Neuroendocrine Cancer: Tumor Regulation by PTHrP In Vitro and In Vivo

项目摘要/摘要： 我们的总体假设是甲状旁腺激素相关蛋白(PTHrP)在卵巢癌中过表达。 前列腺癌的特征是从三者中产生新的癌症特异性多肽。 这种癌蛋白的天然异构体以及这些新的多肽可以调节肿瘤的发生和 前列腺癌的生长和发展，尤其是在骨骼中。我们的总体目标是确定 这些多肽及其在生长调节和肿瘤进展中的作用 了解这种恶性肿瘤的病理生物学。 具体目标1.鉴定和全面鉴定来源于 前列腺癌中的天然甲状旁腺素受体多肽。我们将识别和描述PTHrP 前列腺癌产生的多肽。这将通过一种多方面的方法来实现， 包括(A)免疫化学程序，如免疫亲和层析、多部位 免疫分析和免疫组织化学，包括西片和(B)生化程序 基于质谱仪(MS)。这些方法将得到额外的分子补充。 甲状旁腺素相关蛋白的研究。 预期结果摘要：我们希望确定PTHrP的前列腺特异性多肽 对前列腺癌生长和增殖相关方面的中介作用。除了PTHrP 经典多肽，我们希望发现可以发挥其分子作用的新多肽 新的分子途径。 具体目的2.确定这些经PTHrP处理的多肽如何调节前列腺癌 骨骼和其他部位的进展。这一目标将在免疫功能受损的情况下实现 通过多肽治疗和直接种植到骨和其他部位的前列腺癌细胞 已经对PTHrP进行了基因工程处理，以分别表现出生长 甲状旁腺素受体及其多肽的调节作用。新的成像程序将被用来监测肿瘤 行为。这些模型将使我们能够研究PTHrP的各自效应和分子相互作用 在体内介导前列腺癌的进展。 预期结果摘要：我们希望确定PTHrP多肽调节各自的 在我们的前列腺癌动物模型中，骨性和非骨性前列腺癌的进展。我们 希望在Aim 1的相应体外研究的基础上，通知和关注这些体内研究 以及我们在这方面的初步成果。我们希望确定并阐明这种增长- PTHrP及其衍生多肽在体内的调节结构域，从而促进对PTHrP及其衍生多肽的开发 这些机制为肿瘤的诊断和治疗靶点的发展奠定了基础。

Project Summary/Abstract: It is our overall Hypothesis that PTHrP (parathyroid hormone related protein) overexpression in prostate cancer is characterized by the generation of novel, cancer-specific peptides from the three native isoforms of this oncoprotein and that these novel peptides can regulate tumorigenesis and the growth and progression of prostate cancer, especially in the skeleton. Our overall Aim is to identify these peptides and their effects on growth-regulation and tumor progression in order to fully understand the pathobiology of this malignancy. Specific Aim 1. To identify and fully characterize the PTHrP peptides that are derived from the native PTHrP polypeptides in prostate cancer. We shall identify and characterize the PTHrP peptides produced by prostate cancers. This will be accomplished by a multifaceted approach that includes (a) immunochemical procedures like immunoaffinity chromatography, multi-site immunoassays, and immunohistochemistry, including Westerns and (b) biochemical procedures based on mass spectrometry (MS). These methods will be complemented by additional molecular studies of PTHrP. Summary of Expected Results: We expect to identify prostate-specific peptides of PTHrP that mediate effects on growth- and proliferation-related aspects of prostate cancer. In addition to PTHrP's classical peptides, we expect to discover new peptides that can exert their molecular action though novel molecular pathways. Specific Aim 2. To determine how these PTHrP-processed peptides regulate prostate cancer progression in skeletal and other sites. This aim will be accomplished in immunocompromised mice by peptide treatment and by directly implanting into bone and other sites prostate cancer cells that have been genetically engineered for PTHrP expression to respectively manifest the growth regulatory effects of PTHrP and its peptides. Novel imaging procedures will be used to monitor tumor behavior. These models will allow us to study PTHrP's respective effects and molecular interactions that mediate in vivo progression of prostate cancer. Summary of Expected Results: We expect to identify PTHrP peptides that regulate the respective progression, both skeletal and non-skeletal, of prostate cancer in our animal model for this tumor. We expect to inform and focus these in vivo studies based on the corresponding in vitro studies of Aim 1 as well as our Preliminary Results in this area. We expect to identify and elucidate the growth- regulatory domains of PTHrP and its derived peptides in vivo and to thus facilitate exploitation of these mechanisms for the development of diagnostic and therapeutic targets for the tumor.