By Sophia Hu
A group of activated fibroblasts called cancer-associated fibroblasts (CAFs) are one of the major components of the tumour microenvironment (TME) in solid tumours. They are found to be associated with poor survival due to their tumour-promoting functions, hence they have been receiving an increasing appreciation in cancer therapeutics development (1). However, recent studies have shown that CAFs may also inhibit cancer development. Here we will discuss the controversial role of CAFs in cancer.
CAFs are identified based on morphology, biomarkers and genetic mutations: elongated spindle-shaped cells that have negative mesenchymal (epithelial, endothelial, and leukocyte) markers, positive mesenchymal markers such as vimentin, platelet-derived growth factor receptor-α (PDGFRα), α-smooth muscle actin (αSMA) and fibroblast activation protein (FAP) and lack cancer-specific mutations (2,3). Nonetheless, these criteria may fail to exclude other mesenchymal lineages such as adipocytes and pericytes (2). Most evidence suggests that CAFs originate from locally activated fibroblasts in tissues, but many studies also support other possible origins including endothelial cells, epithelial cells, stellate cells, pericytes, adipocytes, cancer stem cells (CSCs), hematopoietic stem cells (HSCs), and bone marrow-derived mesenchymal stem cells (MSCs) (1). This diverse origin partially explains the heterogeneity of CAF in terms of their biomarkers, subtypes, and functions (1). Since different CAF origins correspond to different sets of active factors/signals, further investigation to uncover their origins could have great therapeutic significance (1).
As mentioned above, CAFs’ heterogeneity is also reflected on their functions. Most studies support CAFs’ major role in tumour promotion (1). CAFs are involved in extracellular matrix (ECM) remodelling (4). ECM is a 3D network consisting of proteoglycans, glycoproteins and collagens that provide structural and biochemical support to surrounding cells (5). Its quantity, stiffness, and organization have impacts on several cancer hallmarks including proliferation, invasion, angiogenesis, metastasis development and inflammation. Additionally, ECM modifications also influence tumour drug resistance by forming a physical barrier and inducing chemo-resistant signalling pathways. CAFs could remodel these ECM features (hence promoting tumour growth) by inducing the production of large amounts of ECM proteins and other proteins such as the crosslinking enzymes lysyl oxidases (LOXs) and matrix metalloproteinases (MMPs) (6). Furthermore, depending on the specific cancer type, CAFs are also able to induce epithelial-mesenchymal transition (EMT), a key characteristic of metastatic cancer cells, by secretion of signalling molecules such as interleukin-6 (IL-6) or transforming growth factor-β1 (TGF-β1), among others (7,8). These and other CAF-secreted factors such as exosomes, IL-8, IL-32, VCAM-1, WNT2 and IL-11 are also involved in EMT, cancer cell migration and metastasis (4).
However, CAFs also have tumour-suppression activity. It has been found that CAFs could produce collagens that encapsulate carcinogens, hence protecting epithelial cells from DNA damage that might lead to tumour development (9). Depletion of CAFs is also associated with invasive tumours with higher levels of hypoxia (low oxygen level), EMT, and cancer stem cells (which drive tumour initiation and relapses), with reduced survival (10). In addition, the removal of sonic hedgehog protein (SHH), an activating ligand of CAFs (11), had led to a more robust tumour with enhanced systemic morbidity and metastasis in pancreatic ductal adenocarcinoma (PDAC) models (12). Similarly, despite the tumorigenesis-promoting function of the Hedgehog (Hh) signalling pathway, Hh signalling activation in CAFs significantly attenuated tumour progression in colorectal cancer models (13). In colitis-associated cancer models, disruption of IKKβ-dependent NF-κB activation in CAFs promote tumour growth by increasing the levels of hepatocyte growth factor (HGF) secretion (14). There is also evidence for tumour suppressive CAFs subsets such as PDGFRα + Saa3- CAFs, RAMP3-/- CAFs and Meflin positive CAFs (15–17). Furthermore, not all CAFs-secreted factors are pro-tumorigenesis. Slit2 ligand derived from CAFs could interact with the Robo1 (Roundabout 1) receptor and inhibit the phosphoinositide 3-kinases (PI3Ks) pathway and subsequent signalling events (18). PI3Ks are a large lipid enzyme family whose pathway is one of the most frequently activated signal transduction pathways in human cancer (19), hence Slit2 is able to suppress tumour progression. More recently, Remsing Rix et al. found that in EGFR (epidermal growth factor receptor)-mutant tumours, CAFs could secrete insulin-like growth factor binding proteins (IGFBPs) that inhibit compensatory signalling induced by drugs, hence sensitise cancer cells to anticancer drugs (20).
These controversial findings revealed that being such a large and diverse group, CAFs’ tumour promoting, and tumour-suppressive functions are highly dependent on the CAF subtypes, cancer type and cancer stage. Such controversy means non-specific targeting or deletion would probably fail to achieve the desired therapeutic effects. Hence, the identification of specific biomarkers and signalling pathways, distinguishing CAFs subtypes and their phenotypes and functions would be essential for specific CAF therapies and CAF reprogramming to either a normal fibroblast or a tumour-suppressive subtype.
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Imperial Bioscience Review 