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: 8397536
• 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/8397536
• 关键词: Adhesives; Affect; Aging; Apoptosis; Apoptotic; Atomic Force Microscopy; BCL2 gene; 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; 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; prostate cancer cell; public health relevance; 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.

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性扩散的分子和细胞机制，并开发新的方法来提高化学疗法对前列腺癌转移的疗效。前列腺癌是美国最常见的癌症，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的发病率和死亡率的主要原因。然而，前列腺癌转移的分子和细胞机制仍然鲜为人知。来自该组和其他组的实验证据的越来越多，表明由癌症相关的Thomsen-Friedenreich（TF）抗原介导的相互作用，这是一种简单的粘蛋白型二糖，GAL21-3GALNAC，在包括前列腺和2-Galactoside racting recting calectin lectectin lectectin calectin calectin calectin calectin calcinomas上表达的GAL21-3GALNAC -3（GAL-3）可能在启动和支持微血管内皮细胞的转移性前列腺癌细胞粘附方面起主要作用。此外，这些相互作用对于促进癌细胞克隆生成的生存以及调节细胞毒性药物引起的凋亡的敏感性也很重要。已经假设TF抗原/Gal-3介导的肿瘤 - 内皮细胞粘合剂相互作用通过1321整合素稳定，并通过SRC激酶依赖性机制在主要信号传导途径之间诱导串扰，从而促进癌症转移。人们已经推测，使用合成甘露糖明乳糖基-L-蛋白（LL）抑制GAL-3抗凋亡功能，将同时靶向转移相关的粘合剂事件，并增强转移性前列腺癌细胞对受细胞毒性药物诱导的凋亡的转移性前列腺癌细胞的敏感性体内，并显着提高化学疗法对前列腺癌骨转移的有效性。为了检验这些假设，提出了以下特定目的：1。研究转移性细胞粘合剂与微血管内皮相互作用的分子机制和时间动力学； 2。研究由2-半乳糖苷介导的内皮细胞和肿瘤细胞中的2-半乳糖苷介导的粘合剂相互作用触发的主要信号通路； 3。研究LL与细胞毒性药物相互作用的分子和细胞机制，以增强人类转移性前列腺癌细胞的凋亡； 4。在体内研究LL在已建立的前列腺癌骨转移酶增强多西他赛有效性的能力。为了实现这些目标，建议将综合方法结合在AIM 1中的体外平行流室技术和原子力显微镜。 AIM 2中的标准细胞生物学技术和磷酸化蛋白质组学方法；通过对AIM 3中线粒体凋亡途径的全面分析，体外实验；在AIM 4中的前列腺癌骨转移的临床前模型中，体内非破坏性定量生物发光成像。前列腺癌与退伍军人的种群高度相关。这项研究的结果最终将增强我们对基于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疗法提供了基本原理。此外，这项研究的结果可能会对治疗转移性前列腺癌的新治疗方法的发展产生直接的影响，这些方法可以在很短的时间内将其转化为临床实践。如果证明成功，这些新的前列腺癌化疗方法可以通过减轻肿瘤负担，增强生活质量以及降低发病率和死亡率来使患有晚期前列腺疾病的患者受益匪浅。

项目成果

MULTISCALE TENSOR ANISOTROPIC FILTERING OF FLUORESCENCE MICROSCOPY FOR DENOISING MICROVASCULATURE.

• DOI: 10.1109/isbi.2015.7163930
• 发表时间: 2015-04
• 期刊: Proceedings. IEEE International Symposium on Biomedical Imaging
• 作者: Prasath VB;Pelapur R;Glinskii OV;Glinsky VV;Huxley VH;Palaniappan K
• 通讯作者: Palaniappan K

Humanization of JAA-F11, a Highly Specific Anti-Thomsen-Friedenreich Pancarcinoma Antibody and InVitro Efficacy Analysis.

JAA-F11（一种高度特异性的抗 Thomsen-Friedenreich 胰腺癌抗体）的人源化和体外功效分析。

• DOI: 10.1016/j.neo.2017.07.001
• 发表时间: 2017
• 期刊: Neoplasia (New York, N.Y.)
• 作者: Tati,Swetha;Fisk,JohnC;Abdullah,Julia;Karacosta,Loukia;Chrisikos,Taylor;Philbin,Padraic;Morey,Susan;Ghazal,Diala;Zazala,Fatma;Jessee,Joseph;Quataert,Sally;Koury,Stephen;Moreno,David;Eng,JingYing;Glinsky,VladislavV;Glinskii
• 通讯作者: Glinskii

Pulsed estrogen therapy prevents post-OVX porcine dura mater microvascular network weakening via a PDGF-BB-dependent mechanism.

• DOI: 10.1371/journal.pone.0082900
• 发表时间: 2013
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Glinskii OV;Huxley VH;Glinskii VV;Rubin LJ;Glinsky VV
• 通讯作者: Glinsky VV

Endothelial integrin α3β1 stabilizes carbohydrate-mediated tumor/endothelial cell adhesion and induces macromolecular signaling complex formation at the endothelial cell membrane.

• DOI: 10.18632/oncotarget.1837
• 发表时间: 2014-03-15
• 期刊: Oncotarget
• 作者: Glinskii OV;Li F;Wilson LS;Barnes S;Rittenhouse-Olson K;Barchi JJ Jr;Pienta KJ;Glinsky VV
• 通讯作者: Glinsky VV