Gaudino Giovanni, Yang Haining, Carbone Michele
University of Hawai'i Cancer Center, 701 Ilalo Street, Honolulu, HI 96813, USA.
Biomedicines. 2014 Nov 14;2(4):327-344. doi: 10.3390/biomedicines2040327.
Malignant mesothelioma (MM) is a highly aggressive cancer related to asbestos or erionite exposure and resistant to current therapies. Hepatocyte Growth Factor (HGF) and its tyrosine kinase receptor Met regulate cell growth, survival, motility/migration, and invasion. HGF and Met are expressed in MM cells, suggesting that the HGF/Met signaling plays a role in development and progression of this tumor, by autocrine and/or paracrine mechanisms. Upregulation and ligand-independent activation of Met, which is under suppressive control of miR-34 family members, correlate with enhanced invasion, migration and metastatic potential in several cancers, including MM. Moreover, Simian Virus 40 (SV40) Tag expression also induces a HGF autocrine circuit in an Rb-dependent manner in human mesothelial cells (HM) and possibly other cell types, enhancing cell adhesion, invasion and angiogenesis. The resulting activation of Met causes HM transformation and cell cycle progression, and contributes to virus particle assembling and infection of adjacent cells. The constitutive activation of Met, frequently occurring in MM, has been successfully targeted in preclinical models of MM. In conclusion, Met expression, activation state, subcellular localization and also HGF co-receptors expression, such as CD44, have clinical relevance for novel targeted therapies in a cancer for which no effective treatment is currently available.
恶性间皮瘤（MM）是一种与接触石棉或毛沸石相关的高度侵袭性癌症，且对当前疗法具有抗性。肝细胞生长因子（HGF）及其酪氨酸激酶受体Met调节细胞生长、存活、运动/迁移和侵袭。HGF和Met在MM细胞中表达，这表明HGF/Met信号通过自分泌和/或旁分泌机制在该肿瘤的发生和发展中起作用。Met的上调和不依赖配体的激活受miR-34家族成员的抑制控制，在包括MM在内的几种癌症中，其与侵袭、迁移和转移潜能增强相关。此外，猿猴病毒40（SV40）大T抗原表达还以Rb依赖的方式在人间皮细胞（HM）及可能的其他细胞类型中诱导HGF自分泌回路，增强细胞黏附、侵袭和血管生成。由此产生的Met激活导致HM转化和细胞周期进程，并有助于病毒颗粒组装和感染邻近细胞。Met的组成性激活在MM中经常发生，已在MM的临床前模型中成功作为靶点。总之，Met的表达、激活状态、亚细胞定位以及HGF共受体如CD44的表达，对于目前尚无有效治疗方法的癌症的新型靶向治疗具有临床意义。
