Heme oxygenase-1 in macrophages controls prostate cancer progression
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Zsuzsanna Nemeth1,6, Mailin Li1,4, Eva Csizmadia1,4, Balazs Döme6,7,8, Martin Johansson5, Jenny Liao Persson5, Pankaj Seth2,3, Leo Otterbein1,4, Barbara Wegiel1,3,4
1Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
2Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
3Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
4Transplant Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
5Department of Laboratory Medicine, Lund University, Malmo, Sweden
6Department of Tumor Biology, National Koranyi Institute of TB and Pulmonology, Budapest, Hungary
7Division of Thoracic Surgery, Medical University of Vienna, Vienna, Austria
8Department of Thoracic Surgery, National Institute of Oncology, Budapest, Hungary
Barbara Wegiel, e-mail: email@example.com
Keywords: tumor-associated macrophages, mitochondria, heme oxygenase-1, E-cadherin, tumor microenvironment
Received: June 11, 2015 Accepted: September 04, 2015 Published: September 16, 2015
Innate immune cells strongly influence cancer growth and progression via multiple mechanisms including regulation of epithelial to mesenchymal transition (EMT). In this study, we investigated whether expression of the metabolic gene, heme oxygenase-1 (HO-1) in tumor microenvironment imparts significant effects on prostate cancer progression.
We showed that HO-1 is expressed in MARCO-positive macrophages in prostate cancer (PCa) xenografts and human prostate cancers. We demonstrated that macrophage specific (LyzM-Cre) conditional deletion of HO-1 suppressed growth of PC3 xenografts in vivo and delayed progression of prostate intraepithelial neoplasia (PIN) in TRAMP mice. However, initiation and progression of cancer xenografts in the presence of macrophages lacking HO-1 resulted in loss of E-cadherin, a known marker of poor prognosis as well as EMT. Application of CO, a product of HO-1 catalysis, increased levels of E-cadherin in the adherens junctions between cancer cells. We further showed that HO-1-driven expression of E-cadherin in cancer cells cultured in the presence of macrophages is dependent on mitochondrial activity of cancer cells.
In summary, these data suggest that HO-1-derived CO from tumor-associated macrophages influences, in part, E-cadherin expression and thus tumor initiation and progression.
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