Bone matrix proteins in prostate cancer progression

前列腺癌进展中的骨基质蛋白

• 批准号: 6899971
• 负责人: PRADIP ROY-BURMAN
• 金额: $ 32.09万
• 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/6899971
• 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前列腺癌模型方面取得了重大成就。在这些模型中的分子变化的全球评估，导致识别的关键基因功能牵连在人类前列腺癌及其转移。这两项职能是本建议的重点。这些分子，既分泌又通常称为骨基质蛋白，是：骨桥蛋白（OPN），一种含RGD的糖基化磷蛋白，和成骨蛋白-1（OP-1或BMP-7），TGF-β超家族的成员。由于前列腺癌具有转移到骨和诱导骨病变的倾向，并且认为这两种蛋白质都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中重要但尚未充分研究的研究领域。在初步的实验中，我们发现，OPN的表达，突出的前列腺癌前病变的小鼠模型，继续增加的进展，浸润性腺癌，和细胞过度表达OPN富集在转移性存款。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，最显著的是人前列腺癌细胞向血管内渗透的能力。我们发现，BMP-7的表达继续增加与我们的小鼠模型中的前列腺癌的生长，它可以调节人前列腺上皮细胞的生长，运动和侵袭特性，它可以诱导上皮间质转化为前列腺癌细胞系。我们暗示BMP受体信号传导的差异与观察到的差异诱导的生物反应。本申请的既定目标是双重的。首先通过结合通过体内生物发光监测肿瘤生长和位点特异性转移或从原发性肿瘤和器官特异性转移中分离癌细胞的能力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。一系列相互关联和平行的研究，使用小鼠模型和癌细胞来源于它，人前列腺癌细胞系，成骨细胞和前体细胞概述，以深入了解OPN和BMP-7如何有助于前列腺癌的进展和前列腺癌介导的成骨机制。