Effects of heme oxygenase-1 on induction and development of chemically induced squamous cell carcinoma in mice
Abstract
Heme oxygenase-1 (HO-1) is an antioxidative and cytoprotective enzyme, which may protect neoplastic cells against anticancer therapies, thereby promoting the progression of growing tumors. Our aim was to investigate the role of HO-1 in cancer induction.
Experiments were performed in HO-1+/+, HO-1 +/- and HO-1 -/- mice subjected to Chemical induction of squamous cell carcinoma with 7.12-dimethylbenz[a]anthracene and phorbol 12-myristate 13-acetate. Measurements of cytoprotective genes in the livers evidenced systemic oxidative stress in the mice of all the HO-1 genotypes.
Carcinogen-induced lesions appeared earlier in H0-1-/- and HO-l+/- than in wild-type animals. They also contained much higher concentrations of vascular endothelial growth factor and keratinocyte chemoattractant, but lower levels of tumor necrosis factor-alpha and interleukin-12.
Furthermore, tumors grew much larger in HO-1 knockouts than in the other groups, which was accompanied by an increased rate of animal mortality. However, pathomorphological analysis indicated that HO-1-/- lesions were mainly large but benign papillomas.
In contrast, in mice expressing HO-1, most lesions displayed dysplastic features and developed to invasive carcinoma. Thus, HO-1 may protect healthy tissues against carcinogen-induced injury, but in already growing tumors it seems to favor their progression toward more malignant forms.