The role of IL-17 in prostate cancer

描述(申请人提供)：慢性炎症与多种人类癌症有关。尽管所有的手术前列腺标本都含有炎症的证据，但炎症和前列腺癌之间的因果关系尚未确定。白细胞介素17(IL-17)已被公认为炎症反应中的关键细胞因子。前列腺癌标本中TH17细胞(分泌IL-17的辅助性T细胞)和IL-17细胞因子均升高，IL-17受体IL-17RA和IL-17RC在前列腺癌细胞中均有表达。然而，IL-17在前列腺癌中是否发挥积极作用这一根本问题还需要确定。我们的初步实验表明，在由前列腺上皮中Pten的条件突变引起的前列腺癌小鼠模型中，与表达IL-17RC的小鼠相比，IL-17RC缺陷(IL-17RC-)小鼠的前列腺较小，侵袭性前列腺癌的数量减少，炎症浸润减少，细胞增殖减少，细胞凋亡增加。此外，IL-17RC小鼠前列腺周围的纤维肌肉间质明显增厚，这一发现与基质金属蛋白酶7(MMP7)的表达减少有关。加入重组小鼠IL-17可诱导MMP7在小鼠前列腺中表达。基于这些发现，我们提出了一个中心假设，即在由Pten突变引起的前列腺癌发生中，IL-17通过MMP7介导的机制促进前列腺癌的形成和生长。这一概念具有临床意义，因为阻断IL-17或其下游效应分子如MMP7有可能成为前列腺癌防治的新疗法；此外，评估IL-17-MMP7信号轴的表达可作为前列腺癌的预后指标。我们建议通过以下三个具体目标来验证我们的中心假说：目的1：MMP7介导的IL-17‘S是否在促进Pten基因缺失小鼠前列腺癌的形成和生长中发挥作用？目的：评价靶向IL-17-MMP7轴对Pten基因缺失小鼠前列腺癌形成和生长的影响。目的3：探讨IL-17-MMP7轴与前列腺癌发生发展的关系。这项拟议研究的成功完成将为IL-17介导的前列腺癌发生的分子机制提供新的见解。此外，如果任何或所有接受测试的药物都显示出疗效，它们可能会被开发成预防和/或治疗前列腺癌和其他IL-17发挥作用的癌症类型的药物。IL-17-MMP7轴可能被用作前列腺癌预后和区分侵袭性和惰性前列腺癌的新的生物标志物。

DESCRIPTION (provided by applicant): Chronic inflammation has been associated with a variety of human cancers. Although all surgical prostate specimens contain evidence of inflammation, the causal relationship between inflammation and prostate cancer has not been established. Interleulin-17 (IL-17) has been well accepted as a critical cytokine in inflammation. Both TH17 cells (T helper cells secreting IL-17) and IL-17 cytokine are increased in prostate cancer specimens, and the IL-17 receptors, IL-17RA and IL-17RC, are expressed in prostate cancer cells. However, the fundamental question of whether IL-17 plays an active role in prostate cancer needs to be determined. Our preliminary experiments revealed that in a mouse model of prostate cancer caused by conditionally mutant for Pten in the prostatic epithelium, IL- 17RC deficient (IL-17RC-) mice displayed smaller prostates and developed a reduced number of invasive prostate cancers with decreased inflammatory infiltration, reduced cellular proliferation, and increased apoptosis, compared to mice that express IL-17RC. Further, the fibromuscular stroma surrounding the prostatic glands was significantly thicker in IL-17RC- mice, a finding that we have associated with a decreased expression of matrix metalloproteinase 7 (MMP7). Addition of a recombinant mouse IL-17 induced the expression of MMP7 in the mouse prostate. Based on these findings, we have formulated a central hypothesis that, in prostate carcinogenesis caused by a Pten mutation, IL-17 facilitates prostate cancer formation and growth through an MMP7-mediated mechanism. This concept has clinical significance because blocking IL-17 or its downstream effectors such as MMP7 has the potential to be developed into new therapeutics in the prevention and treatment of prostate cancer; further, assessing the expression of IL-17- MMP7 signaling axis can be utilized as a prognostic indicator of prostate cancer. We propose to test our central hypothesis through the following three specific aims: Aim 1: Does MMP7 mediate IL-17's function in facilitating prostate cancer formation and growth in Pten- null mice? Aim 2: Assess the efficacy of targeting IL-17-MMP7 axis in preventing prostate cancer formation and growth in Pten-null mice. Aim 3: Determine the association between the IL-17-MMP7 axis and progression of human prostate cancer. Successful completion of the proposed studies will provide new insights into the molecular mechanisms underlying IL-17-mediated prostate carcinogenesis. Further, if any or all of the tested agents show efficacy, they can potentially be developed into preventive and/or therapeutic drugs against prostate cancer and other cancer types where IL-17 plays a role. The IL-17-MMP7 axis can potentially be utilized as new biomarkers in the prognosis of prostate cancer and in distinguishing between aggressive and indolent prostate cancers.