Bone matrix proteins in prostate cancer progression

描述(由申请人提供)：我们最近在用小鼠模拟人类前列腺癌方面取得了重大成就。对这些模型中分子变化的全球评估导致了与人类前列腺癌及其转移有关的关键基因功能的确定。两个这样的功能是这项提案的重点。这些分子包括：骨桥蛋白(OPN)和成骨蛋白-1(OP-1或BMP-7)，前者是一种含有RGD的糖基化磷酸蛋白，后者是转化生长因子-β超家族的成员。由于前列腺癌具有骨转移和骨损伤的倾向，而且这两种蛋白都被认为与成骨细胞分化和骨形成有关，因此这些分子构成了前列腺癌生物学中一个重要但尚未得到充分研究的领域。在初步实验中，我们发现OPN在小鼠前列腺癌前病变中的表达随着侵袭性腺癌的进展而继续增加，并且OPN过度表达的细胞在转移沉积中丰富。到目前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，最显著的是影响人类前列腺癌细胞血管内皮细胞的能力。我们在小鼠前列腺癌模型中发现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，并可以诱导上皮-间充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。这个应用程序的声明目标有两个。首先，改进我们的转移性前列腺癌模型，包括通过体内生物发光技术监测肿瘤生长和特定部位转移的能力，或从原发肿瘤和器官特异性转移中分离癌细胞的能力。第二是确定OPN或BMP-7可能对前列腺癌进展和转移产生积极影响的分子/细胞参数。概述了一系列相互关联的平行研究，使用了小鼠模型及其衍生的癌细胞、人类前列腺癌细胞系、成骨细胞和前体细胞，以深入了解OPN和BMP-7可能如何促进前列腺癌的进展，以及前列腺癌介导的成骨机制。

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.