Abstract
Objective: Heme oxygenase-1 (HO-1) is a cytoprotective, proangiogenic and anti-inflammatory enzyme that is often upregulated in tumors. Overexpression of HO-1 in melanoma cells leads to enhanced tumor growth, augmented angiogenesis and resistance to anticancer treatment. The effect of HO-1 in host cells on tumor development is, however, hardly known. Methods and results: To clarify the effect of HO-1 expression in host cells on melanoma progression, C57BL/6xFvB mice of different HO-1 genotypes, HO-1+/+, HO-1+/−, and HO-1−/−, were injected with the syngeneic wild-type murine melanoma B16(F10) cell line. Lack of HO-1 in host cells did not significantly influence the host survival. Nevertheless, in comparison to the wild-type counterparts, the HO-1+/− and HO-1−/− males formed bigger tumors, and more numerous lung nodules; in addition, more of them had liver and spleen micrometastases. Females of all genotypes developed at least 10 times smaller tumors than males. Of importance, the growth of primary and secondary tumors was completely blocked in HO-1+/+ females. This was related to the increased infiltration of leukocytes (mainly lymphocytes T) in primary tumors. Conclusions: Although HO-1 overexpression in melanoma cells can enhance tumor progression in mice, its presence in host cells, including immune cells, can reduce growth and metastasis of melanoma.
Highlights
Heme oxygenase-1 (HO-1, heat shock protein 32, encoded by HMOX1) is widely expressed by mammalian cells
We found that: (1) females grew much smaller tumors than males after both intracutaneous and intravenous injection with melanoma cells, (2) growth of primary tumors and lung nodules was completely inhibited in HO-1+/+ females, which was associated with the augmented leukocyte infiltration of primary tumors with lymphocytes T as a major subpopulation, and (3) HO-1+/− and HO-1−/− males formed bigger primary tumors and more numerous lung nodules than their wild-type counterparts, as well as more of them showed micrometastases in liver and spleen
We previously discovered that HO-1 upregulates production of vascular endothelial growth factor (VEGF) in endothelial cells [63] and that overexpression of HO-1 in melanoma cells increases the levels of VEGF leading to increased angiogenesis in tumors [15]
Summary
Heme oxygenase-1 (HO-1, heat shock protein 32, encoded by HMOX1) is widely expressed by mammalian cells. HO-1 may accelerate angiogenesis through a variety of mechanisms, including induction of vascular endothelial growth factor (VEGF) transcription and increased production of pro-angiogenic carbon monoxide [3]. In a previous study [15] we have shown that melanoma cells B16(F10) overexpressing HO-1 [B16(F10)-HO-1] displayed increased proliferation, stronger angiogenic potential, and were more resistant to oxidative stress induced by hydrogen peroxide. Melanoma cells overexpressing HO-1 generated more packed tumors with augmented vascularization and higher production of VEGF. HO-1 overexpression in melanoma cells resulted in shortened survival of hosts. In another model, B16(F10)-HO-1 cells injected intravenously formed more nodules in the lungs [15]
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