Immune-inflammatory signaling and hormone-refractory prostate cancer evolution.

描述（申请人提供）：前列腺癌（PCa）是一种异质性疾病，从前列腺上皮内瘤变到局部浸润性腺癌，再到激素难治性癌。对于局限于前列腺的肿瘤，根治性前列腺切除术和放疗是有效的。然而，对于激素难治性前列腺癌尚无有效的治疗方法。雄激素剥夺疗法（ADT）是晚期前列腺癌的初始全身治疗，可作为高风险疾病局部治疗的辅助治疗，但不幸的是，晚期疾病的反应只是短暂的。因此，对激素难治性前列腺癌形成机制的研究，特别是可能产生新的治疗方法的研究，具有重要意义。在我们的初步研究中，选择性阻断NF-？B是免疫细胞中的主要炎症转录因子，在转基因和异种移植前列腺癌小鼠模型中显著损害去势抵抗性前列腺癌（CR-PCa）的发展。我们还发现这种炎症反应的关键参与者之一是肿瘤浸润性B细胞，它产生LTa：¿异源三聚体，刺激PCa细胞上的LTa：¿R诱导IKKa核易位和激活，从而增强雄激素非依赖性生长。因此，我们建议明确LTs和LTs诱导的IKKa核易位和激活如何介导CR-PCa的形成，以及LTs表达、IKKa核定位和激活与人类前列腺癌的相关性。我们相信我们的研究将为B细胞来源的LTs如何控制CR-PCa提供新的见解，并将为开发治疗和/或预防激素难治性PCa的新治疗策略奠定基础。

DESCRIPTION (provided by applicant): Prostate cancer (PCa) is a heterogeneous disease that progresses from prostatic intraepithelial neoplasia to locally invasive adenocarcinoma and then to hormone-refractory carcinoma. In tumors confined to the prostate, radical prostatectomy and radiotherapy are effective. However, no effective treatments are available for hormone-refractory PCa. Androgen deprivation therapy (ADT) is initial systemic therapy for advanced PCa and is used as an adjuvant to local therapy for high-risk disease, but, tragically, responses in advanced disease are only transient. Thus, research on the mechanisms of hormone refractory PCa formation, especially studies that are likely to result in novel therapeutic approaches, is of great importance. In our Preliminary Studies, selectively blocking NF-?B, the principle inflammatory transcription factor, in immune cells, dramatically impairs the development of castration resistant prostate cancer (CR-PCa) in both transgenic and xenograft PCa mouse models. We also found that one of the critical participants in this inflammatory response is tumor infiltrating B cells, which produce LTa:¿ heterotrimers that stimulate LT¿R on PCa cells to induce IKKa nuclear translocation and activation, thereby enhancing androgen-independent growth. Accordingly, we propose to define how LTs and LTs-induced IKKa nuclear translocation and activation mediate the formation of CR-PCa, and the relevance of LTs expression, IKKa nuclear localization and activation to human prostate cancer. We believe our studies will provide new insights into how B cells-derived LTs control CR-PCa, and will lay the foundation for developing novel therapeutic strategies for the treatment and/or prevention of hormone refractory PCa.