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.
Inflammation, a seven hallmark of cancer, is a critical component of cancerogenesis and in many situations is present before a malignant transformation occurs. Heme oxygenase-1 (HO-1), a member of the family of immunoregulatory proteins, is the rate-limiting enzyme in the degradation of heme and we posit is critical in tumor-associated inflammation and control of tumorigenesis. We hypothesized that induction of HO-1 and application of carbon monoxide will lead to faster and more efficient reprogramming of innate immune towards anti-cancerous response. We will dissect the role of the heme pathway by using our newly generated HO-1(hmox-1-fl/fl) conditional knockout mice in the transgenic model of PCa and/or infection-associated PCa.
|Wegiel, Barbara; Larsen, Rasmus; Gallo, David et al. (2014) Macrophages sense and kill bacteria through carbon monoxide-dependent inflammasome activation. J Clin Invest 124:4926-40|
|Wegiel, B; Hedblom, A; Li, M et al. (2014) Heme oxygenase-1 derived carbon monoxide permits maturation of myeloid cells. Cell Death Dis 5:e1139|