Oncotarget

Research Papers:

Heme oxygenase-1 in macrophages controls prostate cancer progression

Zsuzsanna Nemeth, Mailin Li, Eva Csizmadia, Balazs Döme, Martin Johansson, Jenny Liao Persson, Pankaj Seth, Leo Otterbein and Barbara Wegiel _

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Oncotarget. 2015; 6:33675-33688. https://doi.org/10.18632/oncotarget.5284

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Abstract

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

Correspondence to:

Barbara Wegiel, e-mail: bwegiel@bidmc.harvard.edu

Keywords: tumor-associated macrophages, mitochondria, heme oxygenase-1, E-cadherin, tumor microenvironment

Received: June 11, 2015     Accepted: September 04, 2015     Published: September 16, 2015

ABSTRACT

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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