Cancer-associated Fibroblasts: Origins, Heterogeneity and Functions in Tumor Microenvironment

Abstract

Current therapeutic strategies targeting cancer cells within solid tumors have displayed limited success owing to the presence of non-cancer components referred to as the tumor stroma within the tumor microenvironment (TM). These stromal cells, extracellular matrix and blood vessels influence cancer cell response to therapy and play key roles in tumor relapse and resistance. Of the stromal cells present in the TM, a lot of attention has been given to cancer-associated fibroblasts (CAFs) as they are the most abundant and are important in cancer initiation, progression and therapy resistance. In this updated review I emphasize the role of CAFs in the regulation of tumor cell behaviour and reveal how CAF-derived factors and signaling influence tumor cell heterogeneity and development of novel strategies to combat cancer. To investigate the expression of CAF markers in tumor tissues versus normal tissues, transcriptomic data from The Cancer Genome Atlas (TCGA) and the Gene Expression Profiling Interactive Analysis (GEPIA) databases was used. Bioinformatic analysis reveals differential expression of CAF markers in several cancer types, underscoring the need for further multiomics and biochemical studies on CAFs, CAF subsets and markers. Differences in CAF markers’ expression could be due to different cellular origins as well as the effect of cancer-specific tumor microenvironmental effect on CAFs. Lastly, I present recent advances in therapeutic targeting of CAFs and the success of such endeavours or its lack thereof. It is recommended that for patients’ outcomes to improve, cancer treatment be combinatorial in nature, targeting both cancer cells and stromal cells and interactions.

The Ferroxidase Hephaestin in Lung Cancer: Pathological Significance and Prognostic Value

“…They not only provide physical support to tumor cells but also play key role in promoting or hampering tumorigenesis in a context-dependent manner. CAFs are tremendously heterogeneous in phenotype, function and prognostic significance ( 58 , 59 ) and can originate from resident fibroblasts, bone marrow-derived progenitor cells or epithelial/endothelial cells that have undergone epithelial to mesenchymal transition ( 60 ). Through HEPH immune-labeling of LUAD and LUSC specimens, we clearly identified HEPH-expressing cells, characterized by the typical elongated spindle-shaped morphology of fibroblasts, enveloping some tumor nests in both LUAD and LUSC cancer histotypes.…”

Coronavirus Disease-2019 Treatment Strategies Targeting Interleukin-6 Signaling and Herbal Medicine

“…Infection of several immune cells by the coronavirus causes the release of inflammatory cytokines as well as IL-6. Several cells, including fibroblasts, dendritic cells, lymphocytes, and endothelial cells, are known to produce large quantities of IL-6 (Dzobo, 2020a(Dzobo, , 2020bDzobo and Dandara, 2020;Jones and Jenkins, 2018;Steyn et al, 2019). These immune cells also include macrophages and monocytes.…”