Activated fibroblasts in cancer: Perspectives and challenges

Abstract

Activated fibroblasts in tumors, or cancer-associated fibroblasts (CAFs), have become a popular research area over the past decade. As important players in many aspects of tumor biology, with functions ranging from collagen deposition to immunosuppression, CAFs have been the target of clinical and pre-clinical studies that have revealed their potential pro- and anti-tumorigenic dichotomy. In this review, we describe the important role of CAFs in the tumor microenvironment and the technological advances that made these discoveries possible, and we detail the models that are currently available for CAF investigation. Additionally, we present evidence to support the value of encompassing CAF investigation as a future therapeutic avenue alongside immune and cancer cells while highlighting the challenges that must be addressed for successful clinical translation of new findings.

Keywords: activated fibroblasts; cancer-associated fibroblasts; stroma; tumor microenvironment.

Figure 1.. Subtypes of CAFs.

Classifications of CAFs across several tumor types broadly converge on three main subtypes of CAFs based on the expression of certain markers, of which the most commonly used are depicted in this schematic representation. In particular, the subtypes so far described have i) myofibroblastic properties (myCAF); ii) inflammatory properties (iCAF); iii) antigen-presenting properties (apCAF). The functions of myCAF and iCAF rely on the secretion of ECM and immunomodulatory factors respectively; while it has been hypothesized that apCAFs interact directly with T cells to promote T cell exhaustion (dotted line).

Figure 2.. Functions of CAFs in the tumor microenvironment.

Functions of CAFs exerted through direct and indirect interaction with other components of the TME. The roles of CAFs range from immunosuppression of cytotoxic immune cells and recruitment of tumor-promoting immune cells, ECM deposition and remodeling, to angiogenesis and promotion of cancer cell invasive properties.

Figure 3.. Signaling pathways leading to fibroblast activation.

Paracrine signaling as well as mechanical stimuli lead to the generation of CAFs. Once activated, CAFs can in turn generate a positive feedback loop to maintain these signaling pathways within the TME and promote the expansion of the CAF population.

Figure 4.. Origin and functions of MAFs in metastasis.

Signaling from cancer cells and CAFs from the primary site act upon resident fibroblasts, hepatic stellate cells, mesothelial and mesenchymal stem cells to promote MAF activation. MAFs functions include decreased proliferation of CD4⁺ and CD8⁺ T cells, increase proliferation of cancer cells and ECM deposition.