The role of IL-17 in prostate cancer

描述（由申请人提供）：慢性炎症与多种人类癌症相关。虽然所有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建立。白细胞介素-17（IL-17）是炎症反应中的重要细胞因子。在前列腺癌样本中，TH 17细胞（分泌IL-17的T辅助细胞）和IL-17细胞因子均增加，并且IL-17受体IL-17 RA和IL-17 RC在前列腺癌细胞中表达。然而，IL-17是否在前列腺癌中发挥积极作用的根本问题需要确定。我们的初步实验显示，在前列腺上皮中Pten的条件性突变体引起的前列腺癌小鼠模型中，与表达IL-17 RC的小鼠相比，IL-17 RC缺陷（IL-17 RC-）小鼠显示出较小的前列腺，并且发生浸润性前列腺癌的数量减少，炎性浸润减少，细胞增殖减少，细胞凋亡增加。此外，IL-17 RC-小鼠前列腺周围的纤维肌基质显著增厚，这一发现与基质金属蛋白酶7（MMP 7）表达降低有关。添加重组小鼠IL-17诱导小鼠前列腺中MMP 7的表达。基于这些发现，我们提出了一个中心假设，即在Pten突变引起的前列腺癌发生中，IL-17通过MMP 7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或其下游效应物如MMP 7有可能被开发成预防和治疗前列腺癌的新疗法;此外，评估IL-17-MMP 7信号传导轴的表达可用作前列腺癌的预后指标。我们提出通过以下三个具体目标来检验我们的中心假设：目标1：MMP 7介导IL-17在Pten缺失小鼠中促进前列腺癌形成和生长的功能吗？目的2：评估靶向IL-17-MMP 7轴在预防Pten敲除小鼠中前列腺癌形成和生长中的功效。目的3：确定IL-17-MMP 7轴与人前列腺癌进展之间的关系。这些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，如果任何或所有测试的药剂显示出功效，则它们可以潜在地开发成针对前列腺癌和其中IL-17起作用的其他癌症类型的预防和/或治疗药物。IL-17-MMP 7轴可以潜在地用作前列腺癌预后和区分侵袭性和惰性前列腺癌的新生物标志物。

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.