Redox control of cancer cell destruction

Abstract

Redox regulation has been proposed to control various aspects of carcinogenesis, cancer cell growth, metabolism, migration, invasion, metastasis and cancer vascularization. As cancer has many faces, the role of redox control in different cancers and in the numerous cancer-related processes often point in different directions. In this review, we focus on the redox control mechanisms of tumor cell destruction. The review covers the tumor-intrinsic role of oxidants derived from the reduction of oxygen and nitrogen in the control of tumor cell proliferation as well as the roles of oxidants and antioxidant systems in cancer cell death caused by traditional anticancer weapons (chemotherapeutic agents, radiotherapy, photodynamic therapy). Emphasis is also put on the role of oxidants and redox status in the outcome following interactions between cancer cells, cytotoxic lymphocytes and tumor infiltrating macrophages.

Keywords: Antioxidants; Cancer; Chemotherapeutics; Cytotoxic lymphocytes; Free radicals; Natural killer cells; Redox regulation.

Fig. 1

Tumor cell recognition by NK cells and CTLs: regulation by MΦs and MDSCs. CD8 positive cytotoxic T lymphocytes (CTLs) express T cell receptors (TCRs) and recognize tumor antigen peptides associated with MHC-I cell surface proteins. NK cells interact with a wide range of activating and inhibitory receptors such as the natural cytotoxicity receptors (NCRs), KIR (killer immunoglobulin-like receptors), C-type lectin receptors and immunoglobulin like transcripts (ILT). Since NK cells express Fc receptors (recognizing the invariable Fc region of immunoglobulins) they can also bind tumor cells via tumor-bound antibodies (e.g. therapeutic antibodies such as anti-EGFR or anti-Her Ab). Tumor-associated macrophages and myeloid-derived suppressor cells (MDSC) exert suppressive effects on both T cells and NK cells. NOX2, eNOS and iNOS are key players in the production of superoxide, hydrogen peroxide, NO and ONOO^- (The small spherical objects inside NK and T cells represent lytic granules which serve to store cytotoxic proteins.).

Fig. 2

Recognition of tumor-associated molecular patterns by macrophages. Surface bound antibodies, externalized calreticulin or released nucleic acids or ATP can modify macrophage phenotype via interactions with specific cell surface receptors.

Fig. 3

Macrophage polarization. Exposure of M0 macrophages to IL-4, IL-13 and IL-10 induces differentiation towards the M2 phenotype. Stimulation by LPS and IFNγ induces M1 polarization. While M2 macrophages promote cancer cell growth, M1 macrophages are potentially cytotoxic to cancer cells.