Cancer associated fibroblasts: the dark side of the coin

Abstract

Valid experimental evidence has recently shown that progression of malignant tumors does not depend exclusively on cell-autonomous properties of the cancer cells, but is also deeply influenced by tumor stroma reactivity and undergoes a strict microenvironmental control. Beside structural environmental components as extracellular matrix (ECM) or hypoxia, stromal cells as macrophages, endothelial cells, and cancer-associated fibroblasts (CAFs) play a definite role in cancer progression. This review summarizes our current knowledge on the role of CAFs in tumor progression towards an aggressive phenotype, with particular emphasis on invasiveness, stemness, and preparation of metastatic niche. The controversial origins of CAFs as well as the therapeutical implications of targeting CAFs for anticancer therapy are discussed.

Keywords: Cancer associated fibroblasts (CAFs); cancer microenvironment; extracellular matrix (ECM); progression; therapy; tumor stroma.

Figure 1

Interplay between CAFs and tumor cells. Tumor progression needs a positive and reciprocal feedback between CAFs and cancer cells. Cancer cells induce and maintain the fibroblasts activated phenotype which, in turn, produce a series of growth factors and cytokines that sustain tumor progression by promoting ECM remodelling, cell proliferation, angiogenesis and EMT.

Figure 2

Multiple origins of CAFs within tumor microenvironment. CAFs can stem from trans-differentiation of resting resident fibroblasts or pericytes within tumor microenvironment, through mesenchymal mesenchymal transition (MMT). Alternatively CAFs could derive from bone marrow mesenchymal stem cells (MSCs), or from epithelial normal or transformed cells via epithelial to mesenchymal trasnsition (EMT), or finally from endothelial cells via endothelial to mesenchymal transition (EndMT).

Figure 3

Metabolic interplay between CAFs and cancer cells. Tumor cells are characterized by an high proliferation rate and consequently undergo a strong activation of anabolic pathways that allow rapid growing. In the model reported in this figure cancer cells force CAFs to undergo aerobic glycolysis, and to produce energy-rich nutrients (lactate or pyruvate) which are used in cancer cells for TCA cycle, ATP production, sustaining anabolism and growth.