Cancer-Associated Fibroblasts Build and Secure the Tumor Microenvironment

Abstract

Tumor cells reside in a highly complex and heterogeneous tumor microenvironment (TME), which is composed of a myriad of genetically stable non-cancer cells, including fibroblasts, immune cells, endothelial cells, and epithelial cells, and a tumor-specific extracellular matrix (ECM). Cancer-associated fibroblasts (CAFs), as an abundant and active stromal cell population in the TME, function as the signaling center and remodeling machine to aid the creation of a desmoplastic tumor niche. Although there is no denial that the TME and CAFs may have anti-tumor effects as well, a great deal of findings reported in recent years have convincingly revealed the tumor-promoting effects of CAFs and CAF-derived ECM proteins, enzymes, chemical factors and other downstream effectors. While there is growing enthusiasm for the development of CAF-targeting therapies, a better understanding of the complexities of CAF-ECM and CAF-cancer cell interactions is necessary before novel therapeutic strategies targeting the malignant tumor “soil” can be successfully implemented in the clinic.

Tumor microenvironment complexity and therapeutic implications at a glance

“…Cancer-associated fibroblasts (CAFs) in the immediate vicinity of cancer cells play an important role in tumorigenesis in various physicochemical ways by reducing apoptosis and improving the proliferation, migration and viability of cancer cells [58,59]. CAFs residing in TME are heterogeneous cells with different origins, different functions (pro or anti-tumor activities) and different surface markers such as alpha-smooth muscle actin (α-SMA), myosin light chain 9 (MYL9), myosin light chain kinase (MYLK), matrix metalloproteinase 2 (MMP2), decorin (DCN) and collagen type I alpha 2 (COL1A2) [60][61][62][63].…”

“…It is a complex network composed of fibrous proteins (collagen, elastin), glycosaminoglycans (hyaluronic acid), proteoglycans (chondroitin sulfate, heparan sulfate), and glycoproteins (fibronectin 1 (FN1), laminins, tenascin C (TNC)) [115,116]. ECM proteins can be produced by many stromal cell types and tumor cells, however, CAFs are the main source for synthesis, secretion, assembly, and modification of the ECM composition and organization [60,117].…”

Modulation of the tumour promoting functions of cancer associated fibroblasts by phosphodiesterase type 5 inhibition increases the efficacy of chemotherapy in human preclinical models of esophageal adenocarcinoma

“…These include targeting the ECM remodeling enzymes such as the lysyl oxidase family and MMPs, or targeting CAF-derived molecular signals (e.g. CXCR4, TGF-B, HGF) (reviewed in 9 ).…”

“…We have previously reported that activated cancer-associated fibroblasts (CAFs) influence outcome in EAC and the biological properties of esophageal CAFs that promote tumor progression 8, 9 . CAFs have also been shown to influence the immune cell infiltrate and response to chemotherapy in a range of tumors 10-12 .…”

An Overview of the Oncogenic Signaling Pathways in Different Types of Cancers

“…Recent studies have also illustrated the correlation between CAF and ECM in the regulation of the metastatic niche and chemoresistance [134]. Cancer associated fibroblasts broadly infiltrate tumor stroma, comprising two different cellular populations (PMID: 15549095), namely cells ancillary to ephitelium and cells with myofibroblastic differentiation, whose phenotype is characterized by alpha-SMA expression and exert a direct modulation to cancer proliferative potential, tumoral angiogenesis and disseminative potential and aggressiveness, in both solid [135,136] and hematological malignancies [137,138].…”