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发展到局部浸润性腺癌，然后发展到激素不敏感的癌。对于仅限于前列腺的肿瘤，根治性前列腺切除术和放射治疗是有效的。然而，激素抵抗型前列腺癌目前还没有有效的治疗方法。雄激素剥夺疗法(ADT)是晚期前列腺癌的初始系统疗法，并被用作高危疾病局部治疗的辅助手段，但可悲的是，晚期疾病的反应仅是短暂的。在我们的初步研究中，选择性地阻断免疫细胞中主要的炎性转录因子--核因子？B，在转基因和异种移植的前列腺癌小鼠模型中，显著地削弱了去势抵抗前列腺癌(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，它们产生LTA：？异源三聚体，刺激PCa细胞上的LT？R，诱导IKKA核移位和激活，从而促进雄激素非依赖性生长。因此，我们建议明确LTS和LTS诱导的Ikka核转位和激活如何介导CR-Pca的形成，以及LTS的表达、Ikka核定位和激活与人前列腺癌的相关性。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的新的治疗策略奠定基础。

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.