Heme oxygenase-1 expression in stromal cells affects melanoma growth and metastases

Heme oxygenase-1 (HO-1) is a cytoprotective, proangiogenic and anti-inflammatory enzyme. In our previous experiments we demonstrated that overexpression of HO-1 in melanoma cells led to decrease in survival time of tumor-bearing mice, inhibition of inflammatory reaction, and increase in tumor vascularization and number of metastases in lungs.

Aims: In present study our aim was to elucidate the effects of HO-1 expressed in stromal cells on melanoma growth and metastases.

Methods and results: In the growing tumors, lack of HO-1 in stromal cells did not influence significantly the host survival, as demonstrated after intracutaneous and intravenous inoculation of mice with B16(F10) melanoma cells. Nevertheless, HO-1+/- and HO-1-/- males formed bigger tumors and more numerous lung metastases, as well as more of them showed the liver and the spleen micrometastases, than their wild type counterparts. Surprisingly, females of all genotypes grew significantly smaller tumors than males. Growth of primary and secondary tumors was completely inhibited in HO-1+/+ females, what was associated with augmented leukocytes infiltration with lymphocytes T as a major subpopulation. Interestingly, in both models levels of inflammatory: IL-6, IL-12, IFNγ, and MCP-1 and angiogenic cytokines: VEGF and KC in sera correlated with HO-1 genotype, but not with the gender of mice. Finally, metastases-bearing mice showed lower rate of blood parameters: WBC, RBC, and platelets than their healthy littermates.Concomitantly, number of WBC was the lowest in HO-1+/+ females.Conclusions: Thus, high expression of HO-1 in host cells could limit melanoma growth and lung metastases mainly through modulation of immune response.