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

描述(由申请人提供)： 胰岛素样生长因子(IGF-1)信号的增加有助于前列腺癌(PCa)的发生、生长和转移，使IGF-1成为前列腺癌预防和治疗策略的靶点。番茄红素是一种饮食中的类胡萝卜素，主要存在于西红柿中，它与降低前列腺癌风险和减缓进展有关。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，之前的人类研究是基于血清IGF-1水平，这可能不能准确反映前列腺中的IGF-1活动。在前列腺中，间质间质分泌IGF-1，IGF-1与附近间质、上皮和血管内皮细胞上的受体相互作用，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了IGF-1途径。此外，我们假设番茄红素对正常前列腺上皮和间质细胞中的IGF-1有直接的抑制作用，并且这种作用在前列腺癌来源的细胞中会更强，因为它们可能更依赖于IGF-1。在R03的应用中，我们将专门测试以下两个假设：1.番茄红素抑制IGF-1诱导的a)细胞增殖的终点，b)细胞内信号转导，和/或c)正常前列腺上皮和间质细胞的生长因子分泌。2.在同一患者体内，恶性前列腺组织来源的上皮细胞对番茄红素对IGF-1的抑制作用比正常组织来源的细胞更敏感。为了验证这些假设，我们将研究IGF-1和番茄红素对原代培养的人前列腺细胞的细胞增殖、细胞内信号和生长因子分泌的影响，包括单独和联合使用。使用原代前列腺细胞培养提供了一个相关和完整的模型来识别前列腺特异性IGF-1通路的变化，因为它允许分离分析来自正常和恶性组织的上皮和间质细胞，为早期前列腺癌提供了一个模型，并包括了已建立的细胞系无法提供的个体间变异。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，我们将把这种作用与腺癌细胞的作用进行比较。

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.