Cancer-associated Fibroblasts

The tumour microenvironment, also termed the tumour stroma or tumour mesenchyme, includes fibroblasts, immune cells, blood vessels and the extracellular matrix and substantially influences the initiation, growth and dissemination of gastrointestinal cancer. Cancer-associated fibroblasts (CAFs) are one of the critical components of the tumour mesenchyme and not only provide physical support for epithelial cells but also are key functional regulators in cancer, promoting and retarding tumorigenesis in a context-dependent manner.

Fig. 1 | Cellular components of the tumour microenvironment.
(Source: Nature reviews. Gastroenterology & hepatology,2019)

Heterogeneity of CAFs

Marker heterogeneity. Representative CAF markers include but are not limited to αSMA, the serine protease fibroblast activation protein (FAP), fibroblast-specific protein 1 (FSP1), platelet-derived growth factor receptor-α (PDGFRα) and PDGFRβ. It is possible that CAFs identified by a single marker are composed of a range of distinct CAF subtypes that have functionally opposing roles in cancer progression.

Functional heterogeneity. Studies suggest that CAFs are composed of various functionally heterogeneous subsets that either promote or restrain cancer growth. CAFs are more than inert cells; they actively modulate their environment.

Intratumoural heterogeneity. Analogous to phenotypic heterogeneity among cancer cells, CAF phenotypes are different not only between tumours (intertumoural heterogeneity) but also within tumours (intratumoural heterogeneity).

Function of CAFs

Stromal and epithelial interactions. CAFs directly confer growth advantages to cancer cells via paracrine signalling, exosome transfer and physical interaction.

Tumour immunology. CAFs are major contributors to an immunosuppressive TME that might act as a restitution programme to help support the epithelium in acute injury but promotes cancer growth in a tumour setting.

Angiogenesis. Neovascularization in cancer is regulated not only by tumour cells but also by stromal cells. Indeed, CAFs promote tumour angiogenesis directly by secreting pro-angiogenic factors and indirectly by producing ECM.

Clinical implementation

Clinical implementation Biomarkers In addition to the functional contribution of CAFs to cancer progression described above, CAFs and their gene expression patterns have diagnostic and prognostic value in clinical oncology. Gene expression analyses and proteome profiling of cancer tissues have revealed that stromal gene signatures predict poor patient outcome in multiple types of gastrointestinal cancer. Because CAFs accumulate at the tumour site at an early stage of tumorigenesis, future investigations will probably identify valuable CAF markers that might facilitate early detection of cancer.

CAFs are important in the development of gastrointestinal cancers, both in their promotion and,in their antagonism. CAFs are not one entity but rather contain heterogeneous functional subpopulations including pCAFs, rCAFs and probably also a neutral subset that neither promotes nor retards (nCAFs). CAF biology is mediated through the direct and paracrine interactions of CAFs with both cellular (tumour cells, immune cells and vascular cells) and acellular (ECM) compartments.

Fibroblasts Antibodies