The Role of Cancer-Associated Fibroblasts in Tumor Progression

Abstract

In the era of genomic medicine, cancer treatment has become more personalized as novel therapeutic targets and pathways are identified. Research over the past decade has shown the increasing importance of how the tumor microenvironment (TME) and the extracellular matrix (ECM), which is a major structural component of the TME, regulate oncogenic functions including tumor progression, metastasis, angiogenesis, therapy resistance, and immune cell modulation, amongst others. Within the TME, cancer-associated fibroblasts (CAFs) have been identified in several systemic cancers as critical regulators of the malignant cancer phenotype. This review of the literature comprehensively profiles the roles of CAFs implicated in gastrointestinal, endocrine, head and neck, skin, genitourinary, lung, and breast cancers. The ubiquitous presence of CAFs highlights their significance as modulators of cancer progression and has led to the subsequent characterization of potential therapeutic targets, which may help advance the cancer treatment paradigm to determine the next generation of cancer therapy. The aim of this review is to provide a detailed overview of the key roles that CAFs play in the scope of systemic disease, the mechanisms by which they enhance protumoral effects, and the primary CAF-related markers that may offer potential targets for novel therapeutics.

Keywords: cancer; fibroblasts; invasion; mesenchymal; metastasis; tumor microenvironment.

Figure 1

This diagram represents how CAFs are recruited into the tumor microenvironment (TME) or activated through various methods. Once activated, CAFs exert several protumoral effects including immune modulation of the TME, tumor cell proliferation and angiogenesis, and promotion of invasion and metastases, among others. TGF-β—transforming growth factor beta, EMT—epithelial mesenchymal transition

Figure 2

Here, we illustrate examples of mechanisms by which CAFs confer therapeutic resistance in three different cancer types. Therapeutic resistance can be promoted by secretion of hormones including hepatocyte growth factor (HGF) or transforming growth factor beta (TGF-β), or production of proteins such as high mobility group box 1 (HMGB1). Identification of these mechanisms and the responsible molecules may offer novel targets for combinatorial treatment regimens to combat or mitigate the development of therapeutic resistance.