Metformin Prevents the Development of Oral Squamous Cell Carcinomas from Carcinogen-Induced Premalignant Lesions

Abstract

Head and neck squamous cell carcinoma (HNSCC) is a major public health concern. The recent identification of the mammalian Target of Rapamycin Complex 1 (mTORC1) signaling pathway as a highly prevalent molecular signature underlying HNSCC pathogenesis has provided the foundation to search for novel therapeutic approaches to prevent and treat HNSCC. Here, we asked whether metformin, the most widely used medication for the treatment of type 2 diabetes, which acts in part by stimulating the AMP-activated protein kinase (AMPK) signaling pathway thereby reducing mTORC1 activity, may lower the risk of HNSCC development. Indeed, we show that metformin reduces the growth of HNSCC cells and diminishes their mTORC1 activity by both AMPK-dependent and –independent mechanisms. We also optimized an oral-specific carcinogenesis mouse model that results in the accumulation of multiple oral premalignant lesions at the end of the carcinogen exposure, some of which then spontaneously progress into HNSCC. Using this mouse model, we observed that metformin specifically inhibits mTORC1 in the basal proliferating epithelial layer of oral premalignant lesions. Remarkably, metformin prevented the development of HNSCC by reducing significantly the size and number of carcinogen-induced oral tumoral lesions, and by preventing their spontaneous conversion to squamous cell carcinomas. Collectively, our data underscore the potential clinical benefits of using metformin as a targeted chemopreventive agent in the control of HNSCC development and progression.

Effects of metformin on head and neck cancer: A systematic review

“…Several studies have provided evidence about this relationship, but most of them have been in vitro or in vivo animal studies [45,46]. We found only 3 prospective cohort studies for inclusion in this review, and all of them supported an association between metformin and decreased risk of HNSCC [9,20,21].…”

“…We identified 11 articles with experimental studies that were in vitro and in vivo animal studies that analyzed the effect of metformin in HNSCC [20,28,45,46,[49][50][51][52][53][54][55] 2 of these studies presented the most important and complete results. Vitale-Cross et al [46] showed that metformin reduced the growth of HNSCC cells and diminished their mTORC1 activity by both AMPK-dependent and AMPK-independent mechanisms.…”

Diabetes mellitus als prognostischer Marker beim Oropharynx- und Larynxkarzinom

“…Jüngste Studien belegen, dass die Einnahme von Metformin bei DM-Patienten sowohl das Risiko für eine Krebserkrankung verringert als auch die Prognose verbessert [6,7,9]. Zusätzlich führt die Applikation von Metformin zu einer signifikanten Reduktion spontaner Konvertierungen von proliferierenden Epithelschichten aus oralen, prämalignen Läsionen in ein Plattenepithelkarzinom [32]. Jedoch wurde für Diabetes Typ 2 bislang lediglich eine inverse Assoziation mit HNSCC festgestellt [26].…”

Dynamic cellular and molecular modulations of diabetes mediated head and neck carcinogenesis

“…For example, metformin might regulate tumorigenesis through the systemic reduction of growth factor insulin and the induction of energetic stress by oxidative phosphorylation [55]. For HNSCC, metformin administration was effective to modulate cell growth via global protein translational regulation in vitro as well as to inhibit mTORC1-mediated cell proliferation in oral epithelial basal cells in vivo implying its significance as anti-neoplastic and anti-diabetic medication in DM patients with HNSCC [56,57]. Interestingly, a very recent study found that metformin facilitated autophagy and triggered apoptosis by down-regulation of oncogenic factor STAT3, one of the glycemia-mediated regulators revealed using the protein array in this study (Supplementary Figure S4B), in esophageal SCC [58] further suggesting potential interplays between different glycemic oncotargets.…”