PROSTATE CANCER, BONE METASTASIS, AND METALLOPROTEINASES

前列腺癌、骨转移和金属蛋白酶

• 批准号: 6378122
• 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/6378122
• 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：（改编自研究者摘要）前列腺转移 骨转移癌导致骨基质周转增加， 伴有疼痛和病理性骨折。放射学上，前列腺癌 转移瘤是“母细胞性的”，然而，在生化水平上，它们都是溶解性的 和爆炸性。细胞和生化机制的增强 与转移性癌症相关的骨基质转换是未知的。的 “前列腺癌转移到骨骼的SCID人类模型”，最近在 我们的实验室在几个层面上模拟临床疾病：前列腺癌 移植到SCID小鼠体内的人骨细胞， 与其他组织环境相比， 矩阵在这个和其他模型中，我们发现前列腺癌细胞生长 在骨中产生和/或分泌基质金属蛋白酶（MMP），包括 MMP-2、MMP-9和MT 1-MMP。这些蛋白酶具有酶促活性， 降解骨基质，它们通常参与几个步骤， 骨基质代谢例如，成骨细胞利用基质金属蛋白酶消化 非矿化骨基质，这导致破骨细胞的募集， 矿化基质的骨细胞降解增强。我们假设 前列腺癌细胞降解非矿化基质的方式与 成骨细胞和MMP-2，MMP-9和MT 1-MMP的产生 前列腺癌细胞可能有助于增强骨基质转换 与转移性疾病有关。使用体内SCID-人系统和 在体外骨器官培养模型中，我们将检验以下假设：（1） 骨环境诱导MMP-2、MMP-9和MT 1-MMP表达上调 在前列腺癌细胞中，MMP-2、MMP-9分泌增加， 活性;（2）在前列腺癌和前列腺增生之间的界面处存在MMP活性。 细胞和非矿化骨基质;和（3）MMP的产生/分泌， 前列腺癌细胞在骨环境导致肿瘤细胞 肿瘤细胞增殖和迁移到骨内膜表面;降解 非矿化骨基质;破骨细胞的募集;和增强 破骨细胞活性和矿化基质降解。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， 主要是成骨细胞这些研究的结果可能会导致新的 治疗策略旨在中断前列腺之间的相互作用， 癌细胞和骨头