Shibue Tsukasa, Weinberg Robert A
Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA.
Proc Natl Acad Sci U S A. 2009 Jun 23;106(25):10290-5. doi: 10.1073/pnas.0904227106. Epub 2009 Jun 5.
The development of metastases is an extended and inefficient process involving multiple steps. The last of these involves the growth of micrometastases into macroscopic tumors. We show here that intravenously injected, nonmetastatic cancer cells cease proliferating after extravasating into the parenchyma of the lungs; this response is attributable to the cells inability to trigger adhesion-related signaling events when they are scattered sparsely within the extracellular matrix (ECM) of the parenchyma. We recapitulate this situation by culturing these nonmetastatic cells at low seeding density in ECM-derived gels in vitro, in which they undergo cell-cycle arrest resulting, in part, from insufficient activation of focal adhesion kinase (FAK). Metastatic cancer cells, in contrast, show sufficient FAK activation to enable their proliferation within ECM gels in vitro and continue cell-cycle progression within the lung parenchyma in vivo. Activation of FAK in these metastatic cells depends on expression of the beta(1) subunit of integrins, and proliferation of these cells after extravasation in the lungs is diminished by knocking down the expression of either FAK or integrin beta(1). These results demonstrate the critical role of integrin beta(1)-FAK signaling axis in controlling the initial proliferation of micrometastatic cancer cells disseminated in the lungs.
转移瘤的形成是一个涉及多个步骤的漫长且低效的过程。其中最后一个步骤涉及微转移灶生长为肉眼可见的肿瘤。我们在此表明，静脉注射的非转移性癌细胞在渗入肺实质后停止增殖；这种反应归因于细胞在稀疏散布于肺实质细胞外基质（ECM）中时无法触发与黏附相关的信号事件。我们通过在体外将这些非转移性细胞以低接种密度培养于ECM衍生的凝胶中来重现这种情况，在这种凝胶中它们会经历细胞周期停滞，部分原因是黏着斑激酶（FAK）激活不足。相比之下，转移性癌细胞显示出足够的FAK激活，使其能够在体外ECM凝胶中增殖，并在体内肺实质内继续细胞周期进程。这些转移性细胞中FAK的激活取决于整合素β1亚基的表达，敲低FAK或整合素β1的表达会减少这些细胞在肺内渗出后的增殖。这些结果证明了整合素β1-FAK信号轴在控制散布于肺内的微转移癌细胞的初始增殖中的关键作用。
