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(American Journal of Pathology. 2006;169:2181-2198.)
© 2006 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2006.051365

Overexpression of Heme Oxygenase-1 in Murine Melanoma

Increased Proliferation and Viability of Tumor Cells, Decreased Survival of Mice

Halina Was*, Tomasz Cichon{dagger}, Ryszard Smolarczyk{dagger}, Dominika Rudnicka*, Magdalena Stopa*, Catherine Chevalier{ddagger}, Jean J. Leger{ddagger}, Bozena Lackowska§, Anna Grochot*, Karolina Bojkowska*, Anna Ratajska, Claudine Kieda||, Stanislaw Szala{dagger}, Jozef Dulak* and Alicja Jozkowicz*

From the Department of Medical Biotechnology,* Faculty of Biotechnology, Jagiellonian University, Krakow, Poland; the Department of Molecular Biology,{dagger} Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice, Poland; the Department of Pathology,§ Oncology Center, Krakow, Poland; the Department of Pathological Anatomy, Medical University of Warsaw, Warsaw, Poland; INSERM U533-Ouest Génopole,{ddagger} Nantes, France; and the Centre of Molecular Biophysics,|| Centre National de la Recherche Scientifique, Orleans, France

Heme oxygenase-1 (HO-1), a cytoprotective enzyme, can be induced in tumors in response to anti-cancer therapies. We investigated the role of HO-1 in B16(F10), S91, and Sk-mel188 melanoma cells. Overexpression of HO-1 after transduction with adenoviral vectors increased cell proliferation, resistance to oxidative stress generated by H2O2, and angiogenic potential as determined by induction of endothelial cell divisions. Likewise, cells stably transfected with HO-1 cDNA (B16-HO-1) showed higher proliferation, stress resistance, and angiogenic activity than the wild-type line (B16-WT). HO-1 overexpression in tumors significantly shortened survival of mice after subcutaneous injection of cancer cells (38 and 22 days for B16-WT and B16-HO-1, respectively; P = 0.017). This also resulted in development of more packed tumors, with more melanoma cells, and reduced inflammatory edemas. Mice injected with B16-HO-1 had lower levels of tumor necrosis factor and higher serum concentrations of its soluble receptor tumor necrosis factor-RI, whereas tumors overexpressing HO-1 displayed augmented vascularization and stronger production of vascular endothelial growth factor. Finally, B16-HO-1 cells injected intravenously formed more metastases in lungs. Thus, HO-1 overexpression increased viability, proliferation, and angiogenic potential of melanoma cells, augmented metastasis, and decreased survival of tumor-bearing mice, suggesting that induction of HO-1 may be detrimental in anti-cancer therapy of melanoma.




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