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a2？1整合素在肿瘤进展和转移的免疫调节中的作用，特别关注c-met和a2？1整合素之间的相互作用。我们提出了令人兴奋的数据，a2？1整合素不仅增强了对病原体的先天免疫反应，而且促进了病毒诱导的鳞癌的进展和转移。在之前的资助期间，我们发现C1q和胶原蛋白家族是a2？1整合素的新配体，并证明了a2？1整合素和c-met之间的串扰，这是肥大细胞激活和分泌IL-6所必需的。我们假设a2？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。在上皮癌变的转基因小鼠模型中，炎症、肥大细胞、T细胞和免疫复合体是肿瘤进展所必需的，在该模型中，人乳头瘤病毒16型(HPV16)早期区域基因在基底角质形成细胞中表达。在这个模型中，侵袭性鳞状细胞癌发生在50%的野生型小鼠身上。我们建立了K14-HPV16/WT和HPV16/a2缺失的小鼠。在HPV16/a2缺失的小鼠中，缺乏a2？1整合素的小鼠的肿瘤潜伏期和肿瘤生长没有改变，但与野生型小鼠相比，a2？1缺失的小鼠的肿瘤负担和有淋巴结转移的动物数量显著减少，这表明a2？1整合素促进炎症和肿瘤进展。我们假设a2？1整合素通过与c-met的相互作用和免疫系统的刺激促进上皮癌的发生。结合小鼠模型、人类肿瘤标本以及体外细胞生物学和分子生物学技术，我们提出了四个目标：特异性目标1：确定a2？1整合素表达促进肿瘤进展的机制。Focus-a2？1整合素与K14-HPV16上皮癌的发生特异性目的2：明确a2？1整合素和HGF/c-MET在肿瘤进展和转移中的相互作用。Focus-a2？1整合素和HGF/c-MET串扰。特异性目的3：明确a2？1整合素对新生血管生成和淋巴管生成的调节作用。焦点-血液和淋巴管内皮细胞。特异性目的4：明确HPV阳性(+)和HPV阴性(-)头颈部鳞状细胞癌(HNSCC)中炎症、肥大细胞浸润、a2？1整合素和c-Met表达与血管生成表型之间的功能和预后相关性。病灶--头颈部鳞状细胞癌。公共卫生相关性：肿瘤的进展和转移受宿主微环境的调节，包括免疫系统的细胞。这项建议的目标是研究一种细胞黏附受体，即调控癌症进展和转移的a2？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.