Abstract 5263: Osteopontin/matrixmetalloproteinasis pathway activation in head and neck cancer

Abstract

Abstract Head and neck cancers are a group of related neoplasms that arise mainly from the mucosal lining epithelium of the oral cavity, pharynx, and larynx (head and neck squamous cell carcinomas- HNSCC). Despite the progress in novel combination therapies, HNSCC remains responsible of about 300,000 deaths worldwide each year. The identification of HNSCC prognostic factor responsible of cancer development and progression may be useful for the discovery of a tailored therapy. It has been shown that MAPK pathway, frequently hyperactivated in HNSCC, is promoted by osteopontin (OPN). OPN contributes to tumorigenesis through both inhibition of apoptosis and activation of various extracellular matrix-degrading proteases such as activation of MMP-2 and MMP-9. The present study was designed to determine whether OPN-mediated MMP activation may be a signal of HNSCC cancer progression that can be also used as therapeutic target for this cancer type. To this aim computational analysis from different gene expression datasets, together with serological analysis of well-defined clinical material were used to demonstrate a correlation between OPN and MMP-9 in HNSCC. Our “in silico” data indicate an increased expression of OPN and MMP-9 in association with the transformation and progression of disease, suggesting their potential usefulness as valid prognostic markers for HNSCC. Immunohistochemical analysis carried on a set of HNSCC samples show that OPN and MMP-9 are mostly released from tumor cells and protein plasma concentrations of the two markers are significantly and concomitantly increased in metastatic HNSCC as compared to healthy donors or non metastatic HNSCC samples. Expression levels of MMP-9 and OPN were always directly correlated in either three groups of plasma samples, suggesting that a common physiological process underlies this correlation. This hypothesis has been confirmed by using bioinformatical tools (Gene Set Enrichment Analysis) which revealed that OPN and MMP-9 could be associated with IL6, RAS, MYB and TGF-beta signaling pathways and was further validated by analyzing TGF-beta levels in peripheral blood from HNSCC patients compared to healthy donors. Moreover MMP-9 plays a crucial promigratory function in HNSCC. To determine whether inhibition of MMP-9 may have effect in cancer cell growth, migration assays performed on human oral carcinoma cell line have been performed. The results showed that migration abilities of cancer cells were almost fully abrogated by treatment with TIMP-1. Taken together these findings underline the relevance of osteopontin/matrix metalloproteinase-9 pathway as a marker for HNSCC progression and provide a promising therapeutic strategy to interfere with signaling pathway(s) that regulate OPN-mediated MMP-9 activation in HNSCC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5263. doi:10.1158/1538-7445.AM2011-5263