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

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.

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。

抗血管生成耐药一直是阻碍抗血管生成治疗疗效的主要问题。解决耐药十分重要。肿瘤干细胞是导致贝伐单抗抗血管生成治疗失败的主要原因之一，其是否也参与了恩度治疗耐药尚不清楚。. 我们的研究主要观察恩度抗血管生成治疗A549荷瘤小鼠后，肿瘤组织中肿瘤干细胞的比例是否上升，同时，我们也观察肿瘤微环境中一些主要炎性细胞和细胞因子是否也发生了变化，我们使用FAP作为肿瘤相关成纤维细胞的标记物，对恩度使用后肿瘤微环境中肿瘤相关成纤维细胞比例的变化进行研究，并检测恩度使用后肿瘤干细胞是否向肿瘤相关成纤维细胞转变。不过，通过进一步的研究，我们发现，将FAP作为肿瘤相关成纤维细胞的标记物并不准确，我们需要进一步研究肿瘤相关成纤维细胞的标记物，然后才能展开研究转化的问题。. 已完成的研究显示：低氧和TGF-β1协同导致肿瘤干细胞比例增加。低氧和TGF-β1协同作用导致肺癌肿瘤干细胞增加，根据我们的发现抑制甚至杀灭肿瘤干细胞能够为解决恩度耐药提供参考，具有十分重要的临床意义。