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

项目总结 我们的目标是确定21整合素在肿瘤进展和免疫调节中的作用 转移，特别关注c-met和21整合素之间的相互作用。我们呈现的是激动人心的 数据表明，21整合素不仅增强了对病原体的先天性免疫反应，而且促进了 病毒诱导的鳞癌的进展和转移。在上一个资助期内，我们 确定C1q和集合素家族为21整合素的新配体，并证明了 肥大细胞活化所需的21整合素和c-met之间的串扰 IL-6。我们假设21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细胞和免疫复合体是必需的 人上皮细胞癌变转基因小鼠模型中的肿瘤进展 人乳头瘤病毒16型(HPV16)早期区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。我们生成了K14-HPV16/WT和 HPV16/2基因缺失小鼠。在HPV16/2阴性小鼠中，缺乏HPV16/2的小鼠的肿瘤潜伏期和肿瘤生长没有改变 21只整合素，但肿瘤负担和有淋巴结转移的动物数量明显不同 与野生型小鼠相比，2缺失小鼠的表达减少，这表明21整合素促进 炎症和肿瘤进展。 我们推测21整合素通过与c-met的相互作用和免疫系统的刺激而被激活。 促进上皮癌的发生。我们提出了四个目标，使用组合的老鼠模型，人类 肿瘤样本，以及体外细胞生物学和分子技术： 特异性目的1：确定21整合素表达促进肿瘤发生的机制 进步。Focus-21整合素与K14-HPV16上皮癌的发生 特异性目的2：明确21整合素和HGF/c-met在肿瘤进展和转移过程中的相互作用 转移。Focus-21整合素和HGF/C-Met CROSSTALK。 特异性目的3：确定21整合素依赖的新生血管生成和淋巴管生成的调节。 创世纪。焦点--血液和淋巴管内皮细胞。 特定目标4：确定炎症、肥大细胞浸润的功能和预后相关性，21 HPV阳性(+)和阴性患者整合素和c-met的表达及血管生成表型 (-)头颈部鳞癌(HNSCC)。焦点--鳞状细胞癌 头部和颈部。

PROJECT SUMMARY Our goal is to define the role of 21 integrin in the immune regulation of tumor progression and metastasis, with specific interest on the interplay between c-met and the 21 integrin. We present exciting data that the 21 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 21 integrin and demonstrated cross-talk between the 21 integrin and c-met that was required for mast cell activation and the secretion of IL-6. We hypothesize that 21 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 cancinogenesis 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 HPV16/2-null mice. In HPV16/2-null mice, tumor latency and tumor growth are not altered in mice lacking the 21 integrin, but tumor burden and the number of animals with lymph node metastasis is markedly decreased in 2-null mice compared to wild type mice, suggesting that the 21 integrin promotes inflammation and tumor progression. We hypothesize that 21 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 21 integrin expression promotes tumor progression. FOCUS - 21 INTEGRIN AND K14-HPV16 EPITHELIAL CARCINOGENESIS. SPECIFIC AIM 2: Define cross-talk between the 21 integrin and HGF/c-met in tumor progression and metastasis. FOCUS - 21 INTEGRIN AND HGF/C-MET CROSSTALK. SPECIFIC AIM 3: Define the 21 integrin-dependent regulation of neoangiogenesis and lymphangio- genesis. FOCUS - BLOOD AND LYMPHATIC ENDOTHELIAL CELLS. SPECIFIC AIM 4: Define the functional and prognostic relevance of inflammation, mast cell infiltration, 21 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.