Phenotypic heterogeneity, stability and plasticity in tumor-promoting carcinoma-associated fibroblasts.

Reciprocal interactions between cancer cells and stromal cells in the tumor microenvironment (TME) are essential for full-blown tumor development. Carcinoma-associated fibroblasts (CAFs) are a key component of the TME together with a wide variety of stromal cell types including vascular, inflammatory, and immune cells in the extracellular matrix. CAFs not only promote tumor growth, invasion, and metastasis, but also dampen the efficacy of various therapies including immune checkpoint inhibitors. CAFs are composed of distinct fibroblast populations presumably with diverse activated fibroblastic states and tumor-promoting phenotypes in a tumor, indicating intratumor heterogeneity in these fibroblasts. Given that CAFs have been implicated in both disease progression and therapeutic responses, elucidating the functional roles of each fibroblast population in CAFs and the molecular mechanisms mediating their phenotypic stability and plasticity in the TME would be crucial for understanding tumor biology. We herein discuss how distinct fibroblast populations comprising CAFs establish their cell identities, in terms of cells-of-origin, stimuli from the TME, and the phenotypes characteristic of activated states.