Department of Physiology and Developmental Biology, Brigham Young University, 574 WIDB, Provo, UT 84602, USA.
Exp Cell Res. 2011 Feb 1;317(3):307-18. doi: 10.1016/j.yexcr.2010.11.002. Epub 2010 Nov 11.
HGF signaling induces epithelial cells to disassemble cadherin-based adhesion and increase cell motility and invasion, a process termed epithelial-mesenchymal transition (EMT). EMT plays a major role in cancer metastasis, allowing individual cells to detach from the primary tumor, invade local tissue, and colonize distant tissues with new tumors. While invasion of vascular and lymphatic networks is the predominant route of metastasis, nerves also can act as networks for dissemination of cancer cell to distant sites in a process termed perineual invasion (PNI). Signaling between nerves and invasive cancer cells remains poorly understood, as does cellular decision making that selects the specific route of invasion. Here we examine how HGF signaling contributes to PNI using reductionist culture model systems. We find that TGFβ, produced by PC12 cells, enhances scattering in response to HGF stimulation, increasing both cell-cell junction disassembly and cell migration. Further, gradients of TGFβ induce migratory mesenchymal cells to undergo chemotaxis towards the source of TGFβ. Interestingly, VEGF suppresses TGFβ-induced enhancement of scattering. These results have broad implications for how combinatorial growth factor signaling contributes to cancer metastasis, suggesting that VEGF and TGFβ might modulate HGF signaling to influence route selection during cancer progression.
HGF 信号诱导上皮细胞分解基于钙黏蛋白的黏附，并增加细胞迁移和侵袭能力，这一过程称为上皮间质转化（EMT）。EMT 在癌症转移中起着重要作用，使单个细胞能够从原发性肿瘤上脱离，侵袭局部组织，并在远处组织中形成新的肿瘤。尽管血管和淋巴管的侵袭是转移的主要途径，但神经也可以作为癌细胞扩散到远处的途径，这一过程称为周围侵袭（PNI）。神经与侵袭性癌细胞之间的信号传递仍然知之甚少，细胞如何做出选择特定侵袭途径的决策也不清楚。在这里，我们使用简化的培养模型系统研究了 HGF 信号如何促进 PNI。我们发现，PC12 细胞产生的 TGFβ 增强了对 HGF 刺激的散射反应，增加了细胞-细胞连接的解体和细胞迁移。此外，TGFβ 梯度诱导迁移的间充质细胞向 TGFβ 的来源发生趋化运动。有趣的是，VEGF 抑制 TGFβ 诱导的散射增强。这些结果对组合生长因子信号如何促进癌症转移具有广泛的意义，表明 VEGF 和 TGFβ 可能调节 HGF 信号，以影响癌症进展过程中的途径选择。
