Functional Analysis of Galectin-1 Ligands in Melanoma Progression

Galectin-1 配体在黑色素瘤进展中的功能分析

• 批准号: 8578572
• 负责人: CHARLES J DIMITROFF
• 金额: $ 35.93万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-02 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8578572
• 关键词: Address; Adhesions; Apoptosis; Australia; Behavior; Benign; Binding; Biological Markers; CD146 antigen; Carbohydrates; Cell Adhesion; Cell Membrane Proteins; Cell surface; Cells; Chimera organism; Clinical; Compound Nevus; Data; Detection; Development; Diagnosis; Disease Progression; Dysplastic Nevus; Engineering; Epidermis; Epitopes; Event; Galactosides; Galectin 1; Glycobiology; Glycoproteins; Goals; Grant; Growth; Histology; Histopathology; Human; Immune; Immunity; Institutes; Investigation; Laboratories; Lectin; Ligand Binding; Ligands; Link; Malignant - descriptor; Malignant Neoplasms; Mediating; Mediator of activation protein; Melanoma Cell; Membrane Glycoproteins; Membrane Proteins; Metastatic Melanoma; Methods; Molecular; Neoplasm Metastasis; Nevus; Outcome; Pathologist; Pathology; Patients; Phase; Polysaccharides; Proteins; Radial; Regulation; Research; Research Project Grants; Severity of illness; Sialyltransferases; Skin; Specimen; Structural Biochemistry; Structure; Surface; T-Lymphocyte; TNFSF11 gene; Tissues; angiogenesis; cancer cell; cell motility; cohort; cytokine; follow-up; glycosyltransferase; human galectin 1; insight; melanocyte; melanoma; migration; neoplastic; neoplastic cell; novel; overexpression; public health relevance; scaffold; sugar; tool; tumor; tumorigenic

DESCRIPTION (provided by applicant): Cell surface carbohydrates and proteins (lectins) that bind them are conspicuously elevated in certain malignancies. These sugar structures and lectins are critically involved in cancer cell motility, invasion and/or migration that ultimately evoke the lethality of cancer. There is a convincing body of evidence suggesting that ss-galactoside-binding lectin, galectin-1 (Gal-1), is a major glycopathogenic mediator of melanoma progression and metastasis. Studies show that melanoma-derived Gal-1 has a major impact on T cell-mediated anti-melanoma immunity. While most have focused on Gal-1 and its functional activity in these malignancy-related events, few have focused on the functional expression of Gal-1 carbohydrate-binding determinants found on the surface of melanoma cells. We have exciting preliminary data showing that human melanoma cells express a robust level of Gal-1-binding carbohydrates, including the membrane protein(s) that display them, that, to our surprise, are conspicuously absent on normal melanocytes and benign melanocytes in mildly dysplastic nevi. Moreover, we have experimental evidence indicating that melanoma cell adhesion molecule (MCAM) is the principal membrane glycoprotein displaying these Gal-1-binding carbohydrates that is also upregulated in malignant melanoma. Differential expression of these Gal-1-binding carbohydrates on distinct glycoproteins, operationally referred to as Gal-1 ligands, could, therefore, functionally correlate with malignant progression of human melanoma. Our central hypothesis is that expression of Gal-1 ligands, namely MCAM, on melanoma cells can not only be used as a biomarker of melanoma progression, but can be functionally associated with malignant transformation. The overall objective of this research project is to analyze the identity, regulation and function of Gal-1 ligands on human malignant melanoma cells and to study the utility of Gal-1 ligands as predictors of human melanoma progression and metastasis. Investigating identity and function of Gal-1 ligands in human melanomas and whether these structures correlate with disease severity and long-term outcome in melanoma patients can be uniquely applied by the tumor biologists and dermato-pathologists collaborating in this proposal. Using new Gal-1 ligand-binding probes developed by our laboratory and our collective expertise in identifying lectin ligands and studying the histopathology of melanomas, the Specific Aims are as follows: (1) To identify and characterize Gal-1 ligands in human melanomas and (2) To study the expression of Gal-1 ligands as predictors of melanoma progression. These studies will implement a unique cohort of human melanoma tissues from the Melanoma Institute of Australia to help determine whether Gal-1 ligand expression correlates with melanoma progression and metastasis. Moreover, we will employ state-of-the-art glycobiological tools to help dissect Gal-1 ligand identity and function. Importantly, our findings will provide novel molecular insights into the glyco-histopathology of melanomas, while offering new glycomic targets for predicting malignancy and/or clinical outcome.

描述（由申请人提供）：结合它们的细胞表面碳水化合物和蛋白质（凝集素）在某些恶性肿瘤中显着升高。这些糖结构和凝集素与癌细胞的运动，侵袭和/或迁移至关重要，最终引起了癌症的致命性。有令人信服的证据表明，SS-半乳糖苷结合凝集素，半乳糖素-1（GAL-1）是黑色素瘤进展和转移的主要糖原性介质。研究表明，黑色素瘤来源的GAL-1对T细胞介导的抗黑色素瘤免疫有重大影响。尽管大多数人都集中在这些与恶性肿瘤相关的事件中的GAL-1及其功能活性上，但很少有人专注于在黑色素瘤细胞表面上发现的GAL-1碳水化合物结合决定因素的功能表达。我们有令人兴奋的初步数据，表明人黑色素瘤细胞表达了强大的GAL-1结合碳水化合物，包括显示它们的膜蛋白（S），令人惊讶的是，在较小的增生性NEVI中，在正常的黑素细胞和良性黑素细胞上显然不存在明显的。此外，我们有实验证据表明，黑色素瘤细胞粘附分子（MCAM）是主要膜糖蛋白，显示出这些GAL-1结合碳水化合物，在恶性黑色素瘤中也被上调。因此，这些GAL-1结合碳水化合物在不同的糖蛋白上的差异表达在操作上称为Gal-1配体，因此在功能上可能与人类黑色素瘤的恶性进展有关。我们的中心假设是，GAL-1配体在黑色素瘤细胞上的表达不仅可以用作黑色素瘤进展的生物标志物，而且在功能上可以与恶性转化有关。该研究项目的总体目的是分析GAL-1配体对人恶性黑色素瘤细胞的认同，调节和功能，并研究GAL-1配体作为人类黑色素瘤进展和转移的预测指标的实用性。研究人类黑色素瘤中GAL-1配体的身份和功能以及这些结构是否与肿瘤生物学家和表皮病理学家合作在此提案中合作，可以独特地应用黑色素瘤患者的疾病严重程度和长期预后。使用我们的实验室开发的新GAL-1配体结合探针以及我们在识别凝集素配体和研究黑色素瘤的组织病理学方面开发的集体专业知识，具体目的如下：（1）识别和表征人黑色素瘤中的GAL-1配体和（2）研究Gal-1 Ligands As-1 As-1 Asefors of Melanaman Preceptors of Melanaman progressors的表达。这些研究将实施来自澳大利亚黑色素瘤研究所的独特人类黑色素瘤组织，以帮助确定GAL-1配体表达是否与黑色素瘤进展和转移相关。此外，我们将采用最先进的糖生物学工具来帮助剖析Gal-1配体的身份和功能。重要的是，我们的发现将提供对黑色素瘤的糖 - 依赖斯托病理学的新分子见解，同时为预测恶性肿瘤和/或临床结果提供新的糖基靶标。