HIF-1alpha介导的肺癌相关性成纤维细胞自噬对吉非替尼敏感性的影响及机制

Gefitinib sensitivity is critical for the effective treatment of late stage non-small cell lung cancer patients. Most studies of gefitinib resistance focus on cancer cell per se but not its microenvironment. Tumor microenvironment has recently gained much attention as a vital determinant of tumor progression. In particular, recent studies have demonstrated autophagic cancer associated fibroblasts (CAFs) promote the survival of cancer cells. However, how autophagic CAFs would affect gefitinib sensitivity of NSCLC is unknown. We previously found co-culture of human fibroblasts and lung cancer cells increase HIF-1 alpha level of fibroblasts alone with up-regulation of autophagy markers. Additionally, increased autophagy level of CAFs lead to lower gefitinib sensitivity of lung cancer cells. Based on preliminary data, we plan to employ co-culture model of CAFs and tumor cells, lung cancer xenotransplantation nude mice model and clinical specimens of lung cancer along with clinical bioinformatics to demonstrate the effects of HIF-1alpha induced autophagic CAFs on gefitinib sensitivity and to further explore the role of TIGAR in this biological process. This project may discover a novel way to promote gefitinib sensitivity of NSCLC.

吉非替尼作为治疗晚期非小细胞肺癌的表皮生长因子受体酪氨酸激酶抑制剂的代表，其敏感性是有效治疗的关键。既往的靶向药物敏感性研究多关注肿瘤细胞本身，而较少注重间质细胞。研究表明肿瘤相关成纤维细胞（CAFs）自噬可促进肿瘤细胞的增殖。然而CAFs的自噬水平对非小细胞肺癌吉非替尼敏感性的影响尚不明确。我们前期发现CAFs与肺癌细胞共培养后，CAFs的HIF-1alpha表达量及自噬水平明显提高，而肺癌细胞的吉非替尼敏感性明显降低。本课题拟借助CAFs/肺癌细胞共培养体系、裸鼠成瘤动物模型以及临床组织标本阐明HIF-1alpha介导的CAFs自噬调控吉非替尼敏感性的分子过程，并探索TIGAR分子在这一调控作用中的角色及相关机制，为临床提高非小细胞肺癌吉非替尼疗效提供新的思路。

表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI）已成为EGFR敏感突变的非小细胞肺癌患者临床一线治疗方案，尽管在无进展生存期和总生存期均优于常规化疗，但大多数患者不可避免的会对其产生获得性耐药，给治疗带来新的挑战。我们发现肿瘤相关成纤维细胞（CAFs）与肺癌细胞共培养后，CAFs的HIF-1alpha表达量及自噬水平明显提高，而肺癌细胞的EGFR-TKI敏感性明显降低。另一方面，EGFR-TKI耐药细胞也较敏感细胞的自噬水平升高，抑制其自噬水平可增加其药物敏感性。我们发现在自噬水平升高的同时伴随着FGFR家族蛋白的水平升高，以及ERK通路磷酸化蛋白的抑制，这可能是自噬调控EGFR-TKI敏感性的关键分子事件。因此，本研究提示肿瘤微环境和肿瘤细胞本身的自噬状态改变及相关分子事件可能影响肺癌细胞的EGFR-TKI耐药，这可能为未来解决肺癌EGFR靶向药物耐药提供了新的思路。