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: 8195581
• 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 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8195581
• 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

Project Summary/Abstract 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, Gal¿1-3GalNAc expressed on most human carcinomas including prostate, and ¿-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 ¿3¿1 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 ¿-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.

项目摘要/摘要 该项目概述了研究旨在研究分子和细胞机制的研究工作 支持前列腺癌的转移性扩散，并开发出提高效率的新方法 前列腺癌转移的化学疗法。前列腺癌是最常见的癌症 男性和在美国男性癌症死亡的第二大原因，而转移是主要原因 前列腺与癌症相关的发病率和死亡率。前列腺癌的分子和细胞机制 然而，转移仍然知之甚少。 来自该组和其他群体的实验证据的安装表明，癌症介导的相互作用 - 相关的Thomsen-friedenreich（TF）抗原，一种简单的粘蛋白型二糖，gAL gAL表达1-3galnac 在大多数人类癌中 在启动和支持微血管的转移性前列腺癌细胞粘附方面发挥主要作用 内皮。此外，这些相互作用在促进癌细胞克隆生成生存和 调节其对细胞毒性药物诱导的凋亡的敏感性。 已经假设TF抗原/gal-3介导的肿瘤 - 内皮细胞粘附相互作用是 通过€3¿1整联蛋白稳定，并通过SRC激酶在主要信号通路之间诱导串扰 促进癌症转移的机制。已经进一步假设抑制GAL-3抗凋亡 使用合成甘露胺乳糖基-L-达糖碱（LL）的功能，将仅针对转移相关 粘合剂事件和增强细胞毒性诱导凋亡的转移性前列腺癌细胞的敏感性 在体外和体内药物，并显着提高了化学疗法对前列腺癌的有效性 骨转移。为了检验这些假设，提出了以下特定目的：1。 转移性细胞粘合剂与微血管的分子机制和临时动力学 内皮； 2。研究由 - 半乳糖苷介导的粘合剂触发的主要信号通路 内皮和肿瘤细胞中的相互作用； 3。研究LL的分子和细胞机制 与细胞毒性药物相互作用，以增强人类转移性前列腺癌细胞的凋亡；和4 在体内调查LL在已建立的前列腺癌中提高多西他赛有效性的能力 骨转移。为了实现这些目标，建议将综合方法结合在体外平行流程中 AIM 1中的腔室技术和原子力显微镜；标准细胞生物学技术和 AIM 2中的磷蛋白质组学方法；通过对综合分析的体外实验 AIM 3中的线粒体凋亡途径；和体内非破坏性定量生物发光成像 AIM 4中前列腺癌骨转移的临床前模型。 前列腺癌与退伍军人人口高度相关。这项研究的结果最终将 增强我们对支撑前列腺癌转移支撑的细胞和分子机制的理解 并为开发这种毁灭性疾病的新基于机制的疗法提供了理由。 此外，这项研究的结果可能会对新的发展产生直接的深远影响 治疗转移性前列腺癌的治疗方法，可以将其转化为临床实践 很短的时间。如果被证明是成功的，这些新的前列腺癌化疗方法可能会受益 通过减少肿瘤伯恩，增强生活质量，大大患有晚期转移性前列腺疾病的患者， 并降低发病率和死亡率。