Carcinoma-associated fibroblasts: orchestrating the composition of malignancy

Philippe Gascard, Thea D Tlsty, Philippe Gascard, Thea D Tlsty

Abstract

The tumor stroma is no longer seen solely as physical support for mutated epithelial cells but as an important modulator and even a driver of tumorigenicity. Within the tumor stromal milieu, heterogeneous populations of fibroblast-like cells, collectively termed carcinoma-associated fibroblasts (CAFs), are key players in the multicellular, stromal-dependent alterations that contribute to malignant initiation and progression. This review focuses on novel insights into the contributions of CAFs to disease progression, emergent events leading to the generation of CAFs, identification of CAF-specific biomarkers predictive of disease outcome, and recent therapeutic approaches aimed at blunting or reverting detrimental protumorigenic phenotypes associated with CAFs.

Keywords: CAF; CAF targeted therapies; carcinoma-associated fibroblasts; field cancerization; microenvironment; stromal–epithelial interactions.

© 2016 Gascard and Tlsty; Published by Cold Spring Harbor Laboratory Press.

Figures

Figure 1.
Figure 1.
Multiple secreted factors and resultant phenotypes stimulated by CAFs. CAFs induce multiple phenotypes in neighboring tumor epithelial cells as well as other stromal cell types. Soluble factors secreted by CAFs have been involved in promoting each of these phenotypes.
Figure 2.
Figure 2.
Birth of a CAF. Example of a p53/activin A/cyclooxygenase-2 (COX-2)-dependent DNA damage pathway originating in epithelial cells that elicits protumorigenic effects in neighboring fibroblasts through paracrine stimulation via activin A. Activation of fibroblasts by activin A triggers a spectrum of COX-2-driven protumorigenic phenotypes, including ECM remodeling, angiogenesis, immune influx, macrophage switch, cell proliferation, DNA damage, and acquisition of a hypoxic/glycolytic microenvironment. Also shown are the signaling pathways that are dysregulated and the CAF-specific proteins whose expression levels change upon acquisition of the CAF phenotype. Dysregulated signaling pathways include up-regulation of TGF-β, bone morphogenetic protein (BMP), Wnt, Sonic hedgehog (Shh), platelet-derived growth factor (PDGF), C-X-C motif ligand 12 (CXCL12)/CXCR4, and integrin-mediated signaling. Changes in protein expression include up-regulation of α-smooth muscle actin (α-SMA), fibroblast-activating protein (FAP), fibroblast-specific protein-1 (FSP1), PDGF receptor a (PDGFRa), PDGFRb, Forkhead box F1 (FOXF1), SPARC, Podoplanin (PDPN), and, more recently, collagen 11-α1 (COL11A1) and microfibrillar-associated protein 5 and down-regulation of CD36.
Figure 3.
Figure 3.
CAF-driven therapeutic opportunities. Drugs specifically targeting CAFs fall into two categories: drugs aimed at (1) reverting the CAF phenotype to a “normal” fibroblast phenotype by targeting pathways responsible for this phenotype (hedgehog, PDGF, or IL-6 CXCR4 signaling), by using anti-fibrotic agents (nonsteroidal anti-inflammatory drugs [NSAIDs] or tranilast) that will modulate ECM remodeling, or by using drugs with wider spectrum of activity such as curcumin; or (2) eliminating CAFs by delivering proapoptotic molecules using “carriers” recognizing CAF-specific proteins (FAP-specific antibodies or PDGF BH3 mimetics). Drugs listed here are those with the most promising outcome, as they specifically target CAFs, for the most part spare healthy epithelial and stromal cells, and have limited/no secondary proinflammatory effects that could spark secondary tumors. Drugs targeting the TGF-β, BMP, activin A, or Wnt pathways are also in development but are more challenging in the clinical setting, as they fulfill key physiological functions in a large variety of cell types.

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Source: PubMed

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