Fibroblast heterogeneity in the cancer wound

Abstract

Fibroblasts regulate the structure and function of healthy tissues, participate transiently in tissue repair after acute inflammation, and assume an aberrant stimulatory role during chronic inflammatory states including cancer. Such cancer-associated fibroblasts (CAFs) modulate the tumor microenvironment and influence the behavior of neoplastic cells in either a tumor-promoting or tumor-inhibiting manner. These pleiotropic functions highlight the inherent plasticity of fibroblasts and may provide new avenues to understand and therapeutically intervene in malignancies. We discuss the emerging themes of CAF biology in the context of tumorigenesis and therapy.

Figure 1.

Molecular definition of cancer-associated fibroblasts. CAFs are composed of two morphologically distinctive populations: fibroblasts and myofibroblasts. Indicated are common molecular markers that define CAFs.

Figure 2.

CAFs promote tumorigenesis: a schematic illustration representing all the fronts in which CAFs boost cancer. By secreting soluble factors and lipid-based particles, transformed epithelium drives recruitment (1) and reprogramming (2) of several types of cells into CAFs, including resident fibroblasts (NAFs) that are naturally tumor-suppressive. CAFs are then activated to promote tumor initiation (3), cancer cell stemness (4), and to change tumor metabolism (5) by intensive cross talk of ligands/receptors, cell–cell contact, and remodeling the ECM (6). Concomitantly, CAFs prevent immune surveillance of tumor cells (7) while balancing inflammation and angiogenesis (8). Finally, CAFs stimulate invasion and metastasis by facilitating tumor cell dissemination, intra- and extravasation, and metastatic colonization (9).

Figure 3.

Principle strategies for targeting CAF-induced pro-tumorigenic effects. Presented are four general approaches to control and diminish CAFs and their activity toward tumorigenesis and drug resistance. Examples of targets that have been hypothesized and/or empirically tested are indicated.