The Role of Beta-Gal Mediated Interactions in Prostate Cancer Metastasis

β-半乳糖介导的相互作用在前列腺癌转移中的作用

• 批准号: 7797062
• 负责人: VLADISLAV V GLINSKII
• 金额: --
• 依托单位: HARRY S. TRUMAN MEMORIAL VA HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-10-01 至 2013-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7797062
• 关键词: Adhesives; Affect; Aging; Apoptosis; Apoptotic; Atomic Force Microscopy; Binding Proteins; Bone Diseases; Carbohydrates; Carcinoma; Caspase; Cell Adhesion; Cell Aggregation; Cell Communication; Cell surface; Cells; Cellular biology; Cessation of life; Chemotherapy-Oncologic Procedure; Citrus; Combined Modality Therapy; Cytotoxic agent; Data; Development; Disaccharides; Disease; Disease Progression; Disseminated Malignant Neoplasm; Distant; Drug effect disorder; Effectiveness; Endothelial Cells; Endothelium; Event; Family; Galactosides; Galectin 2; Galectin 3; Goals; Growth; Health; Homeostasis; Human; Image; In Vitro; Injection of therapeutic agent; Integrin alpha3beta1; Integrins; Intractable Pain; Leucine; Luciferases; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of prostate; Maps; Mediating; Metastatic Neoplasm to the Bone; Metastatic Prostate Cancer; Mitochondria; Modality; Modeling; Molecular; Monitor; Morbidity - disease rate; Mucins; Neoplasm Metastasis; Organ; Pathological fracture; Pathway interactions; Patients; Pectins; Phosphorylation; Play; Population; Pre-Clinical Model; Predisposition; Process; Property; Prostate; Prostate carcinoma; Prostatic Diseases; Protein Dynamics; Quality of life; Regimen; Regulation; Relative (related person); Research; Role; Signal Pathway; Skeleton; Techniques; Testing; Thompson-Friedenreich Antigen; Time; TimeLine; Translating; Tumor Burden; Veterans; adhesion process; base; beta-galactoside; bone; cancer cell; cancer diagnosis; cell motility; chemotherapy; clinical practice; docetaxel; in vivo; inhibitor/antagonist; male; men; mortality; mouse model; neoplastic cell; new therapeutic target; novel; novel strategies; novel therapeutic intervention; prevent; research study; spinal cord compression; src-Family Kinases; therapeutic target; tumor

DESCRIPTION (provided by applicant): This project outlines a research effort aiming to investigate the molecular and cellular mechanisms supporting metastatic spread of prostate cancer and to develop new approaches toward increasing the efficacy of chemotherapy upon prostate cancer metastasis. Prostate carcinoma is the most common cancer among men and the second leading cause of male cancer death in the US, while metastasis is the major cause of prostate cancer-related morbidity and mortality. The molecular and cellular mechanisms of prostate cancer metastasis, however, are still poorly understood. Mounting experimental evidence from this and other groups suggest that interactions mediated by cancer- associated Thomsen-Friedenreich (TF) antigen, a simple mucin-type disaccharide, Gal21-3GalNAc expressed on most human carcinomas including prostate, and 2-galactoside-binding lectin galectin-3 (Gal-3) are likely to play a leading role in initiating and supporting metastatic prostate cancer cell adhesion to microvascular endothelium. In addition, these interactions are also important in promoting cancer cell clonogenic survival and regulating their susceptibility to apoptosis induced by cytotoxic drugs. It has been hypothesized that TF antigen/Gal-3 mediated tumor-endothelial cell adhesive interactions are stabilized by 1321 integrin and induce a crosstalk between major signaling pathways via Src kinase dependent mechanisms promoting cancer metastasis. It has been further hypothesized that inhibiting Gal-3 anti-apoptotic function using synthetic glycoamine Lactulosyl-L-Leucine (LL), will simultaneously target metastasis-associated adhesive events and augment sensitivity of metastatic prostate cancer cells to apoptosis induced by cytotoxic drugs in vitro and in vivo and significantly increase the effectiveness of chemotherapy upon prostate cancer bone metastasis. To test these hypotheses, the following specific aims are proposed: 1. To investigate the molecular mechanisms and temporal dynamics of metastatic cell adhesive interactions with microvascular endothelium; 2. To investigate major signaling pathways triggered by 2-galactoside-mediated adhesive interactions in endothelial and tumor cells; 3. To investigate molecular and cellular mechanisms of LL interactions with cytotoxic drugs to enhance apoptosis in human metastatic prostate carcinoma cells; and 4. To investigate in vivo the ability of LL to increase effectiveness of docetaxel upon established prostate cancer bone metastases. To achieve these goals, an integrated approach is suggested combining in vitro parallel flow chamber techniques and atomic force microscopy in Aim 1; standard cell biology techniques and phosphoproteomic approaches in Aim 2; in vitro experimentation employing comprehensive analysis of the mitochondrial apoptosis pathway in Aim 3; and in vivo nondestructive quantitative bioluminescent imaging in a preclinical model of prostate cancer bone metastasis in Aim 4. Prostate cancer is highly relevant to the veterans' population. The results of this study will ultimately enhance our understanding of cellular and molecular mechanisms underpinning prostate cancer metastasis and provide the rationale for the development of new mechanism-based therapies of this devastating disease. Further, the results of this study may have an immediate profound effect on the development of new therapeutic approaches to treat metastatic prostate cancer, which could be translated into clinical practice in a very short time. If proven successful, these new approaches to prostate cancer chemotherapy could benefit greatly patients with advanced metastatic prostate disease by reducing tumor burden, enhancing quality of life, and reducing morbidity and mortality. PUBLIC HEALTH RELEVANCE: Project Narrative Prostate carcinoma is the most common cancer among men and the second leading cause of male cancer death in the US. It was projected that there will be 186,320 new cases of prostate cancer diagnosed, and 28,660 men will die from the disease in the US in 2008. Currently incurable, metastasis (a spread of cancer to distant organs) is the major cause of prostate cancer-related morbidity and mortality among aging veterans. This project aims to identify new therapeutic targets for preventing and controlling metastatic cancer spread and enhance the efficacy of chemotherapy upon established prostate cancer metastases using non-toxic carbohydrate-based compounds. If successful, the results of this study will be ultimately translated into clinical practice and will benefit veteran patients with prostate cancer by reducing tumor burden, enhancing quality of life, and reducing morbidity and mortality.

描述（由申请人提供）： 该项目概述了一项研究工作，旨在研究支持前列腺癌转移扩散的分子和细胞机制，并开发新方法来提高化疗对前列腺癌转移的疗效。前列腺癌是男性中最常见的癌症，也是美国男性癌症死亡的第二大原因，而转移是前列腺癌相关发病率和死亡率的主要原因。然而，人们对前列腺癌转移的分子和细胞机制仍知之甚少。 来自该小组和其他小组的越来越多的实验证据表明，由癌症相关的 Thomsen-Friedenreich (TF) 抗原（一种简单的粘蛋白型二糖）、在大多数人类癌症（包括前列腺癌）中表达的 Gal21-3GalNAc 和 2-半乳糖苷结合凝集素半乳糖凝集素介导的相互作用-3 (Gal-3) 可能在启动和支持转移性前列腺癌细胞粘附到微血管内皮方面发挥主导作用。此外，这些相互作用对于促进癌细胞克隆存活和调节其对细胞毒性药物诱导的细胞凋亡的易感性也很重要。 据推测，TF 抗原/Gal-3 介导的肿瘤-内皮细胞粘附相互作用由 1321 整联蛋白稳定，并通过 Src 激酶依赖性机制诱导主要信号传导途径之间的串扰，促进癌症转移。进一步假设，使用合成糖胺乳糖基-L-亮氨酸 (LL) 抑制 Gal-3 抗凋亡功能，将同时靶向转移相关的粘附事件，并增强转移性前列腺癌细胞对体外细胞毒性药物诱导的细胞凋亡的敏感性在体内并显着提高化疗对前列腺癌骨转移的有效性。为了检验这些假设，提出以下具体目标： 1. 研究转移细胞与微血管内皮粘附相互作用的分子机制和时间动力学； 2. 探讨2-半乳糖苷介导的内皮细胞和肿瘤细胞粘附相互作用触发的主要信号通路； 3. 探讨LL与细胞毒药物相互作用促进人转移性前列腺癌细胞凋亡的分子和细胞机制； 4. 体内研究 LL 提高多西紫杉醇对已确定的前列腺癌骨转移的有效性的能力。为了实现这些目标，目标 1 中建议采用一种综合方法，将体外平行流室技术和原子力显微镜相结合；目标 2 中的标准细胞生物学技术和磷酸化蛋白质组学方法；体外实验，综合分析 Aim 3 中的线粒体凋亡途径；以及目标 4 中前列腺癌骨转移临床前模型中的体内无损定量生物发光成像。前列腺癌与退伍军人群体高度相关。这项研究的结果将最终增强我们对前列腺癌转移的细胞和分子机制的理解，并为开发这种破坏性疾病的新的基于机制的疗法提供依据。此外，这项研究的结果可能对治疗转移性前列腺癌的新治疗方法的开发产生直接深远的影响，并可以在很短的时间内转化为临床实践。如果被证明成功，这些新的前列腺癌化疗方法可以通过减少肿瘤负担、提高生活质量、降低发病率和死亡率，使晚期转移性前列腺疾病患者受益匪浅。 公共卫生相关性： 项目叙述 前列腺癌是男性中最常见的癌症，也是美国男性癌症死亡的第二大原因。据预测，2008 年美国将新增 186,320 例前列腺癌确诊病例，并将有 28,660 名男性死于该病。目前无法治愈的转移（癌症向远处器官扩散）是前列腺癌的主要原因。老年退伍军人的相关发病率和死亡率。该项目旨在确定新的治疗靶点，用于预防和控制转移性癌症扩散，并使用无毒的碳水化合物化合物增强化疗对已确定的前列腺癌转移的疗效。如果成功，这项研究的结果将最终转化为临床实践，并将通过减少肿瘤负担、提高生活质量、降低发病率和死亡率，使患有前列腺癌的退伍军人患者受益。