干细胞标志CD133在肝癌组织中的表达及阳性亚群耐药特性的研究
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摘要
近年来,随着对肿瘤和干细胞生理研究的深入,越来越多的证据表明:肿瘤包含有一部分比例很小的肿瘤干细胞,这些肿瘤干细胞具有无限增殖、自我更新和多向分化潜能,并且驱动肿瘤生长。目前,已从多种肿瘤细胞系及肿瘤组织(包括白血病、神经胶质瘤、前列腺癌、结肠癌、胰腺癌、肺癌及乳腺癌等)中分离出肿瘤干细胞。根据肿瘤干细胞学说,这些肿瘤干细胞具有正常干细胞类似的特性,决定着肿瘤起始和增殖,因而可能影响临床肿瘤耐药、复发及转移等行为。因此,肿瘤干细胞的分离和鉴定成为肿瘤研究的新热点。
原发性肝细胞癌是我国常见恶性肿瘤之一,其死亡率在所有恶性肿瘤中居第三位。在过去的几十年里,尽管在肝癌诊断及传统治疗上取得了巨大的进步,但肝癌患者长期生存率仍然很低,这主要是由于肝癌术后的高复发和高转移。因此,对肝癌的发病机理及其生物学特性的研究尤为必要。
肝癌组织具有明显的形态学多样性,表达一系列谱系标志,同时肝癌细胞和干细胞存在某些共性。实际上,多个实验已经证实肝干细胞广泛的参与肝癌的发生和发展的各个阶段;尤其是最近,以CD133为标志成功从多个肝癌细胞系分离出肝癌干细胞:CD133~+亚群具有无限增殖、自我更新和多向分化潜能,决定着肝癌的发生和发展,进一步支持CSC学说。此外,在大鼠大部分肝切除模型中检测到CD133的重新激活,表明CD133和肝细胞的增殖密切相关,可能和肝癌的发生有关。因此,展开以CD133为标志的肝癌干细胞的研究对于阐明肝癌的发病机理、揭示肝癌的耐药、复发和转移的机制具有重要的意义,并为肝癌的治疗提供一个新的策略。
目的:
1)检测干细胞标志CD133在临床肝癌组织标本中的表达情况,并分析CD133的表达和临床肝癌病理特征、病程进展及术后预后关系;
2)检测化疗药物对肝癌细胞的杀伤作用,探讨转运蛋白ABCG2在CD133~+肝癌CSC耐药中的作用。
方法:
1)采用免疫组织化学法检测63例肝癌癌组织CD133的表达,分析CD133表达与临床病理特征、肝癌进展及预后的相关性;
2)流式检测CD133在肝癌细胞系中的表达;
3)化疗药物对肝癌细胞杀死作用的研究;
4)应用半定量RT-PCR检测ABCG2在CD133~+及CD133~-细胞的表达。
结果:
1)所有的63例肝癌标本中均检测到CD133表达,其中增强的CD133表达占26例(41.3%),4例胎肝组织CD133染色阳性,但正常肝组织CD133不表达;
2)增强的CD133表达和肝癌的临床分期(P﹤0.01)、病理分级(P﹤0.01)及血浆AFP水平(P﹤0.05)密切相关;
3) Kaplan–Meier分析表明:和低表达的CD133相比,增强者生存时间更短(P﹤0.01)而肝癌复发率增高(P=0.01);多参分析提示:增强的CD133表达是肝癌患者长期生存(相对危险度RR=2.443,P=0.017)及肝癌复发(相对危险度RR=2.445,P=0.011))的一个独立预后因子;
4)流式检测结果显示:CD133分子的表达在肝癌细胞系普遍存在,其含量是0.1-61%;
5)化疗药物对CD133~-肝癌细胞有选择性杀伤作用;
6)半定量RT-PCR结果都证实ABCG2优先表达于CD133~+肝癌CSC(P﹤0.05);
结论:
1)重新激活的CD133~+CSC在临床肝癌标本中普遍存在; 2) CD133~+ CSC不仅参与了肝癌的起始,而且可能在肝癌进展中扮演着重要的角色;
3) CD133的表达倾向于恶性程度较高的肝癌,因此可能影响肝癌患者的预后,这些结果进一步支持CSC假说;
4) ABCG2的优先表达可能是CD133~+CSC耐药机制之一;因此,除了抗凋亡通路的激活,CD133~+CSC耐药可能和多个通路异常有关。
With great advances in stem cell and tumor biology, more and more evidences indicate that cancer may be maintained by a rare fraction of cancer stem cells (CSCs) that are able to self-renew, differentiate into multiple cell lineages, and drive tumor continuous growth. The existence of CSCs was well documented in many different cancers including acute myeloid leukemia, breast cancer, and brain cancer. Cancer stem cell hypothesis asserts that CSCs share many properties of normal stem cells and thus account for the clinical outcomes such as recurrence, metastasis and multi-drug resistance. Therefore, the isolation and identification of cancer stem cell has been become a new hot spot in tumor research.
Hepatocellular carcinoma (HCC) is one of the most common tumors in our country, and is currently the third-leading cause of cancer death among men in China. Although advance of conventional clinical treatment for HCC has been achieved, the mortality has not been improved significantly over the past several decades, which is largely the result of a high rate of recurrence or metastasis after operation. Therefore, it is necessarry to enforce the studies of the molecular mechanisms of hepatocarcinogenesis and the biologic behaviors of HCC.
In HCC, morphologically diverse cells express a variety of hepatic lineage markers and share the similar properties with adult stem cell in many characteristics. In fact, many studies have shown that stem/progenitor cells are involved in hepatocarcinogenesis in certain rodent models and activated stem/progenitor cells are present in human HCC. More recently, a CD133~-positive subpopulation of multipotent cells with extensive proliferative and self-renewal abilities was identified as CSCs in several HCC cell lines, and was proven to contribute to the initiation and growth of HCC, supporting the cancer stem cell hypothesis. Furthermore, re-expression of CD133 has been reported in regenerating rat liver, indicating that CD133 is associated with liver cell proliferation, a possible link to HCC. Thus, isolation and identification of CD133~+ CSCs could elucidate the cellular origin of HCC tumor cells, providing insight into the molecular mechanisms of carcinogenesis, recurrence and metastasis of HCC, and a new strategy for HCC therapy
Object:
1) To investigate the expression of stem cell marker CD133 in HCC, and then examine the potential prognostic value of CD133 expression in patients with HCC;
2) To detect the the sensivities of CD133~+ CSCs to chemotherapic drugs. Furthermore, investigate the expression of ABCG2 in CD133~+ CSCs for helping understand the mechanism of drug resistance.
Method:
1) Sixty-three resected specimens were collected from HCC patients. The expression of CD133 protein was analyzed by immunohistochemistry, and the association of CD133 expression with clinicopathological characteristics, tumor recurrence and survival of the patients was evaluated.
2) The expression of CD133 was explored using flow cytometry in HCC cell lines.
3) The killing effects of chemotherapic drugs were performed in HuH-7 cell line in vitro.
4) The ABCG2 mRNA expression was determined by semi-quantitative reverse transcription-PCR in CD133~+ and CD133~- subpopulations of HuH-7 cell lines.
Result:
1) Immunohistochemical analysis of 63 HCC tissue specimens revealed that CD133 positive tumor cells were frequently present in HCC. Increased CD133 immunostaining was found in 26 specimens (41.3%).
2) Increased CD133 expression levels were correlated with increased tumor grade (P﹤0.01), advanced disease stage (P﹤0.01), and elevated serum alpha-fetoprotein (AFP) levels (P﹤0.05).
3) Kaplan–Meier analysis indicated that patients with increased CD133 levels had shorter overall survival (P﹤0.01)and higher recurrence (P=0.01) rates compared to patients with low CD133 expression. Multivariate analyses revealed that increased CD133 expression was an independent prognostic factor for survival(RR=2.443, P=0.017) and tumor recurrence(RR=2.445, P=0.011) in patients with HCC.
4) CD133~+ cells are frequently present in alll of HCC cell lines contain and it ranges from 0.1% to 61%.
5) The chemosensivity of drugs showed that CD133~- cells were preferential killed after 24h and 48h of incubation with Dox and 5-Fu compared with CD133~+ cells.
6) The result of semi-quantitative RT-PCR showed a preferential expression of ABCG2 mRNA in CD133~+ CSCs cells than CD133~- cells(P﹤0.01)).
Conclusion:
1) These findings suggest that reactivated CD133 positive cells are frequently present in HCC;
2) CD133~+ CSCs not only take part in the initiation of hepatocarcinogeneis but also play an import role in the progression of HCC;
3) Increased CD133 expression corresponds with higher stage tumors in HCC, thus indicating a poor prognosis for patients. These data support the cancer stem cell hypothesis;
4) There is a preferential expression of ABCG2 in CD133~+ CSC cells. Thus, multi-pathways may take part in multidrug resistance of CD133~+ CSCs except for the activation of anti-apoposis pathway.
原发性肝细胞癌是我国常见恶性肿瘤之一,其死亡率在所有恶性肿瘤中居第三位。在过去的几十年里,尽管在肝癌诊断及传统治疗上取得了巨大的进步,但肝癌患者长期生存率仍然很低,这主要是由于肝癌术后的高复发和高转移。因此,对肝癌的发病机理及其生物学特性的研究尤为必要。
肝癌组织具有明显的形态学多样性,表达一系列谱系标志,同时肝癌细胞和干细胞存在某些共性。实际上,多个实验已经证实肝干细胞广泛的参与肝癌的发生和发展的各个阶段;尤其是最近,以CD133为标志成功从多个肝癌细胞系分离出肝癌干细胞:CD133~+亚群具有无限增殖、自我更新和多向分化潜能,决定着肝癌的发生和发展,进一步支持CSC学说。此外,在大鼠大部分肝切除模型中检测到CD133的重新激活,表明CD133和肝细胞的增殖密切相关,可能和肝癌的发生有关。因此,展开以CD133为标志的肝癌干细胞的研究对于阐明肝癌的发病机理、揭示肝癌的耐药、复发和转移的机制具有重要的意义,并为肝癌的治疗提供一个新的策略。
目的:
1)检测干细胞标志CD133在临床肝癌组织标本中的表达情况,并分析CD133的表达和临床肝癌病理特征、病程进展及术后预后关系;
2)检测化疗药物对肝癌细胞的杀伤作用,探讨转运蛋白ABCG2在CD133~+肝癌CSC耐药中的作用。
方法:
1)采用免疫组织化学法检测63例肝癌癌组织CD133的表达,分析CD133表达与临床病理特征、肝癌进展及预后的相关性;
2)流式检测CD133在肝癌细胞系中的表达;
3)化疗药物对肝癌细胞杀死作用的研究;
4)应用半定量RT-PCR检测ABCG2在CD133~+及CD133~-细胞的表达。
结果:
1)所有的63例肝癌标本中均检测到CD133表达,其中增强的CD133表达占26例(41.3%),4例胎肝组织CD133染色阳性,但正常肝组织CD133不表达;
2)增强的CD133表达和肝癌的临床分期(P﹤0.01)、病理分级(P﹤0.01)及血浆AFP水平(P﹤0.05)密切相关;
3) Kaplan–Meier分析表明:和低表达的CD133相比,增强者生存时间更短(P﹤0.01)而肝癌复发率增高(P=0.01);多参分析提示:增强的CD133表达是肝癌患者长期生存(相对危险度RR=2.443,P=0.017)及肝癌复发(相对危险度RR=2.445,P=0.011))的一个独立预后因子;
4)流式检测结果显示:CD133分子的表达在肝癌细胞系普遍存在,其含量是0.1-61%;
5)化疗药物对CD133~-肝癌细胞有选择性杀伤作用;
6)半定量RT-PCR结果都证实ABCG2优先表达于CD133~+肝癌CSC(P﹤0.05);
结论:
1)重新激活的CD133~+CSC在临床肝癌标本中普遍存在; 2) CD133~+ CSC不仅参与了肝癌的起始,而且可能在肝癌进展中扮演着重要的角色;
3) CD133的表达倾向于恶性程度较高的肝癌,因此可能影响肝癌患者的预后,这些结果进一步支持CSC假说;
4) ABCG2的优先表达可能是CD133~+CSC耐药机制之一;因此,除了抗凋亡通路的激活,CD133~+CSC耐药可能和多个通路异常有关。
With great advances in stem cell and tumor biology, more and more evidences indicate that cancer may be maintained by a rare fraction of cancer stem cells (CSCs) that are able to self-renew, differentiate into multiple cell lineages, and drive tumor continuous growth. The existence of CSCs was well documented in many different cancers including acute myeloid leukemia, breast cancer, and brain cancer. Cancer stem cell hypothesis asserts that CSCs share many properties of normal stem cells and thus account for the clinical outcomes such as recurrence, metastasis and multi-drug resistance. Therefore, the isolation and identification of cancer stem cell has been become a new hot spot in tumor research.
Hepatocellular carcinoma (HCC) is one of the most common tumors in our country, and is currently the third-leading cause of cancer death among men in China. Although advance of conventional clinical treatment for HCC has been achieved, the mortality has not been improved significantly over the past several decades, which is largely the result of a high rate of recurrence or metastasis after operation. Therefore, it is necessarry to enforce the studies of the molecular mechanisms of hepatocarcinogenesis and the biologic behaviors of HCC.
In HCC, morphologically diverse cells express a variety of hepatic lineage markers and share the similar properties with adult stem cell in many characteristics. In fact, many studies have shown that stem/progenitor cells are involved in hepatocarcinogenesis in certain rodent models and activated stem/progenitor cells are present in human HCC. More recently, a CD133~-positive subpopulation of multipotent cells with extensive proliferative and self-renewal abilities was identified as CSCs in several HCC cell lines, and was proven to contribute to the initiation and growth of HCC, supporting the cancer stem cell hypothesis. Furthermore, re-expression of CD133 has been reported in regenerating rat liver, indicating that CD133 is associated with liver cell proliferation, a possible link to HCC. Thus, isolation and identification of CD133~+ CSCs could elucidate the cellular origin of HCC tumor cells, providing insight into the molecular mechanisms of carcinogenesis, recurrence and metastasis of HCC, and a new strategy for HCC therapy
Object:
1) To investigate the expression of stem cell marker CD133 in HCC, and then examine the potential prognostic value of CD133 expression in patients with HCC;
2) To detect the the sensivities of CD133~+ CSCs to chemotherapic drugs. Furthermore, investigate the expression of ABCG2 in CD133~+ CSCs for helping understand the mechanism of drug resistance.
Method:
1) Sixty-three resected specimens were collected from HCC patients. The expression of CD133 protein was analyzed by immunohistochemistry, and the association of CD133 expression with clinicopathological characteristics, tumor recurrence and survival of the patients was evaluated.
2) The expression of CD133 was explored using flow cytometry in HCC cell lines.
3) The killing effects of chemotherapic drugs were performed in HuH-7 cell line in vitro.
4) The ABCG2 mRNA expression was determined by semi-quantitative reverse transcription-PCR in CD133~+ and CD133~- subpopulations of HuH-7 cell lines.
Result:
1) Immunohistochemical analysis of 63 HCC tissue specimens revealed that CD133 positive tumor cells were frequently present in HCC. Increased CD133 immunostaining was found in 26 specimens (41.3%).
2) Increased CD133 expression levels were correlated with increased tumor grade (P﹤0.01), advanced disease stage (P﹤0.01), and elevated serum alpha-fetoprotein (AFP) levels (P﹤0.05).
3) Kaplan–Meier analysis indicated that patients with increased CD133 levels had shorter overall survival (P﹤0.01)and higher recurrence (P=0.01) rates compared to patients with low CD133 expression. Multivariate analyses revealed that increased CD133 expression was an independent prognostic factor for survival(RR=2.443, P=0.017) and tumor recurrence(RR=2.445, P=0.011) in patients with HCC.
4) CD133~+ cells are frequently present in alll of HCC cell lines contain and it ranges from 0.1% to 61%.
5) The chemosensivity of drugs showed that CD133~- cells were preferential killed after 24h and 48h of incubation with Dox and 5-Fu compared with CD133~+ cells.
6) The result of semi-quantitative RT-PCR showed a preferential expression of ABCG2 mRNA in CD133~+ CSCs cells than CD133~- cells(P﹤0.01)).
Conclusion:
1) These findings suggest that reactivated CD133 positive cells are frequently present in HCC;
2) CD133~+ CSCs not only take part in the initiation of hepatocarcinogeneis but also play an import role in the progression of HCC;
3) Increased CD133 expression corresponds with higher stage tumors in HCC, thus indicating a poor prognosis for patients. These data support the cancer stem cell hypothesis;
4) There is a preferential expression of ABCG2 in CD133~+ CSC cells. Thus, multi-pathways may take part in multidrug resistance of CD133~+ CSCs except for the activation of anti-apoposis pathway.
引文
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