SDF-1α/CXCR4信号通路通过激活PAK1促进胃癌进展及5-氟尿嘧啶化疗抵抗的作用研究

Gastric cancer is one of the most common malignancies worldwide and accounts for the second leading cause of cancer-related mortality globally. At present, 5-fluorouracil (5-FU) is widely used for the treatment of advanced gastric cancer, however, because of drug resistance, its clinical application is limited. Haematological and solid tumour cells interact with their microenvironment through membrane chemokine receptors and their corresponding ligands, which are expressed in the tumor microenvironment. The C-X-C chemokine receptor type 4 (CXCR4) and its chemokine ligand stromal cell-derived factor-1α (SDF-1α) are two key factors in the cross-talking between cancer cells and their microenvironment, what could promote the tumor progression and make them the promising targets for cancer therapy. Our previous study has identified that the protein level of CXCR4 was upregulation in gastric cancer tissues, and the protein level of SDF-1α was upregulation in peritumoral tissues. Both CXCR4 and SDF-1α expression are the independent prognostic factors for patients with gastric cancer. Applying the prognostic value of intratumoral CXCR4 density to TNM stage system showed a better prognostic value in patients with gastric cancer. SDF-1α and CXCR4 also have roles in tumor growth, and may induce the chemotherapy resistance of 5-FU. In addition, SDF-1α and CXCR4 could activate the p21-activated kinase 1 (PAK1). On the basis of previous studies, this project will further clarify the phenomenon that SDF-1α/CXCR4 could promote the progression of gastric cancer and induce the chemotherapy resistance of 5-FU through activating PAK1. This project will construct a SDF-1α/CXCR4 and PAK1/pPAK1 based molecular chemotherapy sensitivity model, and provide a new idea for the individual treatment of gastric cancer patients.

胃癌化疗用药以5-氟尿嘧啶（5-FU）为基础，但由于耐药等原因，在一定程度上限制了5-FU的临床应用。趋化因子SDF-1α及其受体CXCR4是肿瘤细胞与其生存微环境交互作用的重要通路。项目申请人前期研究发现：胃癌组织中CXCR4和癌旁组织中SDF-1α的高表达是影响胃癌预后的独立因子；胃癌细胞中SDF-1α/CXCR4信号通路的活化可以促进胃癌细胞增殖和对5-FU的化疗抵抗；此外，胃癌细胞中SDF-1α/CXCR4信号通路的活化还可以激活PAK1，促进pPAK1的形成，而PAK1的活化亦可导致消化道细胞的恶性转化和凋亡抵抗。本项目拟在前期研究的基础上，进一步明确SDF-1α/CXCR4信号通路通过激活PAK1促进胃癌进展及5-FU化疗抵抗的作用，构建基于SDF-1α/CXCR4和PAK1/pPAK1表达的胃癌预后及5-FU化疗敏感性和效果判断的分子分型模型，为胃癌的个体化治疗提供新的思路。

肿瘤微环境的形成是肿瘤细胞与肿瘤间质相互作用的结果。肿瘤组织中免疫抑制的微环境可以促进肿瘤细胞免疫逃逸。在肿瘤进展过程中，不同的细胞因子、生长因子和趋化因子，如CXCL12、CXCL13、CCL22、CXCL5、IL-6和IL-11等，可以诱导不同表型的免疫抑制细胞在肿瘤组织中聚集和活化，从而在肿瘤间质中形成免疫抑制的微环境，促进肿瘤细胞免疫逃逸。在青年科学基金项目的资助下，项目负责人对上述不同因子在胃癌肿瘤微环境中分布情况以及与胃癌患者预后和化疗敏感性之间的相关性进行了深入的研究。研究发现：（1）趋化因子CCL22招募并活化调节性T细胞向胃癌肿瘤微环境浸润进而抑制杀伤性CD8+T细胞介导的抗肿瘤免疫反应，形成免疫逃逸肿瘤微环境，促进胃癌发生发展、复发转移和治疗抵抗过程，在此基础上我们进一步确认其在胃癌分子分型和5-FU治疗反应预测中的临床应用价值（OncoImmunology. 2018;6;7(6):e1433517.）；（2）胃癌组织中趋化因子CXCL13的高表达可以通过其受体CXCR5诱导肿瘤相关的巨噬细胞在胃癌组织中聚集活化，形成免疫抑制的肿瘤微环境，进而促进胃癌的发生发展和治疗抵抗（Cancer Immunology Immunotherapy. 2018;67(2):261-269.）；（3）胃癌组织中O6-甲基鸟嘌呤-DNA甲基转移酶（O6-methylguanine-DNA methyltransferase，MGMT）的低表达是胃癌患者不良预后的独立影响因子，高表达MGMT的TNM II期胃癌患者可以从5-FU为基础药物的术后化疗中获益（JAMA Surgery. 2017;152(11):e173120.）；（4）炎症相关细胞因子IL-6/IL-11作用于胃癌细胞表面高表达的糖蛋白gp130后可以激活下游STAT3信号通路，促进胃癌的侵袭进展，进而导致了胃癌患者的不良预后（Scientific Reports. 2016;6:38364.）。上述研究结果使我们更深入、全面的了解不同的细胞因子、生长因子和趋化因子在形成免疫抑制微环境和促进胃癌免疫逃逸中的作用，从而为建立胃癌免疫治疗反应性的分子调控和预测干预模型以及胃癌的个体化精准免疫治疗提供了新的思路。