Heme degradation pathway and immunomodulation in prostate cancer.

描述(申请人提供)：前列腺癌(PCA)仍然是美国癌症相关死亡的主要原因，晚期疾病的治疗仍然有限。由于前列腺癌的进展过程可能有很大的差异，识别与侵袭性形式的肿瘤优先相关的因素对于提高晚期疾病的治疗至关重要。包括前列腺癌在内的几乎三分之一的人类癌症被证明与慢性炎症和感染有关。前列腺癌的风险与前列腺癌的持续性炎症密切相关。在过去的十年中，血红素加氧酶-1(HO-1)和血红素降解产物一氧化碳(CO)已经进化成炎症、增殖和氧化应激相关疾病中公认的保护分子，这些观察结果得到了来自HO-1基因敲除小鼠和HO-1缺陷者的最大支持。然而，肿瘤相关巨噬细胞中的血红素降解途径对调节肿瘤生长的重要性尚未被研究。我们的主要假设是，HO-1通过CO作用，通过调节巨噬细胞的吞噬和细胞因子的产生，通过NALP3-caspase-1-IL1信号通路来抑制前列腺癌的发生和发展。在这项提案中，我们将测试HO-1和血红素降解产物在前列腺癌肿瘤相关巨噬细胞中作为保护分子的作用。

DESCRIPTION (provided by applicant): Prostate cancer (PCa) is still a leading cause of cancer related-deaths in the US and the treatment of advanced disease is still limited. As prostate cancer can have a widely variable course of progression, identification of factors that preferentially associate with aggressive form of tumors is of the utmost importance to be able to improve treatment for advanced disease. Almost one third of human cancers including PCa are proved a causative link with chronic inflammation and infection. The risk of prostate cancer is strongly associated with persistent inflammation in the prostate. Over the past decade, heme oxygenase-1 (HO-1) and heme degradation product, carbon monoxide (CO) have evolved into accepted protective molecules in inflammatory, proliferative and oxidative-stress related disorders with the greatest support for these observations coming from the knockout mice and HO-1-deficient human. The importance of heme degradation pathway in tumor-associated macrophages to modulate cancer growth however has not been yet studied. Our major hypothesis is that HO-1 acting via CO constrains the development and progression of prostate cancer via modulation of macrophage activities: phagocytosis and cytokine production through Nalp3-caspase-1-IL1¿ signaling pathway. In this proposal, we shall test the role of HO-1 and heme degradation products as protective molecules in tumor-associated macrophages in prostate cancer.