The alpha 2 beta 1 Integrin: Innate Immunity to Pathogens & Tumors

描述（由申请人提供）：我们的目标是确定α 2 <$1整联蛋白在肿瘤进展和转移的免疫调节中的作用，特别关注c-met和α 2 <$1整联蛋白之间的相互作用。 我们提供了令人兴奋的数据，即α 2 <$1整合素不仅增强了对病原体的先天免疫应答，而且促进了病毒诱导的鳞状细胞癌的进展和转移。 在之前的资助期间，我们鉴定了C1 q和胶原聚集蛋白家族作为α 2 <$1整联蛋白的新型配体，并证明了α 2 <$1整联蛋白和c-met之间的串扰，这是肥大细胞活化和IL-6分泌所必需的。 我们假设α 2 <$1整合素介导的免疫细胞和肿瘤细胞之间的相互作用调节肿瘤的进展和转移。 炎症、肥大细胞、T细胞和免疫复合物是上皮癌变转基因小鼠模型中肿瘤进展所必需的，其中人乳头瘤病毒16型（HPV 16）早期区基因在基底角质形成细胞中表达。 在该模型中，50%的野生型小鼠发生浸润性鳞状细胞癌。 我们产生了K14-HPV 16/WT和HPV 16/a2缺失小鼠。 在HPV 16/a2-null小鼠中，肿瘤潜伏期和肿瘤生长在缺乏α 2 <$1整联蛋白的小鼠中没有改变，但与野生型小鼠相比，α 2-null小鼠中的肿瘤负荷和淋巴结转移的动物数量显著减少，表明α 2 <$1整联蛋白促进炎症和肿瘤进展。 我们推测α 2 <$1整合素通过与c-met相互作用和刺激免疫系统促进上皮细胞癌变。 我们提出了四个目标，使用小鼠模型，人类肿瘤样本的组合，并在体外细胞生物学和分子技术：具体目标1：确定α 2 <$1整合素表达促进肿瘤进展的机制。 FOCUS -α 2 <$1整合素与K14-HPV 16上皮癌发生。 具体目标2：定义在肿瘤进展和转移中α 2 <$1整合素和HGF/c-met之间的相互作用。 FOCUS -α 2 - 1整联蛋白和HGF/c-met串扰。 具体目标3：定义α 2 <$1整合素依赖性调节新生血管和淋巴管生成。 焦点-血液和淋巴管内皮细胞。 具体目标4：明确炎症、肥大细胞浸润、α 2 <$1整合素和c-met表达以及HPV阳性（+）和HPV阴性（-）头颈部鳞状细胞癌（HNSCC）中血管生成表型的功能和预后相关性。 重点-头颈部鳞状细胞癌。 公共卫生相关性：肿瘤进展和转移受宿主微环境（包括免疫系统细胞）调节。 这项计划的目标是研究一种细胞粘附受体，即调节癌症进展和转移的α 2 <$1整合素。

DESCRIPTION (provided by applicant): Our goal is to define the role of a2¿1 integrin in the immune regulation of tumor progression and metastasis, with specific interest on the interplay between c-met and the a2¿1 integrin. We present exciting data that the a2¿1 integrin not only augments the innate immune response to pathogens, but promotes progression and metastasis of virus-induced squamous carcinoma. During the previous funding period we identified C1q and the collectin family of proteins as novel ligands for the a2¿1 integrin and demonstrated cross-talk between the a2¿1 integrin and c-met that was required for mast cell activation and the secretion of IL-6. We hypothesize that a2¿1 integrin-mediated interactions between immune cells and tumor cells regulate tumor progression and metastasis. Inflammation, mast cells, T cells and immune complexes are required for tumor progression in the transgenic mouse model of epithelial carcinogenesis in which the human papillomavirus type 16 (HPV16) early region genes are expressed in basal keratinocytes. In this model, invasive squamous cell carcinoma occurs in 50% of wild type mice. We generated K14-HPV16/WT and HPV16/a2-null mice. In HPV16/a2-null mice, tumor latency and tumor growth are not altered in mice lacking the a2¿1 integrin, but tumor burden and the number of animals with lymph node metastasis is markedly decreased in a2-null mice compared to wild type mice, suggesting that the a2¿1 integrin promotes inflammation and tumor progression. We hypothesize that a2¿1 integrin via interactions with c-met and stimulation of the immune system promotes epithelial carcinogenesis. We propose four aims using a combination of mouse models, human tumor samples, and in vitro cell biological and molecular techniques: SPECIFIC AIM 1: Determine the mechanism by which a2¿1 integrin expression promotes tumor progression. FOCUS - a2¿1 integrin and K14-HPV16 epithelial carcinogenesis. SPECIFIC AIM 2: Define cross-talk between the a2¿1 integrin and HGF/c-met in tumor progression and metastasis. FOCUS - a2¿1 integrin and HGF/c-met crosstalk. SPECIFIC AIM 3: Define the a2¿1 integrin-dependent regulation of neoangiogenesis and lymphangiogenesis. FOCUS - Blood and lymphatic endothelial cells. SPECIFIC AIM 4: Define the functional and prognostic relevance of inflammation, mast cell infiltration, a2¿1 integrin and c-met expression and the angiogenic phenotype in HPV-positive (+) and HPV-negative (-) squamous cell carcinoma of the head and neck (HNSCC). FOCUS - Squamous cell carcinoma of the head and neck. PUBLIC HEALTH RELEVANCE: Tumor progression and metastasis are regulated by the host microenvironment including cells of the immune system. The goal of this proposal is to study a cell adhesion receptor, the a2¿1 integrin that regulates cancer progression and metastasis.