Heme degradation pathway and immunomodulation in prostate cancer.

前列腺癌中的血红素降解途径和免疫调节。

• 批准号: 8715735
• 负责人: Barbara Wegiel
• 金额: $ 18.35万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-06 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8715735
• 关键词: Bilirubin; Biliverdin reductase; Biliverdine; Binding; Cancer Etiology; Cancerous; Carbon Monoxide; Caspase-1; Cells; Cessation of life; Chronic; DNA Damage; Degradation Pathway; Development; Enzymes; Equilibrium; Exposure to; Family member; Gases; Generations; Growth; Growth and Development function; Heme; Human; Immune; Immune Cell Activation; Immune response; Infection; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Injury; Interleukin-1; Iron; Knockout Mice; Lead; Leucine-Rich Repeat; Link; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Mutation; Myeloid Cells; Natural Killer Cells; Necrosis; Neoplasms; Nucleotides; Oxidative Stress; Participant; Pathway interactions; Phagocytosis; Phenotype; Prevalence; Primary Neoplasm; Process; Production; Property; Prostate; Protein Isoforms; Proteins; Regulation; Risk; Role; Scheme; Signal Pathway; Signal Transduction; Testing; Tissues; Transgenic Model; Tumor Angiogenesis; Tumor Suppressor Proteins; Tumor-Derived; advanced disease; angiogenesis; cancer cell; cytokine; cytotoxic; cytotoxicity; heme oxygenase-1; high risk; immunoregulation; improved; killings; macrophage; neoplastic cell; public health relevance; receptor; response; sensor; stress related disorder; tumor; tumor growth; tumorigenesis; tumorigenic

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.

描述（由适用提供）：前列腺癌（PCA）仍然是美国与癌症有关的主要原因，并且晚期疾病的治疗仍然受到限制。由于前列腺癌的进展可能很大，因此鉴定出优选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。证明包括PCA在内的人类癌症中几乎有三分之一与慢性感染和感染是一种致病联系。前列腺癌的风险与前列腺持续感染密切相关。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）已演变为炎症，增生和氧化应激相关疾病中公认的受保护分子，对这些观察结果的最大支持来自基因敲除小鼠和HO-1-缺乏人类。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，通过CO作用HO-1通过调节巨噬细胞活性来限制前列腺癌的发育和进展：通过NALP3-Caspase-1-IL1-信号途径通过NALP3-Caspase-1-IL1-产生吞噬作用和细胞因子。在此提案中，我们应测试HO-1和血红素降解产物作为前列腺癌肿瘤相关巨噬细胞中受保护的分子的作用。

项目成果

Heme oxygenase-1 in macrophages controls prostate cancer progression.

• DOI: 10.18632/oncotarget.5284
• 发表时间: 2015-10-20
• 期刊: Oncotarget
• 作者: Nemeth Z;Li M;Csizmadia E;Döme B;Johansson M;Persson JL;Seth P;Otterbein L;Wegiel B
• 通讯作者: Wegiel B