PROSTATE CANCER, BONE METASTASIS, AND METALLOPROTEINASES

前列腺癌、骨转移和金属蛋白酶

• 批准号: 6192818
• 负责人: MICHAEL L CHER
• 金额: $ 26.82万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-01 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6192818
• 关键词: SCID mouse; bone neoplasms; cell migration; cell proliferation; clinical research; disease /disorder model; enzyme activity; enzyme induction /repression; human subject; metalloendopeptidases; metastasis; mixed tissue /cell culture; model design /development; organ culture; osteoblasts; osteoclasts; prostate neoplasms

DESCRIPTION: (Adapted from the investigator's abstract) Metastasis of prostate cancer to bone causes increased turnover of bone matrix and is frequently accompanied by pain and pathological fractures. Radiologically, prostate cancer metastases are "blastic," however, on a biochemical level, they are both lytic and blastic. The cellular and biochemical mechanisms underlying the enhanced turnover of bone matrix associated with metastatic cancer are unknown. The "SCID-human model of prostate cancer metastasis to bone," recently developed in our laboratory, mimics clinical disease on several levels: prostate cancer cells home to human bone implanted in SCID mice, they grow more rapidly in bone as compared to other tissue environments, and there is rapid turnover of bone matrix. In this and other models, we found that prostate cancer cells growing in bone produce and/or secrete matrix metalloproteinases (MMPs) including MMP-2, MMP-9 and MT1-MMP. These proteinases are enzymatically competent to degrade bone matrix, and they normally participate in several of the steps of bone matrix metabolism. For example, osteoblasts use MMPs to digest nonmineralized bone matrix, and this leads to recruitment of osteoclasts and enhanced osteoclastic degradation of mineralized matrix. We hypothesize that prostate cancer cells degrade nonmineralized matrix in a fashion similar to osteoblasts and that production of MMP-2, MMP-9, and MT1-MMP by metastatic prostate cancer cells may contribute to the enhanced bone matrix turnover associated with metastatic disease. Using the in vivo SCID-human system and an in vitro bone organ culture model, we will test the hypothesis that: (1) the bone environment induces an upregulation of MMP-2, MMP-9 and MT1-MMP expression in prostate cancer cells and an increase in MMP-2, MMP-9 secretion and activity; (2) there is MMP activity at the interface between prostate cancer cells and the nonmineralized bone matrix; and (3) MMP production/secretion by prostate cancer cells in the bone environment leads to tumor cell proliferation, and migration of tumor cells to endosteal surfaces; degradation of nonmineralized bone matrix; recruitment of osteoclasts; and enhanced osteoclast activity and degradation of mineralized matrix. These experiments will take advantage of our model systems and a variety of prostate cancer cells that produce a spectrum of response in bone ranging from primarily osteolytic to primarily osteoblastic. The results of these studies may lead to new therapeutic strategies aimed at interrupting the interactions between prostate cancer cells and bone.

描述：（根据调查员的摘要改编）前列腺转移 癌症导致骨基质的营业额增加，并且经常是 伴随着疼痛和病理骨折。放射学，前列腺癌 但是，转移是“ Blastic”，但是，在生化水平上，它们都是裂解的 和混乱。增强的细胞和生化机制 与转移性癌有关的骨基质的营业额尚不清楚。这 最近在 我们的实验室，模仿临床疾病多个级别：前列腺癌 细胞植入SCID小鼠的人骨头，它们在骨骼中生长更快 与其他组织环境相比，骨骼的周转速度很快 矩阵。在此和其他模型中，我们发现前列腺癌细胞生长 在骨产物和/或分泌基质金属蛋白酶（MMP）中 MMP-2，MMP-9和MT1-MMP。这些蛋白酶在酶上具有 降解骨基质，通常参与 骨基质代谢。例如，成骨细胞使用MMP消化 非矿物化骨基质，这导致了破骨细胞和 增强矿化基质的破骨降解。我们假设这一点 前列腺癌细胞以类似于类似的方式降解非矿物化基质 成骨细胞以及MMP-2，MMP-9和MT1-MMP的产生 前列腺癌细胞可能有助于增强的骨基质周转 与转移性疾病有关。使用体内scid-human系统和 在体外骨骼器官培养模型，我们将检验以下假设：（1） 骨环境诱导MMP-2，MMP-9和MT1-MMP表达的上调 在前列腺癌细胞中，MMP-2，MMP-9分泌和 活动; （2）前列腺癌之间的界面有MMP活性 细胞和非矿物化骨基质； （3）MMP生产/分泌 骨环境中的前列腺癌细胞导致肿瘤细胞 增殖和肿瘤细胞向内膜表面的迁移；降解 非矿物化骨基质；招募破骨细胞；并增强 破骨细胞活性和矿化基质的降解。这些实验 将利用我们的模型系统和各种前列腺癌细胞 在骨骼中产生一系列反应的范围从主要骨化 主要是成骨细胞。这些研究的结果可能导致新的 旨在中断前列腺相互作用的治疗策略 癌细胞和骨骼。