NO/cGMP signaling in the tumor micro­environment

The NO/cGMP signaling cascade is a central regulator of vascular homeostasis. The tumor microvasculature is often abnormal, decreasing immune cell infiltration and the efficacy of anti-cancer therapies. We investigated whether genetic or pharmacological modulation of the NO-sensitive guanylyl cyclase (NO‑GC) affects tumor growth in mouse models of melanoma and breast cancer. Using a combination of immunofluorescence staining and real-time cGMP imaging in tumors of transgenic cGMP sensor mice, we found that the NO/cGMP signaling axis is exclusively present in pericytes of the tumor microvessels. Genetic ablation of NO‑GC in pericytes decreased tumor growth, and administration of a clinically used NO‑GC stimulator increased it. In an in vitro model of human microvessels, pharmacologic NO‑GC inhibition decreased vessel branching and pericyte coverage, while NO‑GC stimulation increased it. Collectively, these results suggest that elevated activity of the NO/cGMP pathway in pericytes may promote tumor growth through unfavorable effects on the tumor microvasculature. Our findings call for studies exploring the possibility of altered tumor growth in cancer patients receiving NO-GC stimulators for cardiovascular indications like heart failure.