Mechanisms of Pancreatic Tumor Nerve Invasion

胰腺肿瘤神经侵犯的机制

• 批准号: 8434822
• 负责人: Isis C Sroka
• 金额: $ 7.58万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8434822
• 关键词: Ablation; Adhesions; Adhesives; Antibodies; Automobile Driving; Axon; Basal lamina; Biological Assay; Blocking Antibodies; Cancer Control; Cancerous; Cell Adhesion; Cell Communication; Cell surface; Clinical; Coculture Techniques; Collaborations; Cytoplasmic Tail; Data; Development; Diagnosis; Disease; Early Diagnosis; Extracellular Matrix; Extracellular Matrix Proteins; Goals; Head and Neck Cancer; Human; In Vitro; Integrin Binding; Integrins; Invaded; Laminin; Laminin Receptor; Malignant neoplasm of pancreas; Malignant neoplasm of prostate; Methods; Modeling; Molecular; Molecular and Cellular Biology; Neoplasm Metastasis; Nerve; Neurons; Neurosciences; Operative Surgical Procedures; Pancreas; Pancreatic Adenocarcinoma; Pathology; Peripheral Nervous System; Phosphorylation; Primary Lesion; Prostate; Proteins; RNA Interference; Recurrence; Recurrent disease; Research; Role; Route; SCID Mice; Schwann Cells; Serine Protease; Signal Transduction; Site; Source; System; Testing; Therapeutic; Tissues; Tumor Cell Invasion; Tumor Cell Line; Urokinase; Urokinase Plasminogen Activator Receptor; Work; Xenograft Model; Xenograft procedure; base; cancer type; cell motility; in vivo; insight; melanoma; migration; mouse model; mutant; myelination; neoplastic cell; neurotropic; novel; novel therapeutics; pancreatic cancer cells; pancreatic neoplasm; perineural; prophylactic; receptor; relating to nervous system; response; tissue culture; tumor

DESCRIPTION (provided by applicant): The goal for this proposal is to understand human pancreatic tumor cell adhesion, migration and invasion on nerves and to use this information to block aggressive spread of disease beyond the pancreas. The central hypothesis is that laminin dependent nerve invasion during pancreatic cancer metastasis is dependent upon A6B1. Specifically, the role of the laminin binding integrin A6B1 at the molecular and cellular level will be evaluated using both an in vitro tissue culture method and in vivo using a xenograft SCID mouse model. Several key observations have stimulated this work. First, laminin binding integrins drive invasion and metastasis of human pancreatic cancer and they are persistently expressed in human pancreatic cancer and during nerve invasion. The extracellular matrix laminin proteins are essential for normal development and function of the peripheral nervous system through Schwann cell myelination of axons and are present on pancreatic nerves. It has been shown that blocking expression or function of A6B1 curtails invasion and metastasis of tumor cells both in vivo and in vitro. How A6B1 facilitates adhesion and migration on pancreatic nerves with subsequent metastasis and/or recurrent disease has yet to be fully elucidated. Early detection and targeting of A6B1 dependent migration and invasion on nerves may eliminate the clinical reality of late diagnosis and apparent metastatic sites. If proven correct, this hypothesis could have important translational implications. The therapeutic strategy would consist of ablation of the primary lesion using surgery with prophylactic anti-integrin antibodies thereby inhibiting the potential source for metastases. This is a new concept of pancreatic cancer control directed at adhesion dependent nerve invasion. We will test our central hypothesis by three specific aims using a combination of expertise including collaborations between experts in Molecular and Cellular Biology, Pathology and Neuroscience. All aims contain functional endpoints of laminin 511 dependent adhesion and migration using a novel in vitro tissue culture method and in vivo, using an orthotopic pancreatic nerve invasion xenograft model. Understanding the fundamental molecular basis of adhesion dependent sanctuary of tumor cells on nerves and their subsequent invasion beyond the pancreas will lend novel insight into mechanisms controlling pancreatic cancer cell migration and metastasis.

描述(申请人提供)：这项建议的目标是了解人类胰腺肿瘤细胞的黏附、迁移和对神经的侵袭，并利用这些信息阻止疾病向胰腺以外的侵袭性扩散。中心假说是，胰腺癌转移过程中层粘连蛋白依赖的神经侵袭依赖于A6B1。具体地说，将使用体外组织培养方法和体内使用异种移植SCID小鼠模型来评估层粘连蛋白结合整合素A6B1在分子和细胞水平上的作用。几个关键的观察结果刺激了这项工作。首先，层粘连蛋白结合整合素推动人胰腺癌的侵袭和转移，并且在人胰腺癌和神经侵袭过程中持续表达。细胞外基质层粘连蛋白对周围神经系统的正常发育和功能至关重要，它通过雪旺细胞的轴突髓鞘作用而存在于胰腺神经中。研究表明，阻断A6B1的表达或功能可抑制肿瘤细胞在体内和体外的侵袭和转移。A6B1如何促进胰腺神经在随后的转移和/或复发疾病中的黏附和迁移尚未完全阐明。及早发现和定位A6B1依赖神经的迁移和侵袭可能会消除延迟诊断和明显转移部位的临床现实。如果被证明是正确的，这一假设可能会有重要的翻译意义。治疗策略将包括使用预防性的抗整合素抗体手术消融原发灶，从而抑制转移的潜在来源。这是针对黏附依赖神经侵袭的胰腺癌控制的新概念。我们将通过三个具体的目标来测试我们的中心假设，使用各种专业知识的组合，包括分子和细胞生物学、病理学和神经科学的专家之间的合作。通过一种新的体外组织培养方法和体内原位胰腺神经侵袭异种移植模型，所有的靶点都含有依赖层粘连蛋白511的黏附和迁移的功能终点。了解肿瘤细胞在神经上的黏附依赖避难所及其随后的胰腺外侵袭的基本分子基础将为控制胰腺癌细胞迁移和转移的机制提供新的视角。