Bone matrix proteins in prostate cancer progression

前列腺癌进展中的骨基质蛋白

• 批准号: 7086405
• 负责人: PRADIP ROY-BURMAN
• 金额: $ 31.42万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7086405
• 关键词: bioluminescence; bone morphogenetic proteins; cell line; cell population study; flow cytometry; genetically modified animals; human genetic material tag; laboratory mouse; metalloendopeptidases; metastasis; neoplastic growth; osteoblasts; osteogenesis; osteopontin; prostate neoplasms

DESCRIPTION (provided by applicant): We have recently contributed to major achievements in modeling human prostate cancer in mice. Global assessment of molecular changes in these models have led to identification of key gene functions implicated in human prostate cancer and its metastases. Two such functions are the focus of this proposal. These molecules, both secretory and commonly referred to as bone matrix proteins, are: osteopontin (OPN), an RGD-containing glycosylated phosphoprotein, and osteogenic protein-1 (OP-1 or BMP-7), a member of the TGF-p superfamily. Since prostate cancer has the propensity to metastasize to bone and to induce bone lesions, and both of these proteins are believed to be involved, in osteoblast differentiation and bone formation, these molecules constitute an important, but yet an understudied area of research in the biology of prostate cancer. In preliminary experiments we find that OPN expression, prominent in prostatic preneoplastic lesions of a mouse model, continues to increase with progression to invasive adenocarcinoma, and cells overexpressing OPN are enriched in the metastatic deposits. Additional data collected to date indicate that OPN upregulation may be a factor in proliferation, motility, invasion, and most remarkably in the ability of the human prostate cancer cells to intravasate blood vessels. We find that BMP-7 expression continues to increase with the growth of the prostate cancer in our mouse model, it can modulate growth, motility and invasion properties of human prostatic epithelial cells, and it can induce epithelial-mesenchymal transition to a prostate cancer cell line. We implicate BMP receptor signaling differences with the observed differential biological responses induced. The stated goals of this application are two-fold. First to refine our metastatic prostate cancer model by incorporating the capability of either to monitor the tumor growth and site-specific metastases by in vivo bioluminescense, or to isolate cancer cells from primary tumor and organspecific metastases. Second is to define the molecular/cellular parameters by which OPN or BMP-7 may positively influence prostate cancer progression and metastases. A series of interconnected and parallel studies using the mouse model and cancer cells derived from it, human prostate cancer cell lines, and osteoblasts and precursors are outlined to obtain insight into how OPN and BMP-7 may contribute to prostate cancer progression and to the mechanism of prostate cancer-mediated osteogenesis.

描述（由申请人提供）：我们最近在小鼠中建立人类前列腺癌模型方面取得了重大成就。这些模型中分子变化的全局评估导致了与人类前列腺癌及其转移相关的关键基因功能的鉴定。两个这样的功能是本提案的重点。这些分泌性和通常被称为骨基质蛋白的分子是：骨桥蛋白（OPN），一种含rgd的糖基化磷酸化蛋白，以及成骨蛋白-1 (OP-1或BMP-7)， TGF-p超家族的成员。由于前列腺癌具有骨转移和诱导骨病变的倾向，而这两种蛋白质被认为参与成骨细胞分化和骨形成，因此这些分子构成了前列腺癌生物学研究的一个重要但尚未充分研究的领域。在初步实验中，我们发现OPN的表达，特别是在前列腺癌前病变的小鼠模型中，随着浸润性腺癌的进展而继续增加，并且在转移沉积物中过度表达OPN的细胞丰富。迄今为止收集的其他数据表明，OPN上调可能是增殖、运动、侵袭的一个因素，最显著的是人类前列腺癌细胞进入血管的能力。在我们的小鼠模型中，我们发现BMP-7的表达随着前列腺癌的生长而持续增加，它可以调节人前列腺上皮细胞的生长、运动和侵袭特性，并诱导上皮-间质向前列腺癌细胞系的转化。我们将BMP受体信号的差异与观察到的诱导的不同生物反应联系起来。这个应用程序的既定目标有两个。首先，通过结合体内生物发光监测肿瘤生长和部位特异性转移的能力，或从原发肿瘤和器官特异性转移中分离癌细胞，来完善我们的转移性前列腺癌模型。其次是确定OPN或BMP-7可能积极影响前列腺癌进展和转移的分子/细胞参数。本文概述了一系列相互关联和平行的研究，使用小鼠模型及其衍生的癌细胞、人类前列腺癌细胞系、成骨细胞和前体，以深入了解OPN和BMP-7如何促进前列腺癌的进展以及前列腺癌介导的成骨机制。