Danen E H, Yamada K M
Division of Cell Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
J Cell Physiol. 2001 Oct;189(1):1-13. doi: 10.1002/jcp.1137.
Cell proliferation is controlled not only by soluble mitogens but also by components of the extracellular matrix (ECM) such as fibronectin, to which cells adhere via the integrin family of transmembrane receptors. Input from both growth factor receptors and integrins is required to stimulate progression through the G1 phase of the cell cycle, via induction of G1 cyclins and suppression of inhibitors of the G1 cyclin-dependent kinases. Extensive crosstalk takes place between integrin and growth factor receptor signaling pathways, and mitogenic signaling is weak and transient in the absence of integrin-mediated cell adhesion. In normal untransformed cells, all of the important mitogenic signal transduction cascades, namely those downstream of the Ras and Rho family small GTPases and the phosphoinositide 3-OH kinase-PKB/Akt pathway, are regulated by integrin-mediated cell adhesion. As a result, these cells are anchorage-dependent for growth. In contrast, constitutive activity of each of these pathways has been reported in cancer cells, which not only reduces their mitogen dependence but also allows these cells to grow in an anchorage-independent fashion.
细胞增殖不仅受可溶性促有丝分裂原调控，还受细胞外基质（ECM）成分（如纤连蛋白）的调控，细胞通过跨膜受体整合素家族与纤连蛋白黏附。细胞周期G1期进程的刺激需要生长因子受体和整合素的共同输入，通过诱导G1期细胞周期蛋白以及抑制G1期细胞周期蛋白依赖性激酶的抑制剂来实现。整合素和生长因子受体信号通路之间存在广泛的相互作用，在没有整合素介导的细胞黏附时，促有丝分裂信号微弱且短暂。在正常未转化细胞中，所有重要的促有丝分裂信号转导级联反应，即Ras和Rho家族小GTP酶下游的级联反应以及磷酸肌醇3-OH激酶-PKB/Akt途径，均受整合素介导的细胞黏附调控。因此，这些细胞的生长依赖于贴壁。相比之下，据报道癌细胞中这些途径中的每一个都具有组成性活性，这不仅降低了它们对促有丝分裂原的依赖性，还使这些细胞能够以不依赖贴壁的方式生长。
