Endostatin诱导肺癌干细胞形成并向肿瘤相关成纤维细胞分化的抗血管生成治疗耐药机制研究

抗血管生成治疗一直是肿瘤研究的热点。以往曾认为抗血管生成可抑制肿瘤生长并减少转移。最近研究表明，抗血管生成可产生耐药，还会增加肿瘤转移复发风险，这涉及到抗血管生成治疗后肿瘤微环境发生的一系列反应性变化。Endostatin，我们推测，正如其他血管生成抑制剂一样，也会加重肿瘤微环境的缺氧，从而促进肿瘤微环境中肿瘤干细胞的形成并向肿瘤相关成纤维细胞分化，最终导致抗血管生成治疗耐药。本研究旨在原有研究的基础上，拟采用细胞生物学、分子生物学、流式细胞术等技术，开展Endostatin对肿瘤微环境中肺癌干细胞和肿瘤相关成纤维细胞的影响研究，探讨Endostatin诱导肿瘤微环境中肺癌干细胞形成并向肿瘤相关成纤维细胞分化的机制。这对阐明抗血管生成治疗后肿瘤转移与复发的耐药机理，验证肿瘤干细胞及肿瘤相关成纤维细胞在肿瘤发生发展中的作用，拓展肿瘤治疗新思维具有开创性科学意义。

Antiangiogenic therapy has been a hot topic of cancer research. Previously antiangiogenic therapy has been thought to inhibit tumor growth and reduce metastasis. Recent studies have shown that antiangiogenic agents lead to drug resistance, and also increase tumor metastasis and recurrence risk, that involves a series of changes developed in tumor microenvironment during antiangiogenic therapy. We speculate that, just as other angiogenesis inhibitors, endostatin might increase the hypoxic tumor microenvironment, thereby promote cancer stem cells in the tumor microenvironment formation and differentiation into cancer-associated fibroblasts, eventually lead to antiangiogenic drug resistance. Based on our previous research, we plan to adopt cell biology, molecular biology and flow cytometry technology to carry out the study of the influence of endostatin on lung cancer stem cells and cancer-associated fibroblasts in the tumor microenvironment. And we will investigate the mechanisms of endostatin inducing lung cancer stem cells in the tumor microenvironment formation and differentiation into cancer-associated fibroblasts. This study is of groundbreaking scientific significance to elucidate the mechanism of tumor metastasis and recurrence after established antiangiogenesis therapy drug resistance, to verify the role of cancer stem cells and cancer-associated fibroblasts in tumor development and to expand new ideas to cancer treatment.