Heme degradation pathway and immunomodulation in prostate cancer.

描述（由申请人提供）：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。由于前列腺癌可能具有广泛可变的进展过程，因此识别优先与侵袭性肿瘤形式相关的因素对于能够改善晚期疾病的治疗至关重要。几乎三分之一的人类癌症，包括前列腺癌，被证明与慢性炎症和感染有因果关系。前列腺癌的风险与前列腺中的持续炎症密切相关。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）已经发展成为炎症、增殖和氧化应激相关疾病中公认的保护性分子，这些观察结果来自基因敲除小鼠和HO-1缺陷的人。然而，血红素降解途径在肿瘤相关巨噬细胞中调节癌症生长的重要性尚未研究。我们的主要假设是，HO-1通过CO起作用，通过调节巨噬细胞的活性来抑制前列腺癌的发展和进展：通过Nalp 3-caspase-1-IL 1？信号通路来调节吞噬作用和细胞因子的产生。在这个提议中，我们将测试HO-1和血红素降解产物作为前列腺癌中肿瘤相关巨噬细胞的保护分子的作用。

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.