The role of IL-17 in prostate cancer

IL-17 在前列腺癌中的作用

• 批准号: 8858592
• 负责人: Zongbing You
• 金额: $ 31.23万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8858592
• 关键词: Animal Model; Antibodies; Apoptosis; Biological Markers; CD4 Positive T Lymphocytes; Cancer Etiology; Cancer Patient; Cell Proliferation; Cells; Chronic; Clinical Markers; Collection; Goals; Growth; Health; Helper-Inducer T-Lymphocyte; Human; Indolent; Infiltration; Inflammation; Inflammatory; Knock-out; Knockout Mice; Knowledge; MAPK3 gene; Malignant Neoplasms; Malignant neoplasm of prostate; Matrilysin; Mediating; Molecular; Mus; Mutation; Operative Surgical Procedures; Pharmaceutical Preparations; Phenotype; Play; Prevention; Preventive; Prognostic Marker; Prostate; Prostatic Epithelium; Recombinants; Resources; Role; Signal Transduction; Specimen; Testing; Therapeutic; Thick; Translating; base; cancer initiation; cancer type; clinically significant; cohort; cytokine; genetic approach; inhibitor/antagonist; insight; knockout animal; mouse model; mutant; novel therapeutics; outcome forecast; prevent; prostate cancer cell; prostate carcinogenesis; receptor; research study; small molecule; tumor progression

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.

描述（由申请人提供）：慢性炎症与各种人类癌症有关。尽管所有手术前列腺标本都包含炎症的证据，但尚未建立炎症与前列腺癌之间的因果关系。白素17（IL-17）在炎症中已被广泛接受为临界细胞因子。在前列腺癌标本中，Th17细胞（分泌IL-17的T辅助细胞分泌IL-17）和IL-17细胞因子均增加，并且在前列腺癌细胞中表达IL-17受体IL-17RA和IL-17RC。但是，需要确定IL-17是否在前列腺癌中起积极作用的基本问题。我们的初步实验表明，在前列腺癌的小鼠模型中，由PTEN在前列腺上皮中有条件突变体引起的IL- 17RC缺陷（IL-17RC-）小鼠显示出较小的前列腺，并产生了减少的炎症前列腺癌，随着炎症降低的细胞渗透率，并增加了侵入性的侵入性癌症，并减少了APTIFERATION，并增加了流动性，并减少了腐蚀性，并比较了鼠标，并比较了鼠标，并比较了疾病，并比较了疾病，比较了疾病，比较了细胞的疾病，并减少了炎性渗透率，并减少了炎性炎性炎症。 IL-17RC。此外，在IL-17RC-小鼠中，周围前列腺周围的纤维肌间基质显着厚，这一发现与基质金属蛋白酶7（MMP7）的表达降低相关。重组小鼠IL-17的添加诱导了小鼠前列腺中MMP7的表达。基于这些发现，我们提出了一个中心假设，即在PTEN突变引起的前列腺致癌作用中，IL-17通过MMP7介导的机制促进了前列腺癌的形成和生长。该概念具有临床意义，因为阻止IL-17或其下游效应子（例如MMP7）有可能发展为预防和治疗前列腺癌的新疗法。此外，评估IL-17-MMP7信号轴的表达可以用作前列腺癌的预后指标。我们建议通过以下三个特定目的测试中心假设：目标1：MMP7是否介导了IL-17在促进PTEN-NULL小鼠促进前列腺癌形成和生长中的功能？ AIM 2：评估靶向IL-17-MMP7轴预防PTEN-NULL小鼠的前列腺癌形成和生长的功效。 AIM 3：确定IL-17-MMP7轴与人前列腺癌进展之间的关联。成功完成拟议的研究将为IL-17介导的前列腺癌变基础的分子机制提供新的见解。此外，如果任何或全部测试的药物显示出疗效，则可以将它们发展为针对前列腺癌和IL-17发挥作用的其他癌症类型的预防和/或治疗性药物。 IL-17-MMP7轴可能被用作前列腺癌预后以及区分侵略性和顽固前列腺癌的新生物标志物。