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, Barbara Wegiel

Research output: Contribution to journalArticlepeer-review

29 Citations (Scopus)
264 Downloads (Pure)

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.

Original languageEnglish
Pages (from-to)33675-88
Number of pages14
JournalOncotarget
Volume6
Issue number32
DOIs
Publication statusPublished - 16 Oct 2015
Externally publishedYes

Keywords

  • Animals
  • Cadherins
  • Cell Line, Tumor
  • Cell Proliferation
  • Disease Progression
  • Heme Oxygenase-1
  • Heterografts
  • Humans
  • Macrophages
  • Male
  • Membrane Proteins
  • Mice
  • Mice, Knockout
  • Prostatic Neoplasms
  • Tumor Microenvironment
  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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