Knuchel Sarah, Anderle Pascale, Werfelli Patricia, Diamantis Eva, Rüegg Curzio
Department of Medicine, Faculty of Science, University of Fribourg, Fribourg, CH-1700, Switzerland.
Swiss Institute of Bioinformatics, Lausanne, CH-1000, Switzerland.
Oncotarget. 2015 Jun 10;6(16):14300-17. doi: 10.18632/oncotarget.3883.
Carcinoma-associated fibroblasts were reported to promote colorectal cancer (CRC) invasion by secreting motility factors and extracellular matrix processing enzymes. Less is known whether fibroblasts may induce CRC cancer cell motility by contact-dependent mechanisms. To address this question we characterized the interaction between fibroblasts and SW620 and HT29 colorectal cancer cells in 2D and 3D co-culture models in vitro. Here we show that fibroblasts induce contact-dependent cancer cell elongation, motility and invasiveness independently of deposited matrix or secreted factors. These effects depend on fibroblast cell surface-associated fibroblast growth factor (FGF) -2. Inhibition of FGF-2 or FGF receptors (FGFRs) signaling abolishes these effects. FGFRs activate SRC in cancer cells and inhibition or silencing of SRC in cancer cells, but not in fibroblasts, prevents fibroblasts-mediated effects. Using an RGD-based integrin antagonist and function-blocking antibodies we demonstrate that cancer cell adhesion to fibroblasts requires integrin αvβ5. Taken together, these results demonstrate that fibroblasts induce cell-contact-dependent colorectal cancer cell migration and invasion under 2D and 3D conditions in vitro through fibroblast cell surface-associated FGF-2, FGF receptor-mediated SRC activation and αvβ5 integrin-dependent cancer cell adhesion to fibroblasts. The FGF-2-FGFRs-SRC-αvβ5 integrin loop might be explored as candidate therapeutic target to block colorectal cancer invasion.
据报道，癌相关成纤维细胞通过分泌运动因子和细胞外基质加工酶促进结直肠癌（CRC）侵袭。关于成纤维细胞是否可通过接触依赖性机制诱导CRC癌细胞运动，人们了解较少。为解决这个问题，我们在体外二维和三维共培养模型中对成纤维细胞与SW620和HT29结直肠癌细胞之间的相互作用进行了表征。在此我们表明，成纤维细胞可独立于沉积基质或分泌因子诱导接触依赖性癌细胞伸长、运动和侵袭。这些效应取决于成纤维细胞表面相关的成纤维细胞生长因子（FGF）-2。抑制FGF-2或FGF受体（FGFRs）信号传导可消除这些效应。FGFRs激活癌细胞中的SRC，抑制或沉默癌细胞而非成纤维细胞中的SRC可阻止成纤维细胞介导的效应。使用基于RGD的整合素拮抗剂和功能阻断抗体，我们证明癌细胞与成纤维细胞的粘附需要整合素αvβ5。综上所述，这些结果表明，成纤维细胞在体外二维和三维条件下通过成纤维细胞表面相关的FGF-2、FGF受体介导的SRC激活以及αvβ5整合素依赖性癌细胞与成纤维细胞的粘附，诱导细胞接触依赖性结直肠癌细胞迁移和侵袭。FGF-2-FGFRs-SRC-αvβ5整合素环可能作为阻断结直肠癌侵袭的候选治疗靶点进行探索。
