间的关系；
(4)比较30例HCC原发灶及肝内转移灶中VEGF表达强度及CD34-MVD的差异；
(5)分析30例HCC原发灶中syndecan-1表达强度与VEGF表达强度及CD34-MVD之间的关系；
(6)分析30例HCC肝内转移灶中syndecan-1表达强度与VEGF表达强度及CD34-MVD之间的关系。2.统计学方法：应用SPSS 13.0软件进行统计学处理,P<0.05则认为具有显著性差异；原发灶、癌旁肝组织及肝内转移灶中syndecan-1表达强度比较采用Kruska-Wallis检验；syndecan-1表达与HCC临床病理因素的关系用Wilcoxon检验(2组比较)或Kruska-Wallis检验(3组比较)；VEGF和CD34-MVD在原发灶与肝内转移灶的比较分别采用Wilcoxon检验和两样本t检验；syndecan-1与Ki-67指数、VEGF及CD34-MVD的相关性采用Spearman相关性检验。
研究结果：
1. Syndecan-1在HCC原发灶中表达增强,在癌旁肝组织中低表达,在肝内转移灶的表达强度显著低于原发灶。
HCC原发灶中syndecan-1高、中、低、无表达者例数分别为9、15、4、2,癌旁肝组织中syndecan-1高、中、低、无表达者例数分别为1、15、14、0,肝内转移灶中syndecan-1高、中、低、无表达者例数分别为0、6、17、7。三组间syndecan-1表达强度有显著性差异(χ2=25.62, P< 0.001)。
2.原发灶中syndecan-1表达强度与HCC临床分期、肿瘤大小、分级、血清AFP水平、Child-Pugh分级、是否伴有肝硬化及癌栓均无关。
Syndecan-1在HCC原发灶中表达强度在临床分期(P=0.143)、肿瘤大小(P=0.980)、分级(P=0.102)、血清AFP水平(P=0.432)、Child-Pugh分级(P=0.822)、是否伴有肝硬化及癌栓间(P分别为0.573和O.137)均无显著性差异。
3.HCC原发灶中syndecan-1表达强度与Ki-67增殖指数呈显著正相关。
HCC原发灶中syndecan-1高、中、低、无表达者的Ki-67增殖指数分别为22.8±20.2%、21.6±21.5%、4.8±8.7%和0.3±0.4%,syndecan-1表达强度与Ki-67增殖指数呈显著正相关(r=0.386,P=0.035)。
4. VEGF表达及CD34-MVD在HCC原发灶及肝内转移灶中无统计学差异。
(1)HCC原发灶中VEGF高、中、低表达例数分别为15、10、5,肝内转移灶中高、中、低表达例数分别为13、15、2,两组间无统计学差异(W=912.5,P=0.968)。
(2)HCC原发灶及肝内转移灶中CD34-MVD分别为308.3-150.0／mm2、329.1±155.4／mm2,两者间无统计学差异(t=-0.528,P=0.600)。
5.HCC原发灶中syndecan-1表达强度与VEGF表达强度、CD34-MVD无统计学相关,但与CD34-MVD之间存在正相关趋势。
HCC原发灶中syndecan-1表达强度与VEGF表达强度无统计学相关性(r=0.319,P=0.086)；原发灶syndecan-1表达强度与CD34-MVD之间无统计学相关性,但存在正相关趋势,在原发灶syndecan-1高、中、低、无表达者的CD34-MVD分别为329.3±140.2/mm2、319.7±176.0/mm2、206.3±66.0/mm2和(?)331.9±8.9/mm2(r= 0.200, P=0.290)。
6.HCC肝内转移灶中syndecan-1表达强度与VEGF表达强度无统计学相关性,与CD34-MVD之间呈显著正相关关系。
HCC肝内转移灶中syndecan-1表达强度与VEGF表达强度无统计学相关性(r=0.124 P=0.513)；肝内转移灶syndecan-1表达强度与CD34-MVD之间呈显著正相关关系,syndecan-1中、低、无表达者的CD34-MVD分别为425.3±121.5／mm2、326.2±170.7/mm2、253.7±103.6/mm2 (r=0.370, P=0.044)。
研究结论：
1. Syndecan-1在HCC肝内转移灶的表达强度显著低于原发灶及癌旁组织,提示syndecan-1表达下降或缺失可能与HCC转移有关。胞膜syndecan-1表达下降或缺失的肿瘤细胞,由于其与基质之间粘附减弱,自由度增大,导致其侵袭转移潜力增强,易于进入循环,形成肝内外转移瘤。
2.HCC原发灶中syndecan-1表达强度与肿瘤细胞增殖指数呈正相关,syndecan-1可能作为多种生长因子的共受体,刺激肿瘤生长。
3.HCC组织中syndecan-1表达强度与肿瘤新生血管呈正相关,提示syndecan-1可能通过易化促血管生成因子相应受体的二聚化过程,增强促血管生成效应,促进肿瘤生长、转移。
4.HCC组织中syndecan-1表达可能影响肿瘤转移、增殖和血管生成。HCC肿瘤细胞的转移可能需要syndecan-1从膜表面脱落、缺失,当肿瘤细胞发生转移,定植于转移部位后,syndecan-1重新在膜表面表达,再次促进肿瘤生长、血管生成。提示syndecan-1在HCC生长和转移中的特殊作用可能为HCC有效治疗策略提供新思路。
Background:
Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world, and the second most common cause of cancer mortality, with a male-female ratio of 4-5:1 in high incidence regions, such as China, which alone accounts for 55% of the world's cases. Hepatic resection and liver transplantation are the two main modalities that may cure HCC, but the long-term patient survival is dependent on the stage of tumor at the time of diagnosis. The treatment challenges of HCC include:①Most of HCC patients with a background in hepatitis B and cirrohsis, usually complicate with abnormal hepatic function;②HCC in the olderly are usually occult in onset and prone to intrahepatic and extrahepatic metastasis, and progress rapidly;③Surgical resection rate is less than 20%, and radical resection rate is lower;④The rate of postoperative recurrence is rather high.The one-year survival rate, three-year survival rate and five-year survival rate were 93.5%,70.1% and 59.1% respectively for the early stage HCC patients. and 65.3%,30.5% and 23.5% respectively for the median stage HCC patients. The half-year, one-year survival rate for the advanced stage HCC patients were 52.5% and 14.7% respectively. Longitudinally compared with the situation of past few decades, the prognosis of HCC has been improved greatly, which was due to improvement of diagnostic lever in the early stage, increasing of the overall resection rate and progress of non-operation treatment. However, in horizontal comparison with breast cancer and colorectal cancer, the outcome for patients with HCC still remains dismal. Currently the mechanism underlying the contribution to tumorigenesis and tumor promotion of HCC is not clear precisely, and the patients cannot receive targeted intervention, which causes poor prognosis of HCC. Therefore, futher exploring the molecular mechanisms that modulate the development and progression of HCC is crucial for the design of therapeutic strategies. There are several pivotal steps in the cell signal transduction and angiogenesis of HCC, whose abnormalities lead to the development, progress and metastasis of HCC, which are the theoretical principles of molecular targeted therapy and the potential key targets. In recent years, the research of HCC molecular targeted therapy has been hot spots. Sorafenib is an oral multikinase inhibitor with antiproliferative and antiangiogenic effects. Based on two multicenter phaseⅢ, randomized, double-blind, placebo-controlled clinical trial (SHARP and Oriental) which showed Sorafenib improved survival in patients with advanced (unresectable and metastatic) HCC, Sorafenib was approved to be used as standard treatment regimen in patients with advanced HCC by EMEA, FDA and SFDA at serial.
Syndecan-1 is a member of syndecans subfamily which belongs to HSPGs. Syndecan-1 is expressed on the surfaces of many cell types and has been shown to modulate tumor cell proliferation, adhesion, migration and angiogenesis, by interacting with stromal cells, extracellular matrix and bioactive moleculars in tumor microenvironment. Expression of syndecan-1 is often alterd in cancer, and several studies suggest that loss of syndecan-1 expression in carcinomas accompany the malignant phenotype. It has been suggested that the loss of syndecan-1 expression render the tumor cells less adhesive, thereby increasing their potential to metatasize. However, in other cancers, such as pancreatic adenocarcinoma and multiple myeloma, syndecan-1 expression on the cell surface remains high even though these tumors disseminate to sites distal from the primary tumor.
The research concerning the correlation between syndecan-1 and HCC has been carried on, mainly including the clinicopathological significance of expression of syndecan-1. The potential mechanism was litter reported. Several research results showed that the loss of syndecan-1 was associated with HCC malignant phenotype, such as poor differentiation, invasion and metastasis. However, the result of another similar research showed that syndecan-1 was highly expressed in poor differentiated HCC. It was contradictory to those of previous studies.
Objective:
To investigate the expression levers of syndecan-1 in HCC primary tumors, adjacent non-tumor live tissues and intrahepatic metastasis tumors, the clinicopathological significance of syndecan-1 in HCC primary tumors and the relationship between syndecan-1 and tumor metastasis, proliferation and angiogenesis in HCC.
Methods:
1. In the study, immunohistochemical staining was utilized for determing syndecan-1 expression in HCC primary tumors, adjacent non-tumor live tissues and intrahepatic metastasis tumors, VEGF and CD34-MVD in primary tumors and intrahepatic metastasis tumors, and Ki-67 in primary tumors.
(1) Compare the differences of the expression levels of syndecan-1 in HCC primary tumors, adjacent non-tumor live tissues and intrahepatic metastasis tumors;
(2) Analysis the correlations between syndecan-1 expression in HCC primary tumors and gender, age, clinical stage, tumor size, differentiation, serum AFP level, Child-Pugh grade, presence of cirrhosis and thrombosis;
(3) Analysis the correlation between syndecan-1 expression and Ki-67 index in HCC primary tumors;
(4) Compare the differences of VEGF expression and CD34-MVD in HCC primary tumors and intrahepatic metastasis tumors;
(5) Analysis the correlations between syndecan-1 expression and VEGF expression and CD34-MVD in HCC primary tumors;
(6) Analysis the correlations between syndecan-1 expression and VEGF expression and CD34-MVD in HCC intrahepatic metastasis tumors.
2. Statistical methods:All statistical analyses were performed using SPSS program package 13.0. Differences were considered as significant when the P value was less than 0.05. Comparison among groups of the rank material was evaluated with the Kruska-Wallis's test, and the measurement material with the independent-samples t test; The clinicopathological significance of syndecan-1 expression in HCC primary tumors was estimated with the generalized Wilcoxon's test (or the Kruska-Wallis's test, where appropriate). The relationship between syndecan-1 expression and VEGF, CD34-MVD and Ki-67 index uses the Spearman correlation analysis.
Results:
1. Compared with adjacent non-tumor live tissues, syndecan-1 expression in HCC primary tumors were significantly enhanced. On contrast, syndecan-1 expression were significantly reduced in intrahepatic metastasis tumors.
The cases of high, middle, low and no syndecan-1 expression in HCC primary tumors were 9,15,4 and 2 respectively. The cases of high, middle, low and no syndecan-1 expression in adjacent non-tumor live tissues were 1,15,14 and 0 respectively. The cases of high, middle, low and no syndecan-1 expression in intrahepatic metastasis tumors were 0,6,17 and 7 respectively. The difference of syndecan-1 expression among three groups was statistically significant (χ2=25.62, P<0.001).
2. Syndecan-1 expression in primary tumors was not associated with HCC clinical stage, tumor size, differentiation, serum AFP level, Child-Pugh grade, presence of cirrhosis and thrombosis.
Syndecan-1 expression in HCC primary tumors was not associated with HCC clinical stage (P=0.143), tumor size (P=0.980), differentiation (P=0.102), serum AFP level (P=0.432), Child-Pugh grade (P=0.822), presence of cirrhosis and thrombosis (P=0.573 and 0.137, respectively)
3. Syndecan-1 expression was positively correlated with the Ki-67 index in HCC primary tumors.
The Ki-67 index were 22.8±20.2%,21.6±21.5%,4.8±8.7% and 0.3±0.4% respectively in HCC patients with high, middle, low and no syndecan-1 expression in primary tumors. Syndecan-1 expression was positively associated with Ki-67 index (r= 0.386, P=0.035).
4.The VEGF expression and CD34-MVD between HCC primary tumors and intrahepatic metastasis tumors was not different significantly.
The cases of high, middle, low VEGF expression were 15,10,9 in HCC primary tumors respectively, and 13,15,2 in intrahepatic metastasis tumors respectively, there was no statistical significance between two groups (W=912.5, P=0.968)
CD34-MVD were 308.3±150.0/mm2 and 329.1±155.4/mm2 in HCC primary tumors and intrahepatic metastasis tumors respectively, there was no statistical significance between two groups (t=-0.528, P=0.600).
5. In HCC primary tumors, syndecan-1 expression was not associated with the expression of VEGF; Even though there was no statistical significance, a tendency of positive correlation was found between syndecan-1 expression and CD34-MVD.
Syndecan-1 expression was not associated with the expression of VEGF in HCC primary tumors (r= 0.319, P=0.086). There was no statistical significance but a positive correlation tendency between syndecan-1 expression and CD34-MVD in primary tumors (r= 0.200, P=0.290). CD34-MVD were 329.3±140.2/mm2, 319.7±176.0/mm2,206.3±66.0/mm2 and 331.9±8.9/mm2 respectively in HCC patients with high, middle, low and no syndecan-1 expression.
6. In HCC intrahepatic metastasis tumors, syndecan-1 expression was not associated with the expression of VEGF; Syndecan-1 expression was positively correlated with CD34-MVD.
Syndecan-1 expression was not associated with the expression of VEGF in intrahepatic metastasis tumors (r=0.124, P=0.513). Syndecan-1 expression was positively correlated with CD34-MVD in intrahepatic metastasis tumors (r= 0.370, P=0.044). CD34-MVD were 425.3±121.5/mm2,326.2±170.7/mm2 and 253.7±103.6/ mm2 respectively in HCC patients with middle, low and no syndecan-1 expression.
Conclusions:
1. Syndecan-1 expression in HCC intrahepatic metastasis tumors was significantly lower than primary tumors and adjacent non-tumor live tissues. It was suggested that the loss of syndecan-1 expression was associated with HCC metastasis. One possibility was that syndecan-1 function in both cell-cell and cell-extracellular matrix adhesion, and the tumor cells that lost syndecan-1 gain freedom (lost their attachment in matrix) and enable to go to circulation and home in distal sites.
2. Syndecan-1 expression was positively associated with cell proliferation. Syndecan-1 may bind growth factors, decisively regulate growth factor signaling and stimulate tumor cell proliferation.
3. Syndecan-1 expression was positively correlated with CD34-MVD, suggesting that as co-receptors, syndecan-1 may stimulate angiogenic factor receptor tyrosine kinase activity.
4. Syndecan-1 on tumor cells surface may promote tumor growth and angiogenesis as co-receptors of many growth factors, but at same time syndecan-1 sticks tumor cells on matrix. Tumor cells need to reduce syndecan-1 on their surface (e.g., by shedding syndecan-1 to the matrix) to be able to gain freedom and perform metastasis. Once tumor cells arrive in metastatic site, they produce surface syndecan-1 again to support the growth and angiogenesis of the tumors. Syndecan-1 may affect tumor metastasis, proliferation and angiogenesis, suggesting that syndecan-1 play a special role in the progress of HCC and may provide new ideas for treatment strategies for HCC.
肝细胞癌(Hepatocellular carcinoma, HCC)是世界第五大恶性肿瘤,全世界肝癌患者中我国约占55%,男性发病率是女性的4-5倍。在我国农村居肿瘤相关死亡率第一位,城市肿瘤相关死亡率仅次于肺癌,居第二位。手术切除和肝移植是治愈HCC的两大手段,但长期生存取决于诊断时的分期。早期HCC患者的1、3、5年生存率分别为93.5%、70.1%和59.1%；中期HCC患者的1、3、5年生存率分别为65.3%、30.5%和23.5%；晚期HCC患者的半年、1年生存率分别为52.5%、14.7%。HCC的治疗难点在于：①大多数患者具有乙肝和肝硬化背景,常合并肝功能障碍；②发病年龄相对较低,起病隐匿,进展迅速,容易发生肝内播散和远处转移；③仅部分患者可接受手术治疗(少于20%),根治性切除率更低；④手术后复发率高。与过去30年纵向比较,由于诊断水平的提高,早期HCC确诊率增高,手术切除比例增高,非手术疗法的进步,我国HCC的生存期及生存率已获得了显著改善。但与乳腺癌、结直肠癌等横向比较,HCC总生存率低、生存期短,主要原因归结为：对于其发生、发展机制了解不够,无法进行针对性治疗,因而探寻HCC的分子机制是目前迫切的需要。HCC发生、发展和转移与细胞信号传导通路和新生血管增生异常等密切相关,其中存在多个关键性环节,是进行分子靶向治疗的理论基础和重要潜在靶点。近年来,分子靶向药物治疗HCC已成为研究热点。索拉非尼是一种口服多靶点、多激酶抑制剂,抑制肿瘤血管生成和肿瘤增殖。基于两项随机、双盲、平行对照的多中心Ⅲ期临床研究结果(SHARP和Oriental研究),索拉非尼能显著延长晚期HCC患者的总生存期和至疾病进展时间,2008年欧洲EMEA、美国FDA和我国SFDA已相继批准索拉非尼用于不能手术切除和远处转移的晚期HCC的标准治疗选择之一。
Syndecan-1是硫酸类肝素蛋白聚糖家族(Heparin-sulphate proteoglycans, HSPGs)的syndecans亚家族成员之一,表达于多种类型细胞表面,通过与肿瘤微环境(Tumor microenvironment)中间质细胞、细胞外基质成分(Extracellular matrix, ECM)、生物活性分子等相互作用,影响肿瘤细胞增殖、粘附、迁移及血管生成等过程。Syndecan-1在不同肿瘤表达水平及临床病理意义不同。有研究表明,syndecan-1表达下降与肿瘤恶性表型有关,细胞表面syndecan-1表达下降使细胞粘附减弱,转移潜力增强。然而,尽管胰腺癌及多发性骨髓瘤肿瘤细胞表面表达syndecan-1,亦容易发生远处转移。
目前关于syndecan-1与HCC相关性研究,主要从syndecan-1在HCC组织表达的临床病理意义方面阐述,可能机制报道甚少。数个研究结果显示syndecan-1表达缺失或下降与HCC分化不良、侵袭转移等恶性表型有关。但是,也有研究显示syndecan-1高表达于HCC低分化癌组织中,与上述研究的结论相互矛盾。
研究目的：
了解syndecan-1在HCC原发灶、癌旁肝组织及肝内转移灶的表达强度,探讨syndecan-1在HCC原发灶表达强度与临床病理因素的相关性,及其与肿瘤转移,增殖和血管生成的关系。
研究方法：
1.应用免疫组织化学(Immunohistochemistry, IHC)方法检测syndecan-1在HCC原发灶、癌旁肝组织和肝内转移灶的表达,血管内皮生长因子(Vascularendothelial growth factor, VEGF)、CD34-微血管密度(Microvessel density，MVD)在原发灶和肝内转移灶的表达及Ki-67在原发灶的表达。
(1)比较30例HCC原发灶、癌旁肝组织及肝内转移灶中syndecan-1表达强度的差异；
(2)分析30例HCC原发灶中syndecan-1表达强度与HCC临床病理因素(包括临床分期、肿瘤大小、分级、血清AFP水平、Child-Pugh肝功能分级、是否伴有肝硬化及癌栓)之间的关系；
(3)分析30例HCC原发灶中syndecan-1表达强度与Ki-67增殖指数之间的关系；
(4)比较30例HCC原发灶及肝内转移灶中VEGF表达强度及CD34-MVD的差异；
(5)分析30例HCC原发灶中syndecan-1表达强度与VEGF表达强度及CD34-MVD之间的关系；
(6)分析30例HCC肝内转移灶中syndecan-1表达强度与VEGF表达强度及CD34-MVD之间的关系。2.统计学方法：应用SPSS 13.0软件进行统计学处理,P<0.05则认为具有显著性差异；原发灶、癌旁肝组织及肝内转移灶中syndecan-1表达强度比较采用Kruska-Wallis检验；syndecan-1表达与HCC临床病理因素的关系用Wilcoxon检验(2组比较)或Kruska-Wallis检验(3组比较)；VEGF和CD34-MVD在原发灶与肝内转移灶的比较分别采用Wilcoxon检验和两样本t检验；syndecan-1与Ki-67指数、VEGF及CD34-MVD的相关性采用Spearman相关性检验。
研究结果：
1. Syndecan-1在HCC原发灶中表达增强,在癌旁肝组织中低表达,在肝内转移灶的表达强度显著低于原发灶。
HCC原发灶中syndecan-1高、中、低、无表达者例数分别为9、15、4、2,癌旁肝组织中syndecan-1高、中、低、无表达者例数分别为1、15、14、0,肝内转移灶中syndecan-1高、中、低、无表达者例数分别为0、6、17、7。三组间syndecan-1表达强度有显著性差异(χ2=25.62, P< 0.001)。
2.原发灶中syndecan-1表达强度与HCC临床分期、肿瘤大小、分级、血清AFP水平、Child-Pugh分级、是否伴有肝硬化及癌栓均无关。
Syndecan-1在HCC原发灶中表达强度在临床分期(P=0.143)、肿瘤大小(P=0.980)、分级(P=0.102)、血清AFP水平(P=0.432)、Child-Pugh分级(P=0.822)、是否伴有肝硬化及癌栓间(P分别为0.573和O.137)均无显著性差异。
3.HCC原发灶中syndecan-1表达强度与Ki-67增殖指数呈显著正相关。
HCC原发灶中syndecan-1高、中、低、无表达者的Ki-67增殖指数分别为22.8±20.2%、21.6±21.5%、4.8±8.7%和0.3±0.4%,syndecan-1表达强度与Ki-67增殖指数呈显著正相关(r=0.386,P=0.035)。
4. VEGF表达及CD34-MVD在HCC原发灶及肝内转移灶中无统计学差异。
(1)HCC原发灶中VEGF高、中、低表达例数分别为15、10、5,肝内转移灶中高、中、低表达例数分别为13、15、2,两组间无统计学差异(W=912.5,P=0.968)。
(2)HCC原发灶及肝内转移灶中CD34-MVD分别为308.3-150.0／mm2、329.1±155.4／mm2,两者间无统计学差异(t=-0.528,P=0.600)。
5.HCC原发灶中syndecan-1表达强度与VEGF表达强度、CD34-MVD无统计学相关,但与CD34-MVD之间存在正相关趋势。
HCC原发灶中syndecan-1表达强度与VEGF表达强度无统计学相关性(r=0.319,P=0.086)；原发灶syndecan-1表达强度与CD34-MVD之间无统计学相关性,但存在正相关趋势,在原发灶syndecan-1高、中、低、无表达者的CD34-MVD分别为329.3±140.2/mm2、319.7±176.0/mm2、206.3±66.0/mm2和(?)331.9±8.9/mm2(r= 0.200, P=0.290)。
6.HCC肝内转移灶中syndecan-1表达强度与VEGF表达强度无统计学相关性,与CD34-MVD之间呈显著正相关关系。
HCC肝内转移灶中syndecan-1表达强度与VEGF表达强度无统计学相关性(r=0.124 P=0.513)；肝内转移灶syndecan-1表达强度与CD34-MVD之间呈显著正相关关系,syndecan-1中、低、无表达者的CD34-MVD分别为425.3±121.5／mm2、326.2±170.7/mm2、253.7±103.6/mm2 (r=0.370, P=0.044)。
研究结论：
1. Syndecan-1在HCC肝内转移灶的表达强度显著低于原发灶及癌旁组织,提示syndecan-1表达下降或缺失可能与HCC转移有关。胞膜syndecan-1表达下降或缺失的肿瘤细胞,由于其与基质之间粘附减弱,自由度增大,导致其侵袭转移潜力增强,易于进入循环,形成肝内外转移瘤。
2.HCC原发灶中syndecan-1表达强度与肿瘤细胞增殖指数呈正相关,syndecan-1可能作为多种生长因子的共受体,刺激肿瘤生长。
3.HCC组织中syndecan-1表达强度与肿瘤新生血管呈正相关,提示syndecan-1可能通过易化促血管生成因子相应受体的二聚化过程,增强促血管生成效应,促进肿瘤生长、转移。
4.HCC组织中syndecan-1表达可能影响肿瘤转移、增殖和血管生成。HCC肿瘤细胞的转移可能需要syndecan-1从膜表面脱落、缺失,当肿瘤细胞发生转移,定植于转移部位后,syndecan-1重新在膜表面表达,再次促进肿瘤生长、血管生成。提示syndecan-1在HCC生长和转移中的特殊作用可能为HCC有效治疗策略提供新思路。
Background:
Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world, and the second most common cause of cancer mortality, with a male-female ratio of 4-5:1 in high incidence regions, such as China, which alone accounts for 55% of the world's cases. Hepatic resection and liver transplantation are the two main modalities that may cure HCC, but the long-term patient survival is dependent on the stage of tumor at the time of diagnosis. The treatment challenges of HCC include:①Most of HCC patients with a background in hepatitis B and cirrohsis, usually complicate with abnormal hepatic function;②HCC in the olderly are usually occult in onset and prone to intrahepatic and extrahepatic metastasis, and progress rapidly;③Surgical resection rate is less than 20%, and radical resection rate is lower;④The rate of postoperative recurrence is rather high.The one-year survival rate, three-year survival rate and five-year survival rate were 93.5%,70.1% and 59.1% respectively for the early stage HCC patients. and 65.3%,30.5% and 23.5% respectively for the median stage HCC patients. The half-year, one-year survival rate for the advanced stage HCC patients were 52.5% and 14.7% respectively. Longitudinally compared with the situation of past few decades, the prognosis of HCC has been improved greatly, which was due to improvement of diagnostic lever in the early stage, increasing of the overall resection rate and progress of non-operation treatment. However, in horizontal comparison with breast cancer and colorectal cancer, the outcome for patients with HCC still remains dismal. Currently the mechanism underlying the contribution to tumorigenesis and tumor promotion of HCC is not clear precisely, and the patients cannot receive targeted intervention, which causes poor prognosis of HCC. Therefore, futher exploring the molecular mechanisms that modulate the development and progression of HCC is crucial for the design of therapeutic strategies. There are several pivotal steps in the cell signal transduction and angiogenesis of HCC, whose abnormalities lead to the development, progress and metastasis of HCC, which are the theoretical principles of molecular targeted therapy and the potential key targets. In recent years, the research of HCC molecular targeted therapy has been hot spots. Sorafenib is an oral multikinase inhibitor with antiproliferative and antiangiogenic effects. Based on two multicenter phaseⅢ, randomized, double-blind, placebo-controlled clinical trial (SHARP and Oriental) which showed Sorafenib improved survival in patients with advanced (unresectable and metastatic) HCC, Sorafenib was approved to be used as standard treatment regimen in patients with advanced HCC by EMEA, FDA and SFDA at serial.
Syndecan-1 is a member of syndecans subfamily which belongs to HSPGs. Syndecan-1 is expressed on the surfaces of many cell types and has been shown to modulate tumor cell proliferation, adhesion, migration and angiogenesis, by interacting with stromal cells, extracellular matrix and bioactive moleculars in tumor microenvironment. Expression of syndecan-1 is often alterd in cancer, and several studies suggest that loss of syndecan-1 expression in carcinomas accompany the malignant phenotype. It has been suggested that the loss of syndecan-1 expression render the tumor cells less adhesive, thereby increasing their potential to metatasize. However, in other cancers, such as pancreatic adenocarcinoma and multiple myeloma, syndecan-1 expression on the cell surface remains high even though these tumors disseminate to sites distal from the primary tumor.
The research concerning the correlation between syndecan-1 and HCC has been carried on, mainly including the clinicopathological significance of expression of syndecan-1. The potential mechanism was litter reported. Several research results showed that the loss of syndecan-1 was associated with HCC malignant phenotype, such as poor differentiation, invasion and metastasis. However, the result of another similar research showed that syndecan-1 was highly expressed in poor differentiated HCC. It was contradictory to those of previous studies.
Objective:
To investigate the expression levers of syndecan-1 in HCC primary tumors, adjacent non-tumor live tissues and intrahepatic metastasis tumors, the clinicopathological significance of syndecan-1 in HCC primary tumors and the relationship between syndecan-1 and tumor metastasis, proliferation and angiogenesis in HCC.
Methods:
1. In the study, immunohistochemical staining was utilized for determing syndecan-1 expression in HCC primary tumors, adjacent non-tumor live tissues and intrahepatic metastasis tumors, VEGF and CD34-MVD in primary tumors and intrahepatic metastasis tumors, and Ki-67 in primary tumors.
(1) Compare the differences of the expression levels of syndecan-1 in HCC primary tumors, adjacent non-tumor live tissues and intrahepatic metastasis tumors;
(2) Analysis the correlations between syndecan-1 expression in HCC primary tumors and gender, age, clinical stage, tumor size, differentiation, serum AFP level, Child-Pugh grade, presence of cirrhosis and thrombosis;
(3) Analysis the correlation between syndecan-1 expression and Ki-67 index in HCC primary tumors;
(4) Compare the differences of VEGF expression and CD34-MVD in HCC primary tumors and intrahepatic metastasis tumors;
(5) Analysis the correlations between syndecan-1 expression and VEGF expression and CD34-MVD in HCC primary tumors;
(6) Analysis the correlations between syndecan-1 expression and VEGF expression and CD34-MVD in HCC intrahepatic metastasis tumors.
2. Statistical methods:All statistical analyses were performed using SPSS program package 13.0. Differences were considered as significant when the P value was less than 0.05. Comparison among groups of the rank material was evaluated with the Kruska-Wallis's test, and the measurement material with the independent-samples t test; The clinicopathological significance of syndecan-1 expression in HCC primary tumors was estimated with the generalized Wilcoxon's test (or the Kruska-Wallis's test, where appropriate). The relationship between syndecan-1 expression and VEGF, CD34-MVD and Ki-67 index uses the Spearman correlation analysis.
Results:
1. Compared with adjacent non-tumor live tissues, syndecan-1 expression in HCC primary tumors were significantly enhanced. On contrast, syndecan-1 expression were significantly reduced in intrahepatic metastasis tumors.
The cases of high, middle, low and no syndecan-1 expression in HCC primary tumors were 9,15,4 and 2 respectively. The cases of high, middle, low and no syndecan-1 expression in adjacent non-tumor live tissues were 1,15,14 and 0 respectively. The cases of high, middle, low and no syndecan-1 expression in intrahepatic metastasis tumors were 0,6,17 and 7 respectively. The difference of syndecan-1 expression among three groups was statistically significant (χ2=25.62, P<0.001).
2. Syndecan-1 expression in primary tumors was not associated with HCC clinical stage, tumor size, differentiation, serum AFP level, Child-Pugh grade, presence of cirrhosis and thrombosis.
Syndecan-1 expression in HCC primary tumors was not associated with HCC clinical stage (P=0.143), tumor size (P=0.980), differentiation (P=0.102), serum AFP level (P=0.432), Child-Pugh grade (P=0.822), presence of cirrhosis and thrombosis (P=0.573 and 0.137, respectively)
3. Syndecan-1 expression was positively correlated with the Ki-67 index in HCC primary tumors.
The Ki-67 index were 22.8±20.2%,21.6±21.5%,4.8±8.7% and 0.3±0.4% respectively in HCC patients with high, middle, low and no syndecan-1 expression in primary tumors. Syndecan-1 expression was positively associated with Ki-67 index (r= 0.386, P=0.035).
4.The VEGF expression and CD34-MVD between HCC primary tumors and intrahepatic metastasis tumors was not different significantly.
The cases of high, middle, low VEGF expression were 15,10,9 in HCC primary tumors respectively, and 13,15,2 in intrahepatic metastasis tumors respectively, there was no statistical significance between two groups (W=912.5, P=0.968)
CD34-MVD were 308.3±150.0/mm2 and 329.1±155.4/mm2 in HCC primary tumors and intrahepatic metastasis tumors respectively, there was no statistical significance between two groups (t=-0.528, P=0.600).
5. In HCC primary tumors, syndecan-1 expression was not associated with the expression of VEGF; Even though there was no statistical significance, a tendency of positive correlation was found between syndecan-1 expression and CD34-MVD.
Syndecan-1 expression was not associated with the expression of VEGF in HCC primary tumors (r= 0.319, P=0.086). There was no statistical significance but a positive correlation tendency between syndecan-1 expression and CD34-MVD in primary tumors (r= 0.200, P=0.290). CD34-MVD were 329.3±140.2/mm2, 319.7±176.0/mm2,206.3±66.0/mm2 and 331.9±8.9/mm2 respectively in HCC patients with high, middle, low and no syndecan-1 expression.
6. In HCC intrahepatic metastasis tumors, syndecan-1 expression was not associated with the expression of VEGF; Syndecan-1 expression was positively correlated with CD34-MVD.
Syndecan-1 expression was not associated with the expression of VEGF in intrahepatic metastasis tumors (r=0.124, P=0.513). Syndecan-1 expression was positively correlated with CD34-MVD in intrahepatic metastasis tumors (r= 0.370, P=0.044). CD34-MVD were 425.3±121.5/mm2,326.2±170.7/mm2 and 253.7±103.6/ mm2 respectively in HCC patients with middle, low and no syndecan-1 expression.
Conclusions:
1. Syndecan-1 expression in HCC intrahepatic metastasis tumors was significantly lower than primary tumors and adjacent non-tumor live tissues. It was suggested that the loss of syndecan-1 expression was associated with HCC metastasis. One possibility was that syndecan-1 function in both cell-cell and cell-extracellular matrix adhesion, and the tumor cells that lost syndecan-1 gain freedom (lost their attachment in matrix) and enable to go to circulation and home in distal sites.
2. Syndecan-1 expression was positively associated with cell proliferation. Syndecan-1 may bind growth factors, decisively regulate growth factor signaling and stimulate tumor cell proliferation.
3. Syndecan-1 expression was positively correlated with CD34-MVD, suggesting that as co-receptors, syndecan-1 may stimulate angiogenic factor receptor tyrosine kinase activity.
4. Syndecan-1 on tumor cells surface may promote tumor growth and angiogenesis as co-receptors of many growth factors, but at same time syndecan-1 sticks tumor cells on matrix. Tumor cells need to reduce syndecan-1 on their surface (e.g., by shedding syndecan-1 to the matrix) to be able to gain freedom and perform metastasis. Once tumor cells arrive in metastatic site, they produce surface syndecan-1 again to support the growth and angiogenesis of the tumors. Syndecan-1 may affect tumor metastasis, proliferation and angiogenesis, suggesting that syndecan-1 play a special role in the progress of HCC and may provide new ideas for treatment strategies for HCC.
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[38]Bayer-Garner IB, Dilday B, Sanderson RD, et al. Syndecan-1 expression is decreased with increasing aggressiveness of basal cell carcinoma. Am J Dermatopathol.2000; 22:119-122.
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[37]Lundin M, Nordling S, Lundin J, et al. Epithelial syndecan-1 expression is associated with stage and grade in colorectal cancer. Oncology.2005; 68(4-6): 306-313.
[38]Bayer-Garner IB, Dilday B, Sanderson RD, et al. Syndecan-1 expression is decreased with increasing aggressiveness of basal cell carcinoma. Am J Dermatopathol.2000; 22:119-122.
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[40]Hasengaowa, Kodama J, Kusumoto T, et al. Prognostic significance of syndecan-1 expression in human endometrial cancer. Ann Oncol.2005; 16(7): 1109-1115.
[41]Wiksten J-P, Lundin J, Nordling S, et al. Epithelial and stromal syndecan-1 expression as predictor of outcome in patients with gastric cancer. Int J Cancer. 2001; 95:1-6.
[42]Seidel C, Sundan A, Hjorth M, et al. Serum syndecan-1:a new independent prognostic marker in multiple myeloma. Blood.2000a; 95:388-392.
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[45]Joensuu H, Anttonen A, Eriksson M, et al. Soluble syndecan-1 and serum basic fibroblast growth factor are new prognostic factors in lung cancer. Cancer Research.2002; 62:5210-5217.
[46]Anttonen A, Leppa S, Heikkila P, et al. Effect of treatment of larynx and hypopharynx carcinomas on serum syndecan-1 concentrations. J Cancer Res Clin Oncol.2006; 132:451-457.
[47]Gui S, Stacy A, Blaine S, et al. Shedding of syndecan-1 by stromal fibroblasts stimulates human breast cancer cell proliferation via FGF-2 activation. J Biol Chem.2007; 282:14906-14915.
[48]Yoshiro Matsumoto, Hideki Fujii, Masanori Matsuda. Multicentric occurrence of hepatocellular carcinoma:diagnosis and clinical significance. J Hepatobiliary Pancreat Surg.2001; 8:435-440.
[49]Shariat SF, Svatek RS, Kabbani W, et al. Prognostic value of syndecan-1 expression in patients treated with radical prostatectomy. BJU Int.2008; 101(2): 232-237.
[50]Roskams T, De Vos R, David G, et al. Heparan sulphate proteoglycan expression in human primary liver tumors. J Pathol.1998; 185(3):290-297.
[51]Matsumoto A, Ono M, Fujimoto Y, et al. Reduced expression of syndecan-1 in human hepatocellular carcinoma with high metastatic potential. Int J Cancer. 1997; 74:482-491.
[52]Li HG, Xie DR, Shen XM, et al. Clinicopathological significance of expression of paxillin, syndecan-1 and EMMPRIN in hepatocellular carcinoma. World J Gastroenterol.2005; 11(10):1445-1451.
[53]成峰,王学浩,钱建民,等.肝癌患者syndecan-1基因蛋白的表达和意义.南京医科大学学报.2001；21(4)：284-286.
[54]Preetha R, Bamidele A, Ronie B, et al. Metastatic Hepatocellular Carcinoma With CD 138 Positivity:An Unusual Mimic of Multiple Myeloma? Diagnostic Cytopathology.2008; 36(10):742-748.
[55]Ito Y, Matsuura N, Sakon M, et al. Both cell proliferation and apoptosis significantly predict shortened disease-free survival in hepatocellular carcinoma. Br J Cancer.1999; 81:747-751.
[56]Ouchi K, Sugawara T, Ono H, et al. Mitotic index is the best predictive factor for survival of patients with resected hepatocellular carcinoma. Dig Surg.2000; 17:42-48.
[57]Maeda T, Desouky J, Friedl A. Syndecan-1 expression by stromal fibroblasts promotes breast carcinoma growth in vivo and stimulates tumor angiogenesis. Oncogene.2006; 25(9):1408-1412.
[58]Hsia E, Richardson TP, Nugent MA. Nuclear localization of basic fibroblast growth factor is mediated by heparan sulfate proteoglycans through protein kinase C signaling. J Cell Biochem.2003; 88(6):1214-1225.
[1]Carey DJ. Syndecans:multifunctional cell-surface co-receptors. Biochem J. 1997; 327:1-16.
[2]Bernfield M, Gotte M, Park PW, et al. Functions of cell surface heparan sulfate proteoglycans. Annu Rev Bio chem.1999; 68:729-777.
[3]Hooper NM, Karran EH, et al. Membrane protein secretases. Biochem J.1997; 321:265-279.
[4]Sanderson RD, Yang Y, Suva LJ, et al. Heparan sulfate proteoglycans and heparanase:partners in osteolytic tumor growth and metastasis. Matrix Biol. 2004; 23(6):341-352.
[5]Sanderson RD, Yang Y, et al. Enzymatic remodeling of heparan sulfate proteoglycans within the tumor microenvironment:growth regulation and the prospect of new cancer therapies. J Cell Biol.2005; 96:897-905.
[6]Numa F, Hirabayashi K, Kawasaki K, et al. Syndecan-1 expression in cancer of uterine cervix:association with lymph node metastasis. Int J Oncol.2002; 20: 39-43.
[7]Sanderson RD. Heparan sulfate proteoglycans in invasion and metastasis. Semin Cell Dev Biol.2001; 12:89-98.
[8]Anttonen A, Kajanti M, Heikkila P, et al. Syndecan-1 expression has prognostic significance in head and neck carcinoma. Br J Cancer.1999; 79:558-564.
[9]Ro Y, Muramatsu T, Shima K, et al. Correlation between reduction of syndecan-1 expression and clinicopathological parameters in squamous cell carcinoma of tongue. Int J Oral Maxillofac Surg.2006; 35(3):252-257.
[10]Shah L, Walter KL, Borczuk AC, et al. Expression of syndecan-1 and expression of epidermal growth factor receptor are associated with survival in patients with non-small cell lung carcinoma. Cancer.2004; 101(7):1632-1638.
[11]Lundin M, Nordling S, Lundin J, et al. Epithelial syndecan-1 expression is associated with stage and grade in colorectal cancer. Oncology.2005; 68(4-6): 306-313.
[12]Bayer-Garner IB, Dilday B, Sanderson RD, et al. Syndecan-1 expression is decreased with increasing aggressiveness of basal cell carcinoma. Am J Dermatopathol.2000; 22:119-122.
[13]Harada K, Masuda S, Hirano M, et al. Reduced expression of syndecan-1 correlates with histologic dedifferentiation, lymph node metastasis, and poor prognosis in intrahepatic cholangiocarcinoma. Hum Pathol.2003; 34(9): 857-863.
[14]Hasengaowa, Kodama J, Kusumoto T, et al. Prognostic significance of syndecan-1 expression in human endometrial cancer. Ann Oncol.2005; 16(7): 1109-1115.
[15]Wiksten J P, Lundin J, Nordling S, et al. Epithelial and stromal syndecan-1 expression as predictor of outcome in patients with gastric cancer. Int J Cancer. 2001; 95:1-6.
[16]Shariat SF, Svatek RS, Kabbani W, et al. Prognostic value of syndecan-1 expression in patients treated with radical prostatectomy. BJU Int.2008; 101(2): 232-237.
[17]Conejo JR, Kleeff J, Koliopanos A, et al. Syndecan-1 expression is up-regulated in pancreatic but not in other gastrointestinal cancers. Int J Cancer 2000; 88: 12-20.
[18]Leivonen M, Lundin J, Nordling S, et al. Prognostic value of syndecan-1 expression in breast cancer. Oncology.2004; 67:11-18.
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