The Expression, Function and Targeting of Haem Oxygenase-1 in Cancer
Mads Duus Hjortso and Mads Hald AndersenAffiliation:
Center for Cancer Immune Therapy (CCIT), Department of Hematology, 54P4, Copenhagen University Hospital, Herlev, Denmark.
Haem oxygenase-1 (HO-1) catalyses the rate-limiting step in haem degradation. All three metabolites resulting from haem degradation (carbon monoxide (CO), biliverdin and free iron) have anti-inflammatory and anti-apoptotic properties. HO-1 is a stress-inducible enzyme found extensively expressed in a vast variety of both human and murine cancers, where it serves as an essential survival molecule by modulating expression of molecules regulating apoptosis and stimulating angiogenesis. In addition, HO-1 contributes in a critical manner to inhibition or termination of inflammation. Consequently, several anticancer strategies aim at targeting HO-1. The inhibition of HO-1 may cause tumour cells to become more sensitive to chemotherapy and radiation therapy. The water-soluble forms of the HO-1 inhibitor Zinc protoporphyrin (ZnPP) have seemed promising in different in-vivo models, in which it has induced growth arrest in tumour cells with few, if any, side effects. Studies have suggested that HO-1 may also function to disrupt the tumour metastasising process, since the expression of the metalloprotease MMP9 is inversely correlated with HO-1 expression.
Additionally, HO-1 has anti-inflammatory functions which play a very important role in the negative regulation of the immune system. Immunological targeting of HO-1 might represent an interesting approach, as epitopes derived from HO- 1 have been found exclusively on tumour tissue. Natural HO-1-specific T-cell responses have been identified in cancer patients. Hence, recently HO-1-specific, CD8+ regulatory T cells were described in cancer patients, which in concert with HO-1 expression might be responsible for a highly immunosuppressive tumour microenvironment.
Here, we summarise current knowledge of the role of HO-1 in cancer, report the different results of the targeting of HO-1 in preclinical and clinical settings, and discuss future opportunities.
Cancer, haem oxygenase-1, regulatory T cells, tumour immunology, zinc protoporphyrin.
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