烷化剂诱导的ADAM8表达上调募集TAMs介导胶质母细胞瘤化疗抵抗的机制研究

Our preliminary study indicated that temozolomide induced overexpression of ADAM8 (A Disintegrin And Metalloprotease 8) in glioblastoma cells along with an increased expression and hydrolysis of c-Met, which promoted TMZ resistance of tumor cells. Nevertheless, the mechanism downstream involved in the chemoresistance is obscure. Emerging evidence suggests that a mutually reinforcing network of HGF upon c-Met paracrine signaling exists between glioma cells and tumor-associated macrophages (TAMs), whereby glioma cells recruit monocytes to establish a microenvironment of chronic inflammation beneficial for tumor progression. TAMs is reported to promote chemoresistance of pancreatic cancer, however, there is rare evidence concerning TAMs enhancing chemoresistance of glioblastoma. In this research project, we assume that induction of ADAM8 by TMZ recruits monocytes to stromal of glioma tissue via the mutually fortifying network of HGF and c-Met and maintains the tumor-supportive characteristics of these M2-type macrophages resulting in enhanced TMZ resistance of glioblastoma, which would be clarified in four distinct aspects (cells experiment, animal model, molecular mechanism, clinical cases). This research work provides a new way of thinking to reverse chemoresistance and to seek for a useful target to treat glioblastoma effectively.

前期研究提示，替莫唑胺（TMZ）诱导胶质母细胞系过表达解聚素金属蛋白酶8（ADAM8）参与肿瘤细胞TMZ耐药，同时伴随肿瘤细胞c-Met表达和水解增强，但下游的化疗抵抗机制尚不清楚。研究证实，c-Met和其配体HGF在胶质瘤细胞与肿瘤相关巨噬细胞（TAMs）间通过旁分泌通路形成相互反复加强的作用网络，可募集更多TAMs以创造一个利于肿瘤生长的慢性炎症微环境。TAMs可促进胰腺癌的化疗耐药性，但对促进胶质母细胞瘤化疗抵抗的作用研究较少。本研究拟从细胞实验、动物模型、分子机制及临床病例四个方面阐明，烷化剂诱导ADAM8高表达可能通过HGF和c-Met间的网络募集TAMs到肿瘤间质并维持其M2型促瘤极性，TAMs可能进而促进胶质母细胞瘤化疗抵抗。为临床寻找针对胶质母细胞瘤有效的治疗靶点和逆转耐药提供新思路。