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有关。尽管所有的前列腺手术标本都含有炎症的证据，但炎症与前列腺癌之间的因果关系尚未确定。白细胞介素-17 （IL-17）已被广泛认为是炎症的关键细胞因子。前列腺癌标本中TH17细胞（分泌IL-17的T辅助细胞）和IL-17细胞因子均增加，IL-17受体IL-17RA和IL-17RC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这一根本问题还有待确定。我们的初步实验显示，在前列腺上皮Pten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-）小鼠表现出更小的前列腺，侵袭性前列腺癌的数量减少，炎症浸润减少，细胞增殖减少，凋亡增加。此外，在IL-17RC-小鼠中，前列腺周围的纤维肌肉间质明显变厚，这一发现与基质金属蛋白酶7 （MMP7）表达降低有关。添加重组小鼠IL-17诱导MMP7在小鼠前列腺中的表达。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或其下游效应物如MMP7有可能发展成为预防和治疗前列腺癌的新疗法；进一步，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设：目标1:MMP7是否介导IL-17在促进Pten缺失小鼠前列腺癌形成和生长中的功能？目的2：评估靶向IL-17-MMP7轴预防pten缺失小鼠前列腺癌形成和生长的效果。目的3：确定IL-17-MMP7轴与人类前列腺癌进展的关系。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，如果任何一种或所有被测试的药物显示出疗效，它们可能被开发成预防和/或治疗前列腺癌和其他类型的癌症的药物，其中IL-17起作用。IL-17-MMP7轴可能被用作前列腺癌预后的新生物标志物，并可用于区分侵袭性和惰性前列腺癌。

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.