Diversity and Biology of Cancer-Associated Fibroblasts

Abstract

Efforts to develop anti-cancer therapies have largely focused on targeting the epithelial compartment, despite the presence of non-neoplastic stromal components that substantially contribute to the progression of the tumor. Indeed, cancer cell survival, growth, migration, and even dormancy are influenced by the surrounding tumor microenvironment (TME). Within the TME, cancer-associated fibroblasts (CAFs) have been shown to play several roles in the development of a tumor. They secrete growth factors, inflammatory ligands, and extracellular matrix proteins that promote cancer cell proliferation, therapy resistance, and immune exclusion. However, recent work indicates that CAFs may also restrain tumor progression in some circumstances. In this review, we summarize the body of work on CAFs, with a particular focus on the most recent discoveries about fibroblast heterogeneity, plasticity, and functions. We also highlight the commonalities of fibroblasts present across different cancer types, and in normal and inflammatory states. Finally, we present the latest advances regarding therapeutic strategies targeting CAFs that are undergoing preclinical and clinical evaluation.

Keywords: fibroblasts; heterogeneity; tumor microenvironment.

Graphical abstract

FIGURE 1.

Models to study cancer-associated fibroblast (CAF) biology. Current models include two-dimensional and three-dimensional cultures. Potential complementary models that have not yet been applied to the study of CAF biology include air-liquid interface cultures, organs-on-chips, three-dimensional bio-printed tissues, and new genetically engineered mouse models (GEMMs) for lineage tracing of CAFs.

FIGURE 2.

Common cancer-associated fibroblast (CAF) markers. Examples of extracellular, intracellular, and surface protein markers of CAFs. LUM, lumican; DCN, decorin; COL, collagen; FAP, fibroblast activation protein; PDPN, podoplanin; PDGFR, platelet-derived growth factor receptor; αSMA, α-smooth muscle actin; VIM, vimentin; FSP-1, fibroblast specific protein 1.

FIGURE 3.

Cancer-associated fibroblast (CAF) heterogeneity across malignancies. Schematic illustration summarizing the distinct CAF populations identified in different cancer types by single-cell RNA-sequencing (scRNA-seq). αSMA, α-smooth muscle actin.

FIGURE 4.

Factors involved in fibroblast reprogramming in inflammation and cancer. Schematic illustration of multiple stimuli that have been shown to determine fibroblast activation. These factors include epithelial and stromal cues, metabolic reprogramming, epigenetic changes, microRNAs, and oxidative stress. CAF, cancer-associated fibroblast; IGF-1, insulin-like growth factor 1; IL-1, interleukin-1; PDGF, platelet-derived growth factor; TGF-β, transforming growth factor-β.

FIGURE 5.

Cell of origin of cancer-associated fibroblasts (CAFs). Schematic illustration of the potential cells of origin of CAFs that have been reported, including epithelial cells, mesothelial cells, resident fibroblasts, pancreatic and hepatic stellate cells, pericytes, adipocytes, mesenchymal stem cells, myeloid cells, fibrocytes, and endothelial cells.

FIGURE 6.

Tumor-promoting cancer-associated fibroblast (CAF) functions. Schematic illustration of the functional heterogeneity of CAFs in the tumor microenvironment. CAFs have been demonstrated to play several roles, including promoting tumor growth and metastasis formation, depositing extracellular matrix (ECM), and establishing an immunosuppressive microenvironment. HA, hyaluronan; HGF, hepatic growth factor; IGF1, insulin growth factor 1; IL-6, interleukin-6; LIF, leukemia inhibitory factor.

FIGURE 7.

Potential tumor-restraining cancer-associated fibroblast (CAF) functions. Schematic illustration of the Hedgehog (Hh) signaling pathway (top) and of the genetic and therapeutic approaches that indicated the presence of tumor-restraining functions of pancreatic ductal adenocarcinoma (PDAC) CAFs (bottom). A: genetic deletion of the Hh ligand sonic hedgehog (SHH) in a mouse model of PDAC led to a reduction in survival and tumor differentiation and to an increase in angiogenesis and cachexia, a highly debilitating muscle-wasting condition (248). GLI1, GLI family zinc finger 1; PTCH1, protein patched homolog 1. αSMA, α-smooth muscle actin. B: genetic depletion of αSMA+ cells in a mouse model of PDAC led to a reduction in survival and tumor differentiation and to an increase in the infiltration of immunosuppressive CD4+ Foxp3+ regulatory T cells (221). C: prolonged pharmacological inhibition of the Smoothened (SMO) receptor in a mouse model of PDAC led to reduced survival and tumor differentiation, and to an increase in angiogenesis and cachexia (248).

FIGURE 8.

Fibroblast activation in inflammation and cancer. Schematic illustration showing the phenotype changes associated with fibroblast activation during inflammation and cancer progression. Compared with normal quiescent fibroblasts, fibroblasts in inflammatory and malignant states have various degrees of increased α-smooth muscle actin (αSMA) expression, secretory phenotype, extracellular matrix (ECM) deposition, proliferation, contractility, and morphological activation. Cancer-associated fibroblasts can also be immunosuppressive.

FIGURE 9.

Cancer-associated fibroblast (CAF) plasticity. Schematic illustration showing the effects of the JAK inhibitor AZD1480 on reprogramming inflammatory CAFs (iCAFs) in a mouse model of pancreatic ductal adenocarcinoma (PDAC) (24). Treatment with the JAK inhibitor shifts the iCAF subtype towards an extracellular matrix (ECM)-producing myofibroblastic CAF (myCAF) population, leading to an increase in the myCAF/iCAF ratio and ECM deposition and to a reduction in tumor cell proliferation and tumor growth.

FIGURE 10.

Stroma-targeting therapies. Schematic illustration of the stroma-targeting strategies that have been tested in preclinical and clinical studies, including agents targeting components of the ECM (e.g., PEGPH20 and FG-3019), anti-immunosuppressive strategies, pathway-specific inhibitors (e.g., SMO inhibitors) and drugs that reprogram CAFs to a quiescent state (e.g., calcipotriol). ATRA, all-trans-retinoic acid; FAK, focal adhesion kinase; FAP, fibroblast activation protein; IL6, interleukin-6; LIF, leukemia inhibitory factor; SMO, Smoothened.

FIGURE 11.

Unanswered questions in cancer-associated fibroblast (CAF) biology. Schematic illustration of key areas in CAF biology that remain underexplored.