Kim Lori C, Song Lanxi, Haura Eric B
University of South Florida College of Medicine, Tampa, FL, USA.
Nat Rev Clin Oncol. 2009 Oct;6(10):587-95. doi: 10.1038/nrclinonc.2009.129.
Src family kinases (SFKs) have a critical role in cell adhesion, invasion, proliferation, survival, and angiogenesis during tumor development. SFKs comprise nine family members that share similar structure and function. Overexpression or high activation of SFKs occurs frequently in tumor tissues and they are central mediators in multiple signaling pathways that are important in oncogenesis. SFKs can interact with tyrosine kinase receptors, such as EGFR and the VEGF receptor. SFKs can affect cell proliferation via the Ras/ERK/MAPK pathway and can regulate gene expression via transcription factors such as STAT molecules. SFKs can also affect cell adhesion and migration via interaction with integrins, actins, GTPase-activating proteins, scaffold proteins, such as p130(CAS) and paxillin, and kinases such as focal adhesion kinases. Furthermore, SFKs can regulate angiogenesis via gene expression of angiogenic growth factors, such as fibroblast growth factor, VEGF, and interleukin 8. On the basis of these important findings, small-molecule SFK inhibitors have been developed and are undergoing early phase clinical testing. In preclinical studies these agents can suppress tumor growth and metastases. The agents seem to be safe in humans and could add to the therapeutic arsenal against subsets of cancers.
Src家族激酶（SFK）在肿瘤发生发展过程中的细胞黏附、侵袭、增殖、存活及血管生成中发挥关键作用。SFK由九个家族成员组成，它们具有相似的结构和功能。SFK在肿瘤组织中经常过度表达或高度活化，并且是肿瘤发生过程中多个重要信号通路的核心介质。SFK可与酪氨酸激酶受体相互作用，如表皮生长因子受体（EGFR）和血管内皮生长因子受体（VEGF受体）。SFK可通过Ras/ERK/MAPK途径影响细胞增殖，并可通过转录因子（如信号转导和转录激活因子（STAT）分子）调节基因表达。SFK还可通过与整合素、肌动蛋白、GTP酶激活蛋白、支架蛋白（如p130（CAS）和桩蛋白）以及黏着斑激酶等激酶相互作用，影响细胞黏附和迁移。此外，SFK可通过血管生成生长因子（如成纤维细胞生长因子、VEGF和白细胞介素8）的基因表达来调节血管生成。基于这些重要发现，小分子SFK抑制剂已被开发出来并正在进行早期临床试验。在临床前研究中，这些药物可抑制肿瘤生长和转移。这些药物在人体中似乎是安全的，可能会增加针对某些癌症亚型的治疗手段。
