Role of MFG-E8 in Tumor Biology ans Immunophysiology

MFG-E8 在肿瘤生物学和免疫生理学中的作用

• 批准号: 7733381
• 负责人: Mark Udey
• 金额: $ 41.2万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7733381
• 关键词: Affinity; Apoptotic; Binding; Binding Sites; Biological; Blood Vessels; Cancer Vaccines; Cell physiology; Cells; Charge; Collaborations; Colon Carcinoma; Dendritic Cells; Endothelial Cells; Epithelial; Glycoproteins; Goals; Homologous Gene; Immunobiology; Immunology; Integrins; Investigation; Laboratories; Langerhans cell; Leukocytes; Link; Locales; Localized; Location; Malignant Neoplasms; Melanocytic Neoplasm; Mus; Mutant Strains Mice; Neutrophil Infiltration; Normal tissue morphology; Patients; Phagocytes; Phospholipids; Play; Proteins; Radiation; Radiation therapy; Role; Serine; Skin Cancer; Structure of beta Cell of islet; Therapeutic; Transgenic Model; Tumor Biology; angiogenesis; cancer therapy; chemotherapy; design; in vivo; insight; interest; macrophage; mouse model; neoplastic cell; polyclonal antibody; research study; therapeutic target; tumor; tumorigenesis

Our interest in the phagocyte- and tumor cell-derived protein MFG-E8 continues. We have generated several MFG-E8 mouse mutants to determine if MFG-E8 has a role tumor biology and immunophysiology in vivo. Results, to date, indicate that tumor cells produce MFG-E8 and that MFG-E8 promotes tumorigenesis in both orthotopic and transgenic models of cancer in mice (melanoma, non-melanoma skin cancer, colon cancer and pancreatic beta-cell cancer). In addition, ongoing experiments suggest that MFG-E8 may be a relevant therapeutic target in cancer. In collaboration with Dr. James Mitchell of the CCR's Radiation Branch, we are attempting to incorporate MFG-E8 related proteins into a tumor vaccine approach that will also involve utilization of radiation therapy and chemotherapy in several mouse models of cancer. In an effort to elucidate mechanisms by which MFG-E8 modulates tumor formation, we are also studying several mouse models of leukocyte recruitment. These studies are being carried out in collaboration with Dr. Trian Chavakis of the CCR's Experimental Immunology Branch. In his laboratory, Dr. Chavakis has been studying the MFG-E8 homolog Del1, and has elucidated an unexpected role for Del1 in neutrophil recruitment. The involvement of MFG-E8 leukocyte recruitment would provide a mechanism by which this protein could either enhance or inhibit tumorigenesis. To gain additional understanding of the roles that MFG-E8 plays in tumor formation and immunophysiology, we are carefully localizing MFG-E8 accumulation in vivo in tumors and in normal tissues. Utilizing highly specific affinity-purified polyclonal antibodies, we have determined that MFG-E8 is found focally in vascular or perivascular locations and in other specific locations as well. It is anticipated that careful characterization of these locales will provide considerable insight into MFG-E8 function in vivo.

我们对吞噬细胞和肿瘤细胞衍生蛋白 MFG-E8 的兴趣仍在继续。我们已经产生了几种 MFG-E8 小鼠突变体，以确定 MFG-E8 是否在体内具有肿瘤生物学和免疫生理学作用。迄今为止的结果表明，肿瘤细胞产生 MFG-E8，并且 MFG-E8 在小鼠癌症的原位和转基因模型（黑色素瘤、非黑色素瘤皮肤癌、结肠癌和胰腺 β 细胞癌）中促进肿瘤发生。此外，正在进行的实验表明 MFG-E8 可能是癌症的相关治疗靶点。我们与 CCR 放射科的 James Mitchell 博士合作，尝试将 MFG-E8 相关蛋白纳入肿瘤疫苗方法中，该方法还涉及在几种小鼠癌症模型中使用放射疗法和化学疗法。 为了阐明 MFG-E8 调节肿瘤形成的机制，我们还在研究几种白细胞募集的小鼠模型。这些研究是与 CCR 实验免疫学分支的 Trian Chavakis 博士合作进行的。 Chavakis 博士在他的实验室中一直在研究 MFG-E8 同源物 Del1，并阐明了 Del1 在中性粒细胞募集中的意想不到的作用。 MFG-E8 白细胞募集的参与将提供一种机制，通过该机制该蛋白质可以增强或抑制肿瘤发生。为了进一步了解 MFG-E8 在肿瘤形成和免疫生理学中发挥的作用，我们正在仔细定位 MFG-E8 在肿瘤和正常组织中体内的积累。利用高度特异性的亲和纯化的多克隆抗体，我们确定 MFG-E8 集中发现于血管或血管周围位置以及其他特定位置。预计对这些区域的仔细表征将为 MFG-E8 体内功能提供深入的了解。