Abstract 415: Dynamic interplay of tumor and microenvironmental contributions of the α2β1 integrin in squamous cell carcinoma

Abstract

The complex interplay between tumor cells and their surrounding microenvironment define cancer progression. The α2β1 integrin, expressed by subsets of epithelial, endothelial, fibroblast, and inflammatory cells, is a receptor for matrix and non-matrix ligands, including collagens, laminins, and immunomodulatory molecules C1q and collectins. Altered α2β1 integrin expression in cancer has been linked to tumor progression; recent studies have linked polymorphisms in the α2β1 integrin with oral, squamous cell carcinoma (SCC). We hypothesized that the α2β1 integrin functions in SCC initiation or progression by modulating interactions between the squamous epithelium and/or tumor microenvironment. To determine the role of α2β1 integrin expression on SCC progression, we crossed α2β1 integrin-null mice with K14-HPV transgenic animals, a well-established model of epithelial carcinogenesis. Progression from hyperplasia to dysplasia and invasive carcinoma was evaluated in HPV-positive, α2β1 integrin-null (HPV/KO) and HPV-positive, wild-type (HPV/WT) animals. Our data demonstrate that during SCC progression, expression of the α2β1 integrin stimulates progression from hyperplasia and papillomatosis to dysplasia. Decreased dysplasia in HPV/KO animals at early time points of tumor progression directly correlated with reduced dermal mast cell infiltration. Moreover, lymph node metastasis was decreased by 31.3% and associated with alterations in lymphatic vasculature within the tumor microenvironment of HPV/KO, compared to HPV/WT, animals. Since these studies utilized global α2β1 integrin knockout mice, we developed primary tumor cell lines to evaluate the integrin-specific impacts on the malignant epithelium versus the host microenvironment. Although transition from dysplasia to carcinoma was unaltered in our original tumor studies, isolated primary HPV/KO SCC cell lines had decreased invasion in a 3D transwell migration assay, compared to HPV/WT cells. When HPV/WT and HPV/KO SCC cell lines were orthotopically injected into either WT or KO hosts, α2β1 integrin-specific expression on tumor cells decreased tumor latency, regardless of host integrin status. HPV/WT SCC lines failed to demonstrate a proliferative advantage in vitro, however, the HPV/WT tumors demonstrated increased growth rates compared to HPV/KO SCC lines in vivo. Therefore, these latter data suggest that contributions of the tumor microenvironment cannot be excluded and are likely modulating SCC growth characteristics. Our studies indicate the α2β1 integrin plays diverse roles during tumor progression, acting on the tumor and tumor microenvironment. Although the α2β1 integrin plays no obvious role during normal development, exposure to physiological stresses, such as cancer, unmasks functions of the α2β1 integrin to reveal its importance in tissue biology. 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 415. doi:10.1158/1538-7445.AM2011-415