与肥胖相关的炎性衰老在前列腺癌变和恶化中的作用

Prostate cancer is associated with advanced age and obesity, but there is little understanding of how age and obesity contributes to prostate cancer. Aging is characterized by a chronic, low-grade inflammation, so called “inflamm-aging”. Data supporting the role of chronic inflammation in prostate cancer comes from a variety of fields. Th17 cells, characterized by production of pro-inflammatory cytokines interleukin (IL)-17, have been shown to provide protective immunity to infections by fungi and extracellular bacteria but are involved in chronic inflammation and autoimmunity. Recent studies have shown that Th17 cells are elevated in aging humans and mice and describe a reciprocal relationship between Th17 and T regulatory (Treg) cells. We have demonstrated that IL-17 promotes formation and growth of prostate adenocarcinoma in Pten-null mice and plays a key role in prostate cancer progression in obese mice. However, whether obesity and age-related elevated Th17 immune responses and Th17/Treg imbalance plays a role in PCa development, progression and aggressiveness in the elderly remains unknown. Thus, we hypothesize that obesity and age-related elevated Th17 immune responses and Th17/Treg imbalance promotes prostate carcinogenesis. The objective of this proposal is to propose two different but integrated specific aims to directly test our central hypothesis. First, define the role of Th17 immune responses in the aging process that drive the development of prostate cancer by using aged versus non-aged obese mouse models with basic leucine zipper transcriptional factor ATF-like (Batf) (Th17 transcription factor) and prostate-specific Pten (tumor suppressor gene) double knockout background. Second, assess the efficacy of therapeutic targeting of the elevated Th17 immune responses and Th17/Treg imbalance in preventing PCa development in aged versus non-aged Pten-null mice. This project is expected to reveal the underlying mechanisms involved in obesity-related inflamm-aging in prostate cancer development and progression is due to the changes in Th17 immune response and Th17/Treg imbalance, thus providing novel targets for prostate cancer therapy in the obese elderly.

年龄和肥胖是前列腺癌的高危因素，特别是老龄肥胖与前列腺癌发生和恶化密切相关，但具体机制尚不清楚。衰老以慢性低强度炎症即所谓“炎性衰老”为特征，慢性炎症在前列腺癌中的作用已被多方证明，而Th17免疫应答在炎性疾病中有重要作用。最新研究表明，人和小鼠Th17免疫应答随年龄增高而增强且出现Th17/Treg失衡。前期研究发现IL-17在Pten (肿瘤抑制基因) 敲除小鼠中能促进前列腺癌的发生与发展，并在肥胖前列腺癌中起重要作用，因此我们假设与肥胖相关的炎性衰老能通过Th17应答促进前列腺癌的发生和发展。本研究拟通过建立不同年龄组（老龄vs非老龄）肥胖小鼠Batf (Th17转录因子)和Pten双敲除前列腺癌模型，研究Th17应答与肥胖老龄前列腺癌的关系，并以Th17细胞为靶点，通过小鼠模型，评估药物阻断Th17应答对前列腺癌的抑制效果，为肥胖老龄前列腺癌的预防和治疗提供理论依据和新的药物靶点。

年龄和肥胖是前列腺癌的高危因素，特别是老龄肥胖与前列腺癌发生和恶化密切相关，但 具体机制尚不清楚。衰老以慢性低强度炎症即所谓“炎性衰老”为特征，慢性炎症在前列腺癌 中的作用已被多方证明，而Th17免疫应答在炎性疾病中有重要作用。人和小鼠 Th17免疫应答随年龄增高而增强且出现Th17/Treg失衡。前期研究发现IL-17在Pten (肿瘤抑 制基因) 敲除小鼠中能促进前列腺癌的发生与发展，并在肥胖前列腺癌中起重要作用，因此 我们假设与肥胖相关的炎性衰老能通过Th17应答促进前列腺癌的发生和发展。本研究拟通过建 立不同年龄组（老龄vs非老龄）肥胖小鼠Batf (Th17转录因子)和Pten双敲除前列腺癌模型， 研究Th17应答与肥胖老龄前列腺癌的关系，并以Th17细胞为靶点，通过小鼠模型，评估药物阻 断Th17应答对前列腺癌的抑制效果，为肥胖老龄前列腺癌的预防和治疗提供理论依据和新的药 物靶点。本研究的主要成果有：1.前列腺的慢性炎症随年龄的增加加重；2.炎性衰老导致 Th17 细胞免疫应答升高，并激活前列腺组织细胞中的NF‐κB 和 ERK1/2信号通路，这是前列腺癌发生和恶化的最重要的两个通路；3. 衰老所导致 Th17 免疫应答的升高是前列腺癌发生和恶化的重要重素。老龄鼠CD4+T细胞分泌蛋白尤其是CD4+ Th17细胞分泌因子能够促进前列腺细胞增生， 移动和侵润。通过建立不同年龄组 Batf（Th17 转录因子）和 Pten（肿瘤抑制基因）双基因敲除前列腺癌小鼠模型，并确定了Th17 免疫响应在衰老进前列腺癌发生发展及恶化中的作用。通过显微注射技术，我们成功地建立了时间和空间可控的用于研究前列腺癌的新型动物模型，并应用该模型研究了衰老与前列腺癌发生发展的关系，取得了重要进展。在药物治疗实验确定了药物因子（SR1555和IL-23p19特异抗体）用法和用量，并在前列腺癌的治疗中取得了进展。对IL-23p19功能性抗体的剂量和用药途径进行了优化。