A subtype of cancer-associated fibroblasts with lower expression of alpha-smooth muscle actin suppresses stemness through BMP4 in oral carcinoma

Abstract

Cancer-associated fibroblasts (CAFs) demonstrate the characteristics of myofibroblast differentiation by often expressing the ultrastructure of alpha-smooth muscle actin (αSMA). However, heterogeneity among cancer-associated fibroblasts (CAFs), with respect to αSMA expression, has been demonstrated in several clinical studies of oral cancer. Like normal stem cells, stem-like cancer cells (SLCCs) are also regulated extrinsically by its microenvironment; therefore, we postulated that the heterogeneous oral-CAFs would differently regulate oral-SLCCs. Using transcriptomics, we clearly demonstrated that the gene expression differences between oral tumor-derived CAFs were indeed the molecular basis of heterogeneity. This also grouped these CAFs in two distinct clusters, which were named as C1 and C2. Interestingly, the oral-CAFs belonging to C1 or C2 clusters showed low or high αSMA-score, respectively. Our data with tumor tissues and in vitro co-culture experiments interestingly demonstrated a negative correlation between αSMA-score and cell proliferation, whereas, the frequency of oral-SLCCs was significantly positively correlated with αSMA-score. The oral-CAF-subtype with lower score for αSMA (C1-type CAFs) was more supportive for cell proliferation but suppressive for the self-renewal growth of oral-SLCCs. Further, we found the determining role of BMP4 in C1-type CAFs-mediated suppression of self-renewal of oral-SLCCs. Overall, we have discovered an unexplored interaction between CAFs with lower-αSMA expression and SLCCs in oral tumors and provided the first evidence about the involvement of CAF-expressed BMP4 in regulation of self-renewal of oral-SLCCs.

The vitamin D analogue calcipotriol promotes an anti-tumorigenic phenotype of human pancreatic CAFs but reduces T cell mediated immunity

“…However, deletion of α-SMA + CAFs in pancreatic cancer has been shown to induce cancer progression instead of its suppression 7 . Recent studies with experimental models of organ fibrosis 36,37 and oral carcinoma 38 also show no correlation with α-SMA expression and the contractile ability of fibroblasts. In line with the study by Öhlund et al suggesting that α-SMA high CAFs display an anti-inflammatory phenotype, other studies have found that over-expression of α-SMA attenuates the proliferative activity of CAFs 30,38 .…”

CAF Subpopulations: A New Reservoir of Stromal Targets in Pancreatic Cancer

“…Considering these studies, investigating the CD10 + GPR77 + CAF subpopulation and NFkB crosstalk in PDAC therefore warrants further study. Conversely, Patel et al reported a myofibroblastic CAF subpopulation that inhibited cancer cell stemness via secretion of bone morphogenetic protein 4 (BMP-4) in oral carcinoma [75], highlighting the tissue-dependent multifaceted role of CAF subpopulations in regulating cancer cell stemness and subsequent chemoresistance.…”

Cancer-Associated Fibroblasts: Understanding Their Heterogeneity

“…In sarcoma and prostatic adenocarcinoma, CAFs secrete TGF-β, IL-6 and tumor necrosis factor-alpha (TNF-α) that activate YAP1/TAZ and NFκB signaling in tumor cells, resulting in inhibition of tumor cell proliferation [ 128 , 129 , 130 , 131 ]. In a murine model of OSCC, a sub-population of CAFs, characterized by low α-SMA expression and secretion of bone morphogenetic protein 4 (BMP4), was reported to decrease cell proliferation and inhibit cancer stem cells [ 132 ]. In intestinal tumors, overactivation of NFκB signaling in CAFs inhibits tumor growth and angiogenesis in vivo, and the depletion of this CAF sub-population induces the increased production of HGF, IL-6 and FGF and increased the recruitment and activity of Treg cells [ 133 ].…”