Growth Factors and Prostate Cancer Risk

生长因子和前列腺癌风险

• 批准号: 6721107
• 负责人: Meir Stampfer
• 金额: $ 65.75万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-02-01 至 2007-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6721107
• 关键词: angiogenesis; apoptosis; biomarker; cancer risk; cell proliferation; clinical research; enzyme linked immunosorbent assay; genetic polymorphism; growth factor receptors; high throughput technology; human data; human genetic material tag; hypoxia inducible factor 1; insulinlike growth factor; microarray technology; neoplasm /cancer relapse /recurrence; pathologic process; polymerase chain reaction; prostate neoplasms; prostate specific antigen; questionnaires; receptor expression; restriction fragment length polymorphism; serology /serodiagnosis; terminal nick end labeling; vascular endothelial growth factors

Widespread prostate specific antigen (PSA) screening underscores the need to identify causes and potential biomarkers of clinically more aggressive prostate cancer. Laboratory and clinical studies suggest that growth factors play an important role in prostate cancer proliferation, apoptosis and angiogenesis. These growth factors include insulin-like growth factor-I (IGF-I) and vascular endothelial growth factor (VEGF). In the Physicians Health Study (PHS), we recently showed that prediagnostic levels of circulating IGF-I were significantly associated with prostate cancer risk, while high levels of IGF binding protein, IGFBP-3, were associated with lower risk. Furthermore, our pilot study data suggests that plasma VEGF levels are significantly higher among patients with metastatic disease compared to patients with localized prostate cancer, and that plasma VEGF levels in advanced prostate cancer patients are prognostic for survival. To understand the underlying nature of these associations, we now propose to extend our previous work on IGF-I and IGFBP-3 to examine the associations of free IGF-I, IGFBP-I, a newly identified polymorphism of IGFBP-3, and circulating levels of VEGF in relation to risk of total and aggressive prostate cancer. We plan to obtain prostate cancer tissue samples from 828 cases to establish biologic links between these epidemiologic findings and phenotypic features of prostate cancer. We will assess the associations of these growth factors with tissue markers for disease progression, including IGF-I downstream signaling (HIF-1 and PTEN), markers of cellular proliferation rate (Ki67), apoptosis (TUNEL), and angiogenesis (VEGF expression and microvascular density). We will also examine the relation of these plasma and tissue markers with prostate cancer relapse and mortality. In the PHS, we have already assembled an extensive prospective clinical and serological database on prostate cancer with almost two decades of follow-up and 1336 prostate cancers. With this proposed study, we will expand upon our epidemiological findings and examine the biology underlying these intriguing results.

广泛的前列腺特异性抗原(PSA)筛查强调了确定临床上更具侵袭性的前列腺癌的原因和潜在生物标志物的必要性。实验室和临床研究表明，生长因子在前列腺癌的增殖、凋亡和血管生成中起重要作用。这些生长因子包括胰岛素样生长因子-I(IGF-I)和血管内皮生长因子(VEGF)。在医生健康研究(PHS)中，我们最近发现，诊断前循环IGF-I水平与前列腺癌风险显著相关，而高水平的IGF结合蛋白IGFBP-3与较低风险相关。此外，我们的初步研究数据表明，与局限性前列腺癌患者相比，转移性疾病患者的血浆血管内皮生长因子水平显著升高，晚期前列腺癌患者的血浆血管内皮生长因子水平是预后的指标。为了了解这些关联的潜在性质，我们现在建议扩展我们先前关于IGF-I和IGFBP-3的工作，以检查游离IGF-I、IGFBP-I、新发现的IGFBP-3的多态性以及循环中的VEGF水平与总前列腺癌和侵袭性前列腺癌风险的关系。我们计划从828例患者中获取前列腺癌组织样本，以建立这些流行病学发现和前列腺癌表型特征之间的生物学联系。我们将评估这些生长因子与疾病进展的组织标记物之间的关系，包括IGF-I下游信号(HIF-1和PTEN)、细胞增殖率标记物(Ki67)、细胞凋亡标记物(TUNEL)和血管生成标记物(VEGF表达和微血管密度)。我们还将研究这些血浆和组织标志物与前列腺癌复发和死亡率的关系。在PHS，我们已经建立了一个关于前列腺癌的广泛的前瞻性临床和血清学数据库，并进行了近20年的随访和1336例前列腺癌。在这项拟议的研究中，我们将扩展我们的流行病学发现，并检查这些有趣结果背后的生物学基础。