期刊
CURRENT CANCER DRUG TARGETS
卷 14, 期 4, 页码 337-347出版社
BENTHAM SCIENCE PUBL LTD
DOI: 10.2174/1568009614666140320111306
关键词
Cancer; haem oxygenase-1; regulatory T cells; tumour immunology; zinc protoporphyrin
类别
资金
- Danish Cancer Society
- Danish Medical Research Council
- Research Foundation at Herlev Hospital
- The Danish Cancer Society [R72-A4460] Funding Source: researchfish
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.
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