Mao W, Irby R, Coppola D, Fu L, Wloch M, Turner J, Yu H, Garcia R, Jove R, Yeatman T J
Department of Surgery, H Lee Moffitt Cancer Center, University of South Florida, Tampa 33612, USA.
Oncogene. 1997 Dec 18;15(25):3083-90. doi: 10.1038/sj.onc.1201496.
Recent data suggest that signal transduction may have a critical role in the development and regulation of the metastatic phenotype. Here, we investigated the role of c-Src activation in the process of human colon cancer metastasis to the liver. Our data, derived from two different sets of human colon cancer cell line metastatic variants, suggest that not only do highly-metastatic cells display constitutively elevated c-Src protein kinase activity when compared to poorly metastatic cells, but also that receptor tyrosine kinases participate in the ligand-activation of c-Src above basal levels. Specifically, the epidermal growth factor receptor (EGFR), p185HER2/Neu and the hepatocyte growth factor receptor (c-Met) appear to be linked to the process because they preferentially activate c-Src in highly-metastatic cells. EGFR was found to associate with c-Src in colon cancer cells and specific inhibitors of the EGFR resulted in a reduction of c-Src activity to basal levels. In addition, c-Src transfectants displayed partially-activated EGFRs, suggesting a feedback role for c-Src in the regulation of the EGFR. p185HER2/Neu was also identified in immunocomplexes of c-Src following ligand activation of the EGFR, but only in highly-metastatic cells. Collectively, these observations suggest a paradigm whereby c-Src interacts with multiple cell-surface growth factors in a catalytic fashion for the development of tumor cells with metastatic potential.
近期数据表明，信号转导可能在转移表型的发展和调控中起关键作用。在此，我们研究了c-Src激活在人结肠癌肝转移过程中的作用。我们的数据来源于两组不同的人结肠癌细胞系转移变体，表明与低转移细胞相比，高转移细胞不仅显示出组成性升高的c-Src蛋白激酶活性，而且受体酪氨酸激酶参与了c-Src在基础水平之上的配体激活。具体而言，表皮生长因子受体（EGFR）、p185HER2/Neu和肝细胞生长因子受体（c-Met）似乎与该过程相关，因为它们在高转移细胞中优先激活c-Src。发现EGFR在结肠癌细胞中与c-Src相关联，并且EGFR的特异性抑制剂导致c-Src活性降低至基础水平。此外，c-Src转染子显示出部分激活的EGFR，表明c-Src在EGFR的调控中具有反馈作用。在EGFR配体激活后，p185HER2/Neu也在c-Src的免疫复合物中被鉴定出来，但仅在高转移细胞中。总体而言，这些观察结果提示了一种模式，即c-Src以催化方式与多种细胞表面生长因子相互作用，以促进具有转移潜能的肿瘤细胞的发展。
