PROSTATE CANCER, BONE METASTASIS, AND METALLOPROTEINASES

描述：(改编自研究人员的摘要)前列腺癌 癌症转化为骨骼会导致骨基质的转换增加，并经常 伴随着疼痛和病理性骨折。放射学上，前列腺癌 转移是“原始的”，然而，在生化水平上，它们都是裂解的。 还很火爆。增强的细胞和生化机制 与转移性癌症相关的骨基质转换尚不清楚。这个 “SCID-前列腺癌骨转移的人类模型”，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 人类骨骼细胞被植入SCID小鼠体内，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。在这个和其他模型中，我们发现前列腺癌细胞生长 在骨产生和/或分泌基质金属蛋白酶(MMPs)中，包括 基质金属蛋白酶-2、基质金属蛋白酶-9和基质金属蛋白酶1-基质金属蛋白酶。这些蛋白水解酶可以在酶的作用下 降解骨基质，它们通常参与以下几个步骤 骨基质代谢。例如，成骨细胞使用基质金属蛋白酶来消化 未矿化的骨基质，这导致破骨细胞和 促进矿化基质的破骨降解。我们假设 前列腺癌细胞降解非矿化基质的方式类似于 成骨细胞与转移过程中基质金属蛋白酶-2、基质金属蛋白酶-9和基质金属蛋白酶1-基质金属蛋白酶的产生 前列腺癌细胞可能与骨基质转换增强有关 与转移性疾病有关。使用体内SCID-人类系统和AN 在体外骨器官培养模型中，我们将检验假设：(1) 骨环境诱导基质金属蛋白酶-2、基质金属蛋白酶-9和基质金属蛋白酶1-基质金属蛋白酶表达上调 前列腺癌细胞中基质金属蛋白酶-2、基质金属蛋白酶-9的分泌增加和 前列腺癌交界处有基质金属蛋白酶活性 细胞和非矿化骨基质；以及(3)通过 骨环境中的前列腺癌细胞导致肿瘤细胞 肿瘤细胞的增殖和向骨内膜表面的迁移；降解 未矿化的骨基质；破骨细胞的招募；以及增强 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的反应，从主要的溶骨性反应 以成骨细胞为主。这些研究的结果可能会导致新的 旨在中断前列腺之间相互作用的治疗策略 癌细胞和骨骼。

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.