Hydrogen Sulfide Signaling in the Tumor Microenvironment: Implications in Cancer Progression and Therapy.

Cancer is a complex and heterotypic structure with a spatial organization that contributes to challenges in therapeutics. Enzymes associated with producing the gasotransmitter hydrogen sulfide (HS) are differentially expressed in tumors. Indeed, critical and paradoxical roles have been attributed to HS in cancer-promoting characteristics by targeting both cancer cells and their milieu. This review focuses on the evidence and knowledge gaps of HS on the tumor redox microenvironment and the pharmacological effects of HS donors on cancer biology. Endogenous and pharmacological concentrations of HS evoke different effects on the same cell type: physiological HS concentrations have been associated with tumor development and progression. In contrast, pharmacological concentrations have been associated with anticancer effects. The exact threshold between the promotion and inhibition of tumorigenesis by HS is largely unknown. The main issues covered in this review include HS-modulated signaling pathways that are critical for cancer cells, the potential effects of HS on cellular components of the tumor microenvironment, temporal modulation of HS in promoting or inhibiting tumor progression (similar to observed for inflammation), and pharmacological agents that modulate HS and which could play a role in antineoplastic therapy. Given the complexity and heterogeneity of tumor composition, mechanistic studies on context-dependent pharmacological effects of HS donors for cancer therapy are necessary. These studies must determine the critical signaling pathways and the cellular components involved to allow advances in the rational use of HS donors as antineoplastic agents. 40, 250-271.