Mechanisms of Pancreatic Tumor Nerve Invasion

描述（由申请人提供）：本申请的目标是了解人类胰腺肿瘤细胞对神经的粘附、迁移和侵袭，并利用这些信息阻止疾病在胰腺以外的侵袭性扩散。核心假设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。具体来说，层粘连蛋白结合整合素A6B1在分子和细胞水平上的作用将通过体外组织培养方法和体内异种移植SCID小鼠模型进行评估。几个关键的观察刺激了这项工作。首先，层粘连蛋白结合整合素驱动人胰腺癌的侵袭和转移，它们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通过轴突的雪旺细胞髓鞘形成对周围神经系统的正常发育和功能至关重要，并存在于胰腺神经中。研究表明，在体内和体外，阻断A6B1的表达或功能可以抑制肿瘤细胞的侵袭和转移。A6B1如何促进胰腺神经的粘附和迁移以及随后的转移和/或复发性疾病尚未完全阐明。早期发现并靶向治疗A6B1依赖性迁移和侵袭神经，可能会消除晚期诊断和明显转移部位的临床现实。如果被证明是正确的，这一假设可能具有重要的翻译意义。治疗策略包括使用手术消融原发病灶，同时使用预防性抗整合素抗体，从而抑制潜在的转移源。这是一种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目标来检验我们的中心假设，这些目标将结合分子和细胞生物学、病理学和神经科学专家的专业知识。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，所有目标都包含层粘连蛋白511依赖的粘附和迁移的功能终点。了解肿瘤细胞在神经上的粘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见解。

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.