Fibroblasts in the Tumor Microenvironment: Shield or Spear?

Abstract

Tumorigenesis is a complex process involving dynamic interactions between malignant cells and their surrounding stroma, including both the cellular and acellular components. Within the stroma, fibroblasts represent not only a predominant cell type, but also a major source of the acellular tissue microenvironment comprising the extracellular matrix (ECM) and soluble factors. Normal fibroblasts can exert diverse suppressive functions against cancer initiating and metastatic cells via direct cell-cell contact, paracrine signaling by soluble factors, and ECM integrity. The loss of such suppressive functions is an inherent step in tumor progression. A tumor cell-induced switch of normal fibroblasts into cancer-associated fibroblasts (CAFs), in turn, triggers a range of pro-tumorigenic signals accompanied by distraction of the normal tissue architecture, thus creating an optimal niche for cancer cells to grow extensively. To further support tumor progression and metastasis, CAFs secrete factors such as ECM remodeling enzymes that further modify the tumor microenvironment in combination with the altered adhesive forces and cell-cell interactions. These paradoxical tumor suppressive and promoting actions of fibroblasts are the focus of this review, highlighting the heterogenic molecular properties of both normal and cancer-associated fibroblasts, as well as their main mechanisms of action, including the emerging impact on immunomodulation and different therapy responses.

Keywords: cancer; cancer-associated fibroblasts; desmoplasia; neighbor suppression; normal fibroblasts; therapy.

Figure 1

The dual action of fibroblast in the TME. Illustrative scheme showing the interactions and products of the anti-tumorigenic normal fibroblasts (upper-left) and the pro-tumorigenic cancer associated fibroblasts (CAFs) (lower-right).

Figure 2

The heterogeneity of CAFs. Immunohistochemical stainings of aSMA (CAB000002), FAP (HPA059739,) and PDGFRβ (CAB018144) of tumor sections from breast (duct carcinoma), ovarian (cystadenocarcinoma, serous), and prostate (adenocarcinoma, high grade) cancers. These stainings show the heterogeneity in CAF markers not only between cancers, but also between patients with the same cancer type. Images were obtained from the Human Protein Atlas (Available from www.proteinatlas.org, [65]).

Figure 3

The origin of CAFs. Different cell types can transdifferentiate and represent the source of CAFs, including: tissue resident fibroblasts, fibrocytes, epithelial cells (through EMT), adipocytes, mesenchymal stem cells, pericytes, and endothelial progenitor cells (through EndMT).