Growth Factors and Prostate Cancer Risk

广泛的前列腺特异性抗原（PSA）筛查强调了识别临床更具侵袭性前列腺癌的病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）。在医师健康研究（PHS）中，我们最近发现，诊断前循环IGF- 1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，我们的前期研究数据表明，转移性前列腺癌患者的血浆VEGF水平明显高于局限性前列腺癌患者，晚期前列腺癌患者的血浆VEGF水平是生存的预后因素。为了了解这些关联的潜在性质，我们现在建议扩展我们之前对IGF-I和IGFBP-3的研究，以检查游离IGF-I、IGFBP-I、一种新发现的IGFBP-3多态性和血管内皮生长因子循环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例病例中获得前列腺癌组织样本，以建立这些流行病学发现与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志物的关联，包括IGF-I下游信号（HIF-1和PTEN）、细胞增殖率（Ki67）、细胞凋亡（TUNEL）和血管生成（VEGF表达和微血管密度）的标志物。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中，我们已经建立了一个广泛的前瞻性前列腺癌临床和血清学数据库，对1336例前列腺癌进行了近20年的随访。通过这项研究，我们将扩展我们的流行病学发现，并研究这些有趣结果背后的生物学基础。

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.