Molecular mechanisms of osteoblastic bone metastasis: Role of endothelin-1

成骨细胞转移是癌症患者的重要临床问题。 它们几乎总是发生在前列腺癌中，也经常发生在其他常见的恶性肿瘤中，如乳腺癌。 成骨细胞转移的病理生理学基础是未知的，因为缺乏这种疾病的可重复动物模型。 在这个项目中，我们开发了一种成骨细胞骨转移的体内模型，该模型是可重复的，可以研究这种疾病的病理生理学。 在该模型中引起成骨细胞转移的人肿瘤细胞产生大量的内皮素-1（ET-1），内皮素-1是成骨细胞生长的刺激物，其最近已与前列腺癌成骨细胞转移相关联。 该项目将描述新模型，严格测试ET-1在成骨细胞转移发生中的作用，并确定成骨细胞病变的其他因素。 将测试以下假设：1）人乳腺癌细胞系ZR-75-1通过分泌可溶性因子或局部刺激成骨细胞增殖和新骨形成的因子介导成骨细胞转移。 2)肿瘤产生的ET-1是前列腺癌和乳腺癌引起的成骨细胞转移的局部介质。 阻断肿瘤产生的ET-1的作用或减少其产生将抑制成骨细胞骨转移的发展和进展。 3)在给定肿瘤中肿瘤产生的成骨细胞刺激因子与破骨细胞刺激因子的相对比率将决定骨中的肿瘤表型。 4)相对于非骨部位，骨微环境增强肿瘤产生ET-1和其他成骨细胞刺激因子。 本研究的具体目的如下：1）探讨ET-1在成骨细胞转移中的作用。 将在体外和体内研究ET-1对新骨形成的作用，并将研究内皮素受体A（ETA）和受体B（ET B）在介导内皮素对成骨细胞功能和成骨细胞骨转移的作用中的相对重要性。2)确定与非骨部位相比，骨微环境是否诱导肿瘤产生成骨因子。将分子技术应用于骨转移模型，以确定哪些成骨细胞刺激因子是由ZR-75-1细胞在骨微环境中产生的，以及ET-1是否是主要因子。 该目标还将确定成骨细胞刺激因子的肿瘤产生是否在骨微环境中相对于非骨部位增强。

Osteoblastic metastases represent a significant clinical problem for patients with cancer. They occur almost always in prostate cancer and frequently in other common malignancies such as breast cancer. The pathophysiology underlying osteoblastic metastases is unknown due to lack of a reproducible animal model of this disease. During this Program Project, we have developed an in vivo model of osteoblastic bone metastases which is reproducible and allows investigation into the pathophysiology of this disease. The human tumor cells which cause osteoblastic metastases in this model produce large amounts of endothelin-1 (ET-1), a stimulator of osteoblast growth, which recently has been linked to prostate cancer osteoblastic metastases. This project will characterize the new model, critically test the role of ET-1 in the genesis of osteoblastic metastases and identify other factors responsible for osteoblastic lesions. The following hypotheses will be tested: 1) The human breast cancer cell line, ZR-75-1, mediates osteoblastic metastases by the secretion of a soluble factor or factors which locally stimulate osteoblast proliferation and new bone formation. 2) Tumor- produced ET-1 is a local mediator of osteoblastic metastases caused by prostate and breast cancer. Blocking the effects of tumor-produced ET-1 or decreasing its production will inhibit the development and progression of osteoblastic bone metastases. 3) The relative ratio of tumor-produced osteoblast-stimulating factors to osteoclast-stimulating factors in a given tumor will determine the tumor phenotype in bone. 4) The bone microenvironment enhances tumor production of ET-1 and other osteoblast-stimulating factors, relative to non bone sites. The following specific aims are proposed: 1) To investigate the role of ET-1 in osteoblastic metastasis. The effect of ET-1 on new bone formation will be studied in vitro and in vivo and the relative importance of endothelin receptor A(ETA) and receptor B (ETB) in mediating the effects of endothelin on osteoblast function and osteoblastic bone metastases will be investigated. 2) To determine if tumor production of osteoblastic factors is induced in the bone microenvironment compared with nonbone sites. Molecular techniques will be applied to the bone metastases model to determine which osteoblast-stimulating factors are produced by the ZR-75-1 cells in the bone microenvironment and if ET-1 is the predominant factor. The aim will also determine if tumor production of osteoblast-stimulating factors are enhanced in the bone microenvironment relative to nonbone sites.