Architecture of Cancer-Associated Fibroblasts in Tumor Microenvironment: Mapping Their Origins, Heterogeneity, and Role in Cancer Therapy Resistance

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 cancerassociated 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.

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

“…Tocilizumab can bind both cell-bound and soluble IL-6R, and thus inhibits the main IL-6 signaling pathways (Dzobo and Dandara, 2020;Hennigan and Kavanaugh, 2008). Tocilizumab has been approved for several conditions, including rheumatoid arthritis, and has been shown to be effective against colorectal and pancreatic cancers (Dijkgraaf et al, 2015;Grivennikov et al, 2009;Navarro et al, 2014).…”

“…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.…”

“…Interleukin-6 signaling cascade and potential inhibitors of the pathways. Figure is adapted fromDzobo and Dandara (2020).…”

Mesenchymal Stromal-Like Cells in the Glioma Microenvironment: What Are These Cells?

“…These reactive astrocytes may originate from local astrocytes or from the migration and differentiation of neural progenitor cells found in the subventricular zone [ 28 ]. Alternatively, as suggested for CAFs, GASCs may arise from the transdifferentiation of pericytes and vascular smooth muscle cells, and from endothelial cells through the process of endothelial-to-mesenchymal transition [ 29 ]. GASCs can also originate from MSCs.…”

CD34+ Stromal Cells/Telocytes as a Source of Cancer-Associated Fibroblasts (CAFs) in Invasive Lobular Carcinoma of the Breast

“…CD34+SCs/TCs are not observed in the stroma of numerous malignant invasive epithelial tumours, where they are replaced by αSMA+ stromal cells (myofibroblasts, cancerassociated fibroblasts: CAFs) [9][10][11][12][13][14][15][16][17][18][19][20][21][22]. Several origins have been proposed for CAFs, including tissue-resident CD34+SCs/TCs, bone marrow derived fibrocytes, pericytes and other possible precursor cells, such as endothelial cells (ECs), smooth muscle cells, adipocytes, and epithelial cells, to which the ability to transition or transdifferentiate has been attributed [23][24][25][26][27][28][29]. Among these cells, the participation of tissue-resident CD34+SCs/TCs as precursors of CAFs is very likely, as the process requiring the cellular loss of CD34 expression and the gain of αSMA expression.…”