Human Prostate Cancer Metastasis and Laminin Binding Integrins

人类前列腺癌转移和层粘连蛋白结合整合素

基本信息

批准号：
8677801
负责人：
ANNE E CRESS
金额：
$ 30.19万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-26 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8677801
关键词：
Ablation Adhesions Antibodies Archives Biological Assay Blocking Antibodies Cancer Control Cell Adhesion Cells Cessation of life Clinical Collaborations Complex Coupled Development Disease Disease Progression Epiphysial cartilage Excision Focal Adhesions Genes Goals Human In Vitro Injection of therapeutic agent Integrin Binding Integrins Laminin Ligand Binding Domain Ligands MSX1 gene Malignant Neoplasms Malignant neoplasm of prostate Metastatic Lesion Metastatic Neoplasm to the Bone Methods Molecular Molecular and Cellular Biology Morbidity - disease rate Neoplasm Metastasis Pain Pathology Patients Peptides Predisposition Primary Lesion Prostate Prostatectomy Prostatic Neoplasms Proteolysis Radiation therapy Radiology Specialty Recurrence Recurrent disease Residencies Role SCID Mice Secondary to Site Source Staging Testing Therapeutic Translating Variant Work X-Ray Computed Tomography Xenograft Model Xenograft procedure base bone cancer cell cancer pain cell motility conventional therapy digital directed attention genome wide association study in vivo inhibitor/antagonist insight migration mimetics mouse model neoplastic cell novel novel therapeutics prevent prophylactic receptor skeletal success tissue culture tumor

项目摘要

DESCRIPTION (provided by applicant): Our goal is to understand human prostate tumor cell adhesion, migration and to use this information to block subsequent aggressive spread to late stage secondary skeletal sites. Specifically, we will identify the role of laminin binding integrins A6B1, A6pB1 and A3B1 at the molecular and cellular level using both in vitro tissue culture and in vivo xenograft SCID mouse models. We will translate these findings to utilize blockers of integrin interactions and aggressive spread. Archived human prostate cancer bone metastases will validate key results. Several key observations have stimulated this work. First, laminin 511 binding integrins drive invasion and metastasis of human prostate cancer. They are persistently expressed in human prostate metastatic lesions, including bone. Recently, a laminin 511 receptor, A6 integrin, was 1 of 7 new prostate cancer susceptibility loci discovered in a genome-wide association study. Lastly, elevated expression of A6B1 is correlated with reduced patient survival in cancer. We and others have shown that blocking expression or function of A6B1 curtails invasion and metastasis of tumor cells both in vivo and in vitro. How they facilitate adhesion and migration, with subsequent metastasis and/or recurrent disease has yet to be fully elucidated. The central hypothesis is that laminin 511 adhesion and colonization of cancer cells in bone is dependent upon laminin binding integrins and regulated by novel pericellular proteolysis involving the uPA/uPAR axis. Early (and often clinically inapparent) bone metastasis can provide a sanctuary site for tumor cells. Deployment of tumor cells from bone via A6pB1 may explain the clinical reality of widespread skeletal recurrence as aggressive metastatic disease 5 to 10 years after primary therapy. If proven correct, this hypothesis could have important translational implications. The therapeutic strategy would consist of ablation of the primary lesion using radiotherapy and/or prostatectomy coupled with prophylactic anti-integrin antibodies or peptide combinations to eliminate osseous sanctuary sites, and thereby the potential source of late bone recurrence. This is a new concept of cancer control directed at adhesion dependent and bone resident cancer. We will test our central hypothesis by three specific aims using a combination of expertise including collaborations between experts in Molecular Cellular Biology, Pathology and Radiology. All aims contain functional endpoints of laminin 511 dependent adhesion and migration using in vitro tissue culture methods and in vivo assays, using an intra- osseous injection xenograft model, digital radiographs and quantitative micro CT imaging. Understanding the fundamental molecular basis of adhesion dependent sanctuary of tumor cells in bone and their subsequent deployment will lend novel insight into mechanisms controlling cancer cell migration and metastasis to secondary skeletal sites. Metastasis to secondary sites is a cause of skeletal morbidity, disease progression, cancer pain or death. Recurrent disease could be potentially eliminated by adding important "pre-emptive" strategies to conventional therapy.

描述（由申请人提供）：我们的目标是了解人类前列腺肿瘤细胞粘附、迁移，并利用这些信息阻止随后向晚期次级骨骼部位的侵袭性扩散。具体来说，我们将使用体外组织培养和体内异种移植 SCID 小鼠模型，在分子和细胞水平上确定层粘连蛋白结合整合素 A6B1、A6pB1 和 A3B1 的作用。我们将把这些发现转化为利用整合素相互作用和侵袭性传播的阻断剂。存档的人类前列腺癌骨转移将验证关键结果。几个关键的观察结果促进了这项工作。首先，层粘连蛋白 511 结合整合素驱动人类前列腺癌的侵袭和转移。它们在人类前列腺转移性病变（包括骨）中持续表达。最近，层粘连蛋白 511 受体（A6 整合素）是全基因组关联研究中发现的 7 个新的前列腺癌易感位点之一。最后，A6B1 表达升高与癌症患者生存率降低相关。我们和其他人已经证明，阻断 A6B1 的表达或功能可以减少体内和体外肿瘤细胞的侵袭和转移。它们如何促进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。中心假设是层粘连蛋白 511 粘附和癌细胞在骨中的定植依赖于层粘连蛋白结合整联蛋白，并受到涉及 uPA/uPAR 轴的新型细胞周蛋白水解作用的调节。早期（通常临床上不明显）骨转移可以为肿瘤细胞提供避难所。通过 A6pB1 从骨中部署肿瘤细胞可以解释初次治疗后 5 至 10 年作为侵袭性转移性疾病广泛骨骼复发的临床现实。如果被证明是正确的，这一假设可能具有重要的转化意义。治疗策略包括使用放射疗法和/或前列腺切除术消融主要病变，并结合预防性抗整合素抗体或肽组合，以消除骨庇护部位，从而消除晚期骨复发的潜在来源。这是针对粘附依赖性癌症和骨驻留癌的癌症控制新概念。我们将利用包括分子细胞生物学、病理学和放射学专家之间的合作在内的专业知识组合，通过三个具体目标来检验我们的中心假设。所有目标均包含使用体外组织培养方法和体内测定、使用骨内注射异种移植模型、数字射线照片和定量显微CT成像的层粘连蛋白511依赖性粘附和迁移的功能终点。了解骨中肿瘤细胞粘附依赖性避难所的基本分子基础及其随后的部署将为控制癌细胞迁移和转移到二级骨骼位点的机制提供新的见解。继发部位转移是骨骼发病、疾病进展、癌症疼痛或死亡的原因。通过在常规治疗中添加重要的“先发制人”策略，可以潜在地消除复发性疾病。