Heterogeneity of cancer-associated fibroblasts in head and neck squamous cell carcinoma: opportunities and challenges

Abstract

Head and neck squamous cell carcinoma (HNSCC) is among the most severe and complex malignant diseases with a high level of heterogeneity and, as a result, a wide range of therapeutic responses, regardless of clinical stage. Tumor progression depends on ongoing co-evolution and cross-talk with the tumor microenvironment (TME). In particular, cancer-associated fibroblasts (CAFs), embedded in the extracellular matrix (ECM), induce tumor growth and survival by interacting with tumor cells. Origin of CAFs is quite varied, and the activation patterns of CAFs are also heterogeneous. Crucially, the heterogeneity of CAFs appears to play a key role in ongoing tumor expansion, including facilitating proliferation, enhancing angiogenesis and invasion, and promoting therapy resistance, through the production of cytokines, chemokines, and other tumor-promotive molecules in the TME. This review describes the various origin and heterogeneous activation mechanisms of CAFs, and biological heterogeneity of CAFs in HNSCC is also included. Moreover, we have highlighted versatility of CAFs heterogeneity in HNSCC progression, and have discussed different tumor-promotive functions of CAFs respectively. In the future, it is a promising strategy for the therapy of HNSCC that specifically targeting tumor-promoting CAF subsets or the tumor-promoting functional targets of CAFs.

Fig. 1. Different origins of cancer-associated fibroblasts (CAFs) in cancer.

The origin of CAFs can be quite heterogeneous, and the main sources of CAFs in TME are NFs. Growth factors like TGF-1 and stromal SDF-1 can be secreted by tumor cells to enable the conversion of NFs into CAFs, and CAFs in the tumor stroma do not undergo apoptosis. Other sources of CAFs include direct generation from MSCs, which can migrate to tumor sites in a way akin to fibroblast migration during wound healing. These migratory cells are drawn to cancer and differentiate into CAFs as a result of their attraction to the disease. In their cytoplasm, these CAFs exhibit particular markers such -SMA, FAP, TNC, and TSP-1. Moreover, epithelial cells can undergo EMT to develop into CAFs, and these CAFs maintain the genetic changes made to the parental genome. Due to the expression of mesenchymal lineage-committed marker genes, CAFs also originate from adipocytes. Endothelial and pericyte cells have the ability to transdifferentiate and add to the CAF population. Proliferating endothelial cells can undergo endothelial to mesenchymal conversions to develop CAFs under the effect of TGF-1 produced by cancer. By the influence of PDGF-BB, pericytes are also a source of CAFs. (Created with BioRender.com).

Fig. 2. Versatility of cancer-associated fibroblasts (CAFs) heterogeneity in HNSCC progression.

By the synthesis of cytokines, chemokines, and the extracellular matrix (ECM) in the TME, CAFs perform a range of roles in carcinogenesis, including proliferation, chemoresistance, invasion, and angiogenesis. As epithelial cells undergo the transformation to become CAFs during the premalignant stage, it is believed that the primary function of CAFs in the development of cancer is to stimulate the proliferation of cancer cells. In the coculture of CAFs/NFs-OCCs, CAFs but not NFs facilitated OCC cell proliferation and invasion, and MMP-2 derived from senescent CAFs induced keratinocyte dis-cohesion and epithelial invasion into collagen gels in a TGF-β-dependent manner. In addition, CAFs can cause angiogenesis in HNSCC by producing PGE2 through COX-2, and VEGF and SDF-1 are required for CAFs to stimulate neoangiogenesis in the tissue of NPC. Moreover, by secreting exosomes to the tumor, CAFs can confer HNSCC therapy resistance, such as chemoresistance. (Created with BioRender.com).