Institute of Bioengineering and Swiss Institute for Experimental Cancer Research, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
Cancer Res. 2011 Feb 1;71(3):790-800. doi: 10.1158/0008-5472.CAN-10-1513. Epub 2011 Jan 18.
Interstitial flow emanates from tumors into the microenvironment where it promotes tumor cell invasion. Fibroblasts are key constituents of the tumor stroma that modulate the mechanical environment by matrix remodeling and contraction. Here, we explore how interstitial fluid flow affects fibroblast-tumor cell interactions. Using a 3-dimensional invasion assay and MDA-MB-435S cells cocultured with dermal fibroblasts in a collagen matrix, we showed a synergistic enhancement of tumor cell invasion by fibroblasts in the presence of interstitial flow. Interstitial flow also drove transforming growth factor (TGF)-β1 and collagenase-dependent fibroblast migration, consistent with previously described mechanisms in which flow promotes invasion through autologous chemotaxis and increased motility. Concurrently, migrating fibroblasts enhanced tumor cell invasion by matrix priming via Rho-mediated contraction. We propose a model in which interstitial flow promotes fibroblast migration through increased TGF-β1 activation and collagen degradation, positioning fibroblasts to locally reorganize collagen fibers via Rho-dependent contractility, in turn enhancing tumor cell invasion via mechanotactic cues. This represents a novel mechanism in which interstitial flow causes fibroblast-mediated stromal remodeling that facilitates tumor invasion.
间质流从肿瘤中涌出进入微环境，促进肿瘤细胞侵袭。成纤维细胞是肿瘤基质的关键组成部分，通过基质重塑和收缩调节机械环境。在这里，我们探讨了间质液流如何影响成纤维细胞-肿瘤细胞相互作用。使用三维侵袭测定法和 MDA-MB-435S 细胞与真皮成纤维细胞在胶原基质中共培养，我们发现间质流存在时，成纤维细胞协同增强了肿瘤细胞的侵袭。间质流还驱动转化生长因子 (TGF)-β1 和胶原酶依赖性成纤维细胞迁移，这与先前描述的流动通过自体趋化作用和增加运动性促进侵袭的机制一致。同时，迁移的成纤维细胞通过基质引发增强了肿瘤细胞的侵袭，通过 Rho 介导的收缩来实现。我们提出了一个模型，其中间质流通过增加 TGF-β1 的激活和胶原蛋白的降解来促进成纤维细胞的迁移，使成纤维细胞能够通过 Rho 依赖性收缩在局部重新组织胶原蛋白纤维，进而通过趋化性信号增强肿瘤细胞的侵袭。这代表了一种新的机制，其中间质流导致成纤维细胞介导的基质重塑，从而促进肿瘤侵袭。
