THE EFFECT OF LYCOPENE ON IGF-1 ACTIVITY AND SECRETION IN PRIMARY CULTURES OF PRO

描述（由申请人提供）： 增加的胰岛素样生长因子（IGF-1）信号有助于前列腺癌（PCa）的发展，生长和转移，使IGF-1成为PCa预防和治疗策略的目标。番茄红素是一种主要存在于番茄中的膳食类胡萝卜素，与PCa风险降低和进展缓慢有关。流行病学、动物和体外研究表明番茄红素抑制IGF-1轴，但研究有限，结果不一致。此外，以前的人体研究是基于IGF-1的血清水平，这可能无法准确反映前列腺中IGF-1的活性。在前列腺中，基质区室分泌IGF-1，其与附近基质、上皮和血管内皮细胞上的受体相互作用以刺激增殖。我们的总体假设是，番茄红素在前列腺中的抗癌活性部分是由于抑制IGF-1途径。此外，我们假设番茄红素对正常前列腺上皮细胞和基质细胞中的IGF-1有直接的抑制作用，并且这些作用在PCa衍生的细胞中会更强，因为它们可能更依赖于IGF-1。在这个R 03应用程序中，我们将专门测试以下两个假设：1。番茄红素抑制正常前列腺上皮细胞和基质细胞中IGF-1诱导的a）细胞增殖、B）细胞内信号传导和/或c）生长因子分泌的终点。2.在同一患者中，来自恶性前列腺组织的上皮细胞比来自正常组织的细胞对番茄红素对IGF-1的抑制作用更敏感。为了检验这些假设，将检查IGF-1和番茄红素对原代人前列腺细胞培养物中的细胞增殖、细胞内信号传导和生长因子分泌的单独和组合的影响。原代前列腺细胞培养物的使用提供了一个相关的和完整的模型，以确定前列腺特异性的IGF-1途径的变化，因为它允许分别分析上皮细胞和基质细胞来源于正常和恶性组织，提供了一个模型的早期PCa，并包括建立细胞系不能提供的个体间的变化。一旦我们确定了番茄红素对正常前列腺细胞中IGF-1诱导的作用的影响，这种影响将与来自腺癌的细胞的影响进行比较。

DESCRIPTION (provided by applicant): Increased insulin-like growth factor (IGF-1) signaling contributes to prostate cancer (PCa) development, growth and metastasis, making IGF-1 a target for both PCa prevention and treatment strategies. Lycopene, a dietary carotenoid found chiefly in tomatoes, has been associated with both a decreased risk and slower progression of PCa. Epidemiological, animal and in vitro studies have suggested inhibition of the IGF-1 axis by lycopene, but the studies have been limited and the results inconsistent. Moreover, the previous human studies were based on serum levels of IGF-1, which may not accurately reflect IGF-1 activity in the prostate. In the prostate, the stromal compartment secretes IGF-1, which interacts with receptors on nearby stromal, epithelial and vascular endothelial cells to stimulate proliferation. Our overall hypothesis is that the anti-cancer activity of lycopene in the prostate is in part due to inhibition of the IGF-1 pathway. Moreover, we postulate there are direct inhibitory effects of lycopene on IGF-1 in normal prostatic epithelial and stromal cells and that these effects will be stronger in PCa-derived cells because they may be more dependent on IGF-1. In this R03 application we will specifically test the following two hypotheses: 1. Lycopene inhibits the IGF-1-induced endpoints of a) cell proliferation, b) intracellular signaling, and/or c) growth factor secretion in normal prostate epithelial and stromal cells. 2. Within the same patient, epithelial cells derived from malignant prostate tissue are more sensitive to the inhibitory effect of lycopene on IGF-1 than cells derived from normal tissue. To test these hypotheses the effects of IGF-1 and lycopene will be examined, both independently and in combination, on cell proliferation, intracellular signaling and growth factor secretion in primary human prostatic cell cultures. The use of primary prostatic cell cultures provides a relevant and complete model to identify prostate-specific changes in IGF-1 pathways because it allows for the separate analysis of epithelial and stromal cells derived from normal and malignant tissue, provides a model for early stage PCa and includes inter-individual variations that established cell lines cannot offer. Once we have determined lycopene's effect on the IGF-1-induced actions in normal prostatic cells, this effect will be compared to those on cells derived from adenocarcinoma.