Heme oxygenase-1 in tumors: is it a false friend?

Abstract

Heme oxygenase-1 (HO-1) catalyzes the oxidation of heme to biologically active products: carbon monoxide (CO), biliverdin, and ferrous iron. It participates in maintaining cellular homeostasis and plays an important protective role in the tissues by reducing oxidative injury, attenuating the inflammatory response, inhibiting cell apoptosis, and regulating cell proliferation. HO-1 is also an important proangiogenic mediator. Most studies have focused on the role of HO-1 in cardiovascular diseases, in which its significant, beneficial activity is well recognized. A growing body of evidence indicates, however, that HO-1 activation may play a role in carcinogenesis and can potently influence the growth and metastasis of tumors. HO-1 is very often upregulated in tumor tissues, and its expression is further increased in response to therapies. Although the exact effect can be tissue specific, HO-1 can be regarded as an enzyme facilitating tumor progression. Accordingly, inhibition of HO-1 can be suggested as a potential therapeutic approach sensitizing tumors to radiation, chemotherapy, or photodynamic therapy.

FIG. 1

Schematic demonstration of HO-1 pathway and biologic activities of HO-1 products.

FIG. 2. Schematic demonstration of the tissue-specific role of the HO-1 pathway in regulation of cell proliferation

Suggested mediators are shown in the boxes.

FIG. 3. Schematic demonstration of the role of the HO-1 pathway in regulation of cell apoptosis

Suggested mediators are shown in the boxes.

FIG. 4. Schematic demonstration of the role of the HO-1 pathway in regulation of angiogenesis in tumors

Suggested mediators are shown in the boxes.

FIG. 5. HO-1 overexpression in murine B16(F10) melanoma cells increases vascularization of tumors grown subcutaneously in mice

Blood vessels were stained in the frozen sections with anti-CD31 antibodies, visualized by peroxidase reaction. Tissues were counterstained with hematoxylin. Representative pictures. Endothelial cells labeled by brownish reaction product are indicated by arrows. WT, tumors formed by the wild-type cells; HO-1, tumors formed by HO-1-overexpressing cells (after 167).

FIG. 6. HO-1 overexpression in the murine B16(F10) melanoma line increases the metastatic potential of cells

Number of metastatic lung nodules in mice 3 weeks after intravenous inoculation with the wild-type (WT) and HO-1-overexpressing (HO-1) melanoma cells. (A) Representative photos showing the lungs fixed with Bouin solution. (B) Quantitative analysis: bars represent the mean ± SEM of 10 values. *p < 0.05 in comparison with B16-WT animals (after 167).

FIG. 7. Schematic demonstration of the role of HO-1 pathway in the regulation of inflammatory reactions in tumors

Suggested mediators are shown in the boxes.

FIG. 8

Schematic summary of possible effects of HO-1 activation on tumor growth.