Identification of Two Distinct Carcinoma-Associated Fibroblast Subtypes with Differential Tumor-Promoting Abilities in Oral Squamous Cell Carcinoma

作者：Daniela Elena Costea, Allison Hills, Amani H. Osman, Johanna K. Thurlow, Gabriela Kalna, Xiaohong Huang, Claudia Pena Murillo, Himalaya Parajuli, Salwa Suliman, Keerthi K. Kulasekara, A. C. Johannessen, Max Partridge · 发表于：Cancer Research · 年份：2013 · DOI：10.1158/0008-5472.can-12-4150 · 被引用次数：176 · 研究领域：Fibroblast Growth Factor Research、Mesenchymal stem cell research、Extracellular vesicles in disease

Heterogeneity of carcinoma-associated fibroblasts (CAF) has long been recognized, but the functional significance remains poorly understood. Here, we report the distinction of two CAF subtypes in oral squamous cell carcinoma (OSCC) that have differential tumor-promoting capability, one with a transcriptome and secretome closer to normal fibroblasts (CAF-N) and the other with a more divergent expression pattern (CAF-D). Both subtypes supported higher tumor incidence in nonobese diabetic/severe combined immunodeficient (NOD/SCID) Ilγ2(null) mice and deeper invasion of malignant keratinocytes than normal or dysplasia-associated fibroblasts, but CAF-N was more efficient than CAF-D in enhancing tumor incidence. CAF-N included more intrinsically motile fibroblasts maintained by high autocrine production of hyaluronan. Inhibiting CAF-N migration by blocking hyaluronan synthesis or chain elongation impaired invasion of adjacent OSCC cells, pinpointing fibroblast motility as an essential mechanism in this process. In contrast, CAF-D harbored fewer motile fibroblasts but synthesized higher TGF-β1 levels. TGF-β1 did not stimulate CAF-D migration but enhanced invasion and expression of epithelial-mesenchymal transition (EMT) markers in malignant keratinocytes. Inhibiting TGF-β1 in three-dimensional cultures containing CAF-D impaired keratinocyte invasion, suggesting TGF-β1-induced EMT mediates CAF-D-induced carcinoma cell invasion. TGF-β1-pretreated normal fibroblasts also induced invasi...