肝癌相关成纤维细胞促进肝癌化疗耐药的分子机制研究

Carcinoma associated fibroblast (CAF), as a major component of tumor stroma, has been confirmed to contribute significantly to the genesis and development of malignant tumor; however, few has been done in the field of chemoresistance induction. We previously have successfully isolated hepatocellular carcinoma (HCC) associated fibroblast (HCC-CAF) and further confirmed that the HCC-CAF suppressed the activation of natural killer cells and created favorable conditions for tumor progression (Cancer Letters, 2012). Furthermore, we found that HCC-CAF could induce chemoresistance of HCC cells under cell co-culture model. And the possible mechanism at least included HCC-CAF's secreting cytokines, such as IL-6 and HGF, and its' regulating microRNA expression of HCC cells including let-7a and miR-21. However, the underling molecular mechanism remains unclear. Compared to hepatocellular carcinoma cells featured by massive heterogeneity, CAFs are highly homogenous with stable phenotype and markers. Thus, biological therapy targeted at HCC-CAF might reverse the HCC chemoresistance persistently, which might be a novel strategy of great potential. Therefore, this study is aimed to specify the latent mechanism which HCC-CAF induced HCC chemoresistance by employing our already established HCC-CAF in vivo and in vitro models. The findings of our research will help to elucidate the mechanism of HCC chemoresistance and to facilitate targeted therapy design based on HCC-CAF.

肿瘤相关成纤维细胞（CAF）作为肿瘤间质的主要成分，能促进肿瘤的发生发展，但其在肿瘤耐药方面罕有报导。在前期研究中我们率先分离鉴定了人肝癌相关成纤维细胞（HCC-CAF），并证实HCC-CAF可以促进肝癌免疫逃逸和侵袭转移（Cancer Letters, 2012）。进一步研究发现HCC-CAF可以通过分泌大量的IL-6、HGF，及调节肝癌miR-21与let-7a的表达来诱导肝癌的化疗耐药，但其具体的分子调控机制亟待明晰。与肿瘤细胞相比，CAF表型稳定、异质性小，因此针对其设计的靶向治疗可能更持久逆转耐药，有望成为肝癌化疗增敏的新策略。本研究拟在此基础上，结合体内外模型及临床验证分析HCC-CAF促进肝癌化疗抵抗的分子机制，阐明其中的关键因子及其潜在调控信号通路。HCC-CAF促进肝癌化疗抵抗分子机制的阐明，可为基于此的靶向治疗提供新颖靶点，有望实现靶向治疗下的化疗增敏。

肿瘤相关成纤维细胞（CAF）作为肿瘤间质的主要成分，能促进肿瘤的发生发展，但其在肿瘤耐药方面罕有报导。在前期研究中我们率先分离鉴定了人肝癌相关成纤维细胞（HCC-CAF），并证实HCC-CAF 可以促进肝癌免疫逃逸和侵袭转移。进一步研究发现CAF的存在可以显著提高肝癌细胞的化疗药物抵抗能力，但其具体的分子调控机制亟待明晰。我们首先证实CAF在体内外可以显著增加肝癌对顺铂等化疗药物的抵抗能力，进而发现CAF是通过分泌IL-6、HGF下调肝癌细胞15-PGDH的表达，而15-PGDH的表达减少后将激活肝癌细胞的自噬通路增加细胞自噬，而肝癌细胞自噬的增加帮助肝癌细胞抵抗化疗药物的损伤。另外，我们还发现CAF一方面通过分泌含有线粒体的微囊泡，将健康的线粒体通过囊泡转运给肿瘤细胞，另一方面通过细胞因子调控的miRNA谱变化改变肿瘤细胞的内吞、自噬功能，使肿瘤细胞加强对CAFs传递的线粒体的“摄取、消化”从而改善在化疗药物损伤时的能量代谢而存活下来。通过本项目的实施，不仅为设计针对肝癌细胞群体耐药的共同诱导因素CAF的靶向治疗策略，探索肝癌治疗的新模式—分子靶向治疗增敏下的化学治疗的可行性，为进一步开发逆转肝癌耐药的靶向药物提供理论依据。