Tumor necrosis factor α induces myofibroblast differentiation in human tongue cancer and promotes invasiveness and angiogenesis via secretion of stromal cell-derived factor-1

Objectives: Cancer-associated fibroblasts (CAFs) play an important role in tumor progression and are associated with a poor prognosis. Tumor necrosis factor alpha (TNF alpha) has been involved in growth and metastasis associated with epithelial-mesenchymal transition (EMT) in many types of cancers. However, the relationship among the TNF alpha, activation of CAFs and their tumor-promoting effects on tongue squamous cell carcinoma (TSCC) remain obscure. Materials and methods: A series of matched primary CAFs and normal fibroblasts (NFs) pairs were cultured, and additionally two TSCC cell lines SCC9 and CAL27, were treated with TNF alpha or CAFs derived stromal cell-derived factor-1 (SDF1) respectively to study invasion and EMT in vitro. In addition, NFs were treated with TNF alpha to detect the expression of myofibroblast markers, invasion, induced collagen gel contraction and enhanced cancer metastasis. Finally, invasion and angiogenesis of human vein endothelial cells (HUVECs) treated with TNF alpha and CAFs derived SDF1 was measured. Results: TNF alpha and CAFs-derived SDF1 induced TSCC cells metastasis and EMT separately. TNF alpha facilitated the transformation of NFs to CAFs-like fibroblasts, which was accompanied by acquisition of similar myofibroblast markers expression and malignant function to CAFs. Furthermore, TNF alpha and CAFs derived SDF1 also promoted invasion and angiogenesis of HUVECs. Conclusion: These results suggest that TNF alpha may not only directly but also indirectly enhance cancer metastasis, EMT and angiogenesis formation in tongue cancer through myofibroblast differentiation via SDF1 secretion. (C) 2015 Elsevier Ltd. All rights reserved.