The life cycle of cancer-associated fibroblasts within the tumour stroma and its importance in disease outcome

Abstract

The tumour microenvironment (TME) determines vital aspects of tumour development, such as tumour growth, metastases and response to therapy. Cancer-associated fibroblasts (CAFs) are abundant and extremely influential in this process and interact with cellular and matrix TME constituents such as endothelial and immune cells and collagens, fibronectin and elastin, respectively. However, CAFs are also the recipients of signals-both chemical and physical-that are generated by the TME, and their phenotype effectively evolves alongside the tumour mass during tumour progression. Amid a rising clinical interest in CAFs as a crucial force for disease progression, this review aims to contextualise the CAF phenotype using the chronological framework of the CAF life cycle within the evolving tumour stroma, ranging from quiescent fibroblasts to highly proliferative and secretory CAFs. The emergence, properties and clinical implications of CAF activation are discussed, as well as research strategies used to characterise CAFs and current clinical efforts to alter CAF function as a therapeutic strategy.

Fig. 1. Overview of the signal inputs and functional outputs of fibroblasts activated across the fibroblast activation spectrum.

Fibroblasts respond to physical cues and chemical signalling factors in the tumour microenvironment (TME) (‘input signals’) by producing a number of molecules that signal in an autocrine and paracrine fashion, as well as by altering the physical properties of the TME (‘output functions’). In contrast to acute wounds, fibroblasts in desmoplasia establish a self-activating and perpetual feedback loop (bottom arrow), which forms the basis of their pro-tumorigenic capacities. Moving from the quiescent phenotype (green, top), to the CAFs in desmoplasia (orange, bottom), the number of known inputs and outputs increases cumulatively. ROS reactive oxygen species, ET endothelin, TGF-β transforming growth factor β, bFGF basic fibroblast growth factor, PDGF platelet-derived growth factor, MMPs matrix metalloproteinases, TIMPs tissue inhibitors of metalloproteinases, VEGF vascular endothelial growth factor, HGF hepatocyte growth factor, IGF insulin-like growth factor, EGF epidermal growth factor, CXCL CXC motif chemokine ligand, SDF-1 stromal-cell-derived factor-1, TNF tumour necrosis factor, IFN-γ interferon-γ, IL interleukin, Shh sonic hedgehog, SPARC secreted protein acidic and rich in cysteine, EDA-FN EDA-containing cellular fibronectin, PGE2 prostaglandin E2, CTGF connective tissue growth factor; NF-κB nuclear factor κB.

Fig. 2. Co-evolution of the tumour and cancer-associated fibroblasts (CAFs) within the tumour stroma.

Schematic overview of the changes in tumour cell and CAF phenotypes in the context of an evolving tumour microenvironment (TME). The bottom panel lists open questions in CAF biology with potential implications for therapeutic interventions. The black arrow in the ‘metastatic spread’ panel indicates metastatic spread of tumour cells.