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.
Highlights
Oral cancer ranks among the top three within the South and Southeast Asian subcontinent and it is rapidly emerging across the globe[1,2]
Our results revealed that subtypes of Cancer-associated fibroblasts (CAFs) exist in both primary cultures and human gingivobuccal oral tumors. αSMA expression in stromal-fibroblasts showed inverse relationship with proliferation of cancer cell population and a positive relation with frequency of stem-like cancer cell in gingivobuccal primary tumor samples and in vitro assays, in BMP4-mediated manner
Differences in αSMA expression in stromal CAFs is very well documented, studies exploring the heterogeneity in CAFs and its probability of exhibiting diverse roles has been limiting in oral cancer
Summary
Oral cancer ranks among the top three within the South and Southeast Asian subcontinent and it is rapidly emerging across the globe[1,2]. In India, oral cancer accounts for over 30% of all cancer cases[3]. Gingivobuccal complex is among the most common sites for the incidence of oral cancer in India[4,5]. Despite the improvement in the standard treatment strategies, the 5-years survival rate has remained around 50% since decades[6,7]. This rate further drops for all patients who are detected with locoregional metastasis[8,9]. Expression of several molecular markers on carcinoma cells has been of prognostic values; owing to the heterogeneity of carcinoma cells, their validity has been conflicting[10,11]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
