Cancer-associated fibroblasts as another polarized cell type of the tumor microenvironment

Abstract

Tumor- or cancer-associated fibroblasts (CAFs) are one of the most abundant stromal cell types in different carcinomas and comprise a heterogeneous cell population. Classically, CAFs are assigned with pro-tumorigenic effects stimulating tumor growth and progression. More recent studies demonstrated also tumor-inhibitory effects of CAFs suggesting that tumor-residing fibroblasts exhibit a similar degree of plasticity as other stromal cell types. Reciprocal interactions with the tumor milieu and different sources of origin are emerging as two important factors underlying CAF heterogeneity. This review highlights recent advances in our understanding of CAF biology and proposes to expand the term of cellular "polarization," previously introduced to describe different activation states of various immune cells, onto CAFs to reflect their phenotypic diversity.

Keywords: cancer; cancer-associated fibroblasts; polarization; tumor microenvironment; tumor promotion; tumor suppression.

Figure 1

Tumor-stimulatory and tumor-inhibitory effects of CAFs. Fibroblasts present in the tumor stroma (CAFs) are predominantly assigned with a tumor-promoting function. CAFs (shown in red) stimulate cancer cell survival, growth, and invasion, enhance the stiffness of the extracellular matrix, contribute to angiogenesis by releasing pro-angiogenic factors, contribute to a pro-inflammatory milieu, and impact on the activation state of various immune cells. More recent data demonstrate that tumor-resident fibroblast (depicted in yellow) can also confer tumor-suppressive effects. However, the mechanisms underlying this inhibitory phenotype are not known but may involve direct inhibition of cancer cells and modulation of immune cell behavior.

Figure 2

Properties of polarized CAFs. Depending on the type of signals, intra-tumoral fibroblasts can be polarized thereby adopting different activation states. Type II polarized fibroblasts (F2) differentiate into pro-tumorigenic fibroblasts under the influence of, e.g., growth factors and chemokines (called “inducer”). Signaling induced by CXCL14, hedgehog (Hh), or TGF-β activates transcription factors that induce a program controlling the expression of a variety of “effector”-molecules (matrix-components, matrix-remodeling enzymes, growth factors, and cytokines) that in turn deploy pro-tumorigenic effects by stimulating other cells in the environment of the local tumor and beyond. In contrast, type I polarized fibroblasts (F1)-expressing molecules such as Wnt3a and Slit2 can exhibit tumor-inhibitory effects by suppressing the action of cancer cells. About the exogenous signals and transcription factors involved in establishing the tumor-suppressive phenotype can only be speculated so far. Potential inducers of type I-CAFs are TNF-α and LPS that have been shown to stimulate Wnt3a and chemokine expression, respectively (92).