Immune modulation by MUC1 secreting tumor cells

分泌MUC1的肿瘤细胞的免疫调节

• 批准号: 7585755
• 负责人: DAN ILKOVITCH
• 金额: $ 3.42万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-03-01 至 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7585755
• 关键词: Accounting; Animals; Antigen Presentation; Antigen-Presenting Cells; Apical; Biological Assay; Breast; CCL2 gene; Cancer Vaccines; Carcinogens; Cell Adhesion; Cell Line; Cell Maturation; Cell surface; Cells; Cessation of life; Characteristics; Chemical Warfare; Chemotactic Factors; Clinical Trials; Colonic Neoplasms; Cytoskeleton; Dendritic Cells; Development; Duct (organ) structure; Effectiveness; Environmental Exposure; Enzyme-Linked Immunosorbent Assay; Extracellular Matrix; Failure; Fellowship; Flow Cytometry; Gel; Gland; Glycoproteins; Goals; Host Defense; Human; Immune; Immune Tolerance; Immune response; Immune system; Immunosuppression; Immunotherapeutic agent; Inbred BALB C Mice; Individual; Inflammatory; Inherited; Integral Membrane Protein; Laboratories; Lead; Malignant Neoplasms; Mammary Neoplasms; Mediating; Methods; Modeling; Molecular; Mucin 1 protein; Mucin-1 Staining Method; Mucins; Mus; Myelogenous; Natural Killer Cells; Normal Cell; Pancreas; Parents; Peptides; Population; Prevention; Production; Property; Protein Isoforms; Proteins; Recruitment Activity; Renal Cell Carcinoma; Risk; Risk Factors; Role; Suppressor-Effector T-Lymphocytes; Surface; T-Cell Activation; Techniques; Testing; Therapeutic; Tissues; Tumor Antigens; Tumor Cell Line; Tumor-Derived; Urokinase; Work; cancer cell; cancer therapy; cancer type; cell motility; cell transformation; chemokine; cytokine; immunogenicity; immunoregulation; in vivo; killings; malignant breast neoplasm; migration; monocyte; neoplastic cell; osteosarcoma; overexpression; prevent; research study; response; tool; tumor; tumor growth; tumorigenic

DESCRIPTION (provided by applicant): While mucins are found on normal cell surfaces, and are proposed to have multiple roles such as providing protection from environmental exposures and carcinogens, and involvement in cell adhesion and migration, altered forms of the MUC1 glycoprotein have been found heavily expressed in human breast cancer tissue, and other tumors. In our laboratory mammary tumor cells expressing the transmembrane isoform of MUC1 develop tumors in vivo and lead to death of the host. In contrast, tumor cells expressing a MUC1 secreted isoform fail to develop tumors by an immunologically regulated mechanism. Furthermore, MUC1 secreting mammary tumor cells confer protection in mice against the parental mammary tumor line, which does not secrete MUC1, and other highly tumorigenic cell lines unrelated to the mammary tumor line. The following proposal aims to dissect some of the molecular mechanisms involved in this phenomenon. The first aim will examine characteristics of the MUC1 secreting tumor cells which may lead to rejection in vivo or failure to grow. Immunological surface molecules, and production of tumor derived factors, such as chemoattractant molecules and extracellular matrix degrading proteins, will be screened by various assays such as flow cytometry, ELISA, and zymography assays. These techniques will identify if there is a variable expression of these molecules by the tumor lines, which may aid in immunoregulation of tumor growth or elimination. The second aim will dissect the effect of these tumor cells differing in MUC1 expression on various immunological parameters including among others migration and activation of different types of lymphoreticular cells, dendritic cell maturation and function, monocyte migration, expansion of immature myeloid suppressor cells and their ability to inhibit anti-tumor immune responses, and induction of immunological tolerance to tumors. This aim will be achieved by different assays including but not limited to flow cytometry, gel matrix cellular recruitment in vivo, T cell activation and proliferation, and use of cellular migration chambers. Furthermore, the purified secreted isoform of MUC1 or an Immuno Enhancing Peptide (IEP) only found in the secreted isoform will be used in parallel experiments to test the ability of changing the parameters analyzed in the two aims. The objective of this proposal is to investigate the immunological and cellular mechanisms involved in the growth of tumors, and examine the immunoregulatory characteristics of the MUC1 glycoprotein, which may have immunoenhancing and anti-tumor properties. Understanding how MUC1 is involved in tumor immunoregulation may potentially lead to its use as an immunotherapeutic agent against various cancers.

描述（由申请人提供）：虽然在正常的细胞表面上发现粘蛋白，并被提议具有多种作用，例如提供免受环境暴露和致癌物的保护，并参与细胞粘附和迁移，但已发现MUC1糖蛋白的变化形式在人类乳腺癌组织和其他肿瘤组织中表达了很大的表现。在我们表达MUC1跨膜同工型的实验室乳腺肿瘤细胞中，体内会出现肿瘤并导致宿主死亡。相反，表达MUC1分泌同种型的肿瘤细胞无法通过免疫学调节的机制发展肿瘤。此外，MUC1分泌乳腺肿瘤细胞可在不分泌MUC1的父母乳腺肿瘤系列中提供保护，以及与乳腺肿瘤系无关的其他高度肿瘤性细胞系。以下建议旨在剖析该现象中涉及的一些分子机制。第一个目标将检查MUC1分泌肿瘤细胞的特征，这可能导致体内排斥或未能生长。免疫表面分子以及肿瘤衍生因子的产生，例如趋化因子分子和细胞外基质降解蛋白，将通过流式细胞仪，ELISA和Zimymography测定法进行筛选。这些技术将确定这些分子是否通过肿瘤线的表达可变，这可能有助于免疫调节肿瘤生长或消除。第二个目的将解剖这些肿瘤细胞在MUC1表达上对各种免疫学参数的影响，包括迁移和激活不同类型的淋巴细胞细胞，树突状细胞成熟和功能，单核细胞迁移，不成熟的髓样抑制细胞的扩展以及抑制免疫反应和抑制免疫的能力。通过不同的测定法，包括但不限于流式细胞术，体内凝胶基质细胞募集，T细胞激活和增殖以及使用细胞迁移室的使用，将实现此目标。此外，仅在分泌的同工型中发现的MUC1的纯化分泌的同工型或免疫增强肽（IEP）将在并行实验中使用，以测试更改两个目标中分析的参数的能力。该提案的目的是研究肿瘤生长中涉及的免疫和细胞机制，并检查MUC1糖蛋白的免疫调节特性，该特征可能具有免疫促和抗肿瘤特性。了解MUC1如何参与肿瘤免疫调节可能会导致其用作对各种癌症的免疫治疗剂。