Exploring senescent oral fibroblasts: Implications in oral squamous cell carcinoma and potential pharmacological interventions

• Published in: Oral surgery, oral medicine, oral pathology and oral radiology oral medicine, oral pathology and oral radiology, 2025-01, Vol.139 (1), p.e34-e34
• Main Authors: Niklander, S, Morales, D, Valencia, C, Faunes, F, Aránguiz, P, Martínez-Flores, R
• Format: Article
• Language: English
• ISSN: 2212-4403
• DOI: 10.1016/j.oooo.2024.10.249

Senescent fibroblasts (SF), by developing the senescence associated secretory phenotype (SASP), have been implicated in the progression of various cancers. There is little knowledge about the presence of SF in oral squamous cell carcinoma (OSCC). This study aims to demonstrate the presence of SF in OSCC biopsies, characterize the SASP of oral SF, and explore pharmacological interventions to modify their SASP. OSCC FFPE samples were obtained from 45 patients. SF were identified assessing the expression of two markers associated with senescence (p16 and yH2AX), and the fibroblast activated protein (FAP), using immunohistochemistry. Normal fibroblasts were obtained from oral biopsies and grown in vitro. Senescence was induced by H2O2 exposure and corroborated by assessing b-galactosidase activity, p16 and IL-6 expression. The SASP was characterized before and after exposure to recombinant (r) IL-1RA and Y27632 (a Rho Kinase [ROCK] inhibitor) using a proteome profiler array that assess 105 cytokines. SF were present in different abundancy in the stroma of OSCC. The SASP from oral SF exhibited an overexpression of more than 20 cytokines when compared to non-senescent fibroblasts. Both rIL1RA and Y27632 were able to modulate the inflammatory component of the SASP from SF, being the effect of rIL-1RA of greater significance. Senescent fibroblasts accumulate in the stroma of OSCC, which has been associated with worst prognosis in other cancers. IL-1 inhibition seems to be a promising strategy to decrease the inflammatory component of the SASP and their oncogenic features, but more functional studies are needed to corroborate this.