A subtype of cancer-associated fibroblasts with lower expression of alpha-smooth muscle actin suppresses stemness through BMP4 in oral carcinoma. (October 2018)

• Record Type: Journal Article
• Authors: Patel, Ankit; Vipparthi, Kavya; Thatikonda, Venu; Arun, Indu; Bhattacharjee, Samsiddhi; Sharan, Rajeev; Arun, Pattatheyil; Singh, Sandeep
• Is Part Of: Oncogenesis. Volume 7(2018:Oct.)
• Page Start: 1
• Page End: 15
• Publication Date: 2018-10
• Subjects: Oncogenes -- Periodicals; Cell Transformation, Neoplastic; Oncogenes; Periodicals; Periodicals; Fulltext; Internet Resources; Periodicals; 616.994042
• DOI: 10.1038/s41389-018-0087-x
• Languages: English
• ISSNs: 2157-9024

Abstract

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.