Molecular Mechanisms of Nitric Oxide in Cancer Progression, Signal Transduction, and Metabolism

Antioxid Redox Signal. 2019 Mar 10;30(8):1124-1143. doi: 10.1089/ars.2018.7527. Epub 2018 May 2.

Abstract

Significance: Cancer is a complex disease, which not only involves the tumor but its microenvironment comprising different immune cells as well. Nitric oxide (NO) plays specific roles within tumor cells and the microenvironment and determines the rate of cancer progression, therapy efficacy, and patient prognosis. Recent Advances: Key understanding of the processes leading to dysregulated NO flux within the tumor microenvironment over the past decade has provided better understanding of the dichotomous role of NO in cancer and its importance in shaping the immune landscape. It is becoming increasingly evident that nitric oxide synthase 2 (NOS2)-mediated NO/reactive nitrogen oxide species (RNS) are heavily involved in cancer progression and metastasis in different types of tumor. More recent studies have found that NO from NOS2+ macrophages is required for cancer immunotherapy to be effective.

Critical issues: NO/RNS, unlike other molecules, are unique in their ability to target a plethora of oncogenic pathways during cancer progression. In this review, we subcategorize the different levels of NO produced by cells and shed light on the context-dependent temporal effects on cancer signaling and metabolic shift in the tumor microenvironment.

Future directions: Understanding the source of NO and its spaciotemporal profile within the tumor microenvironment could help improve efficacy of cancer immunotherapies by improving tumor infiltration of immune cells for better tumor clearance.

Keywords: cancer; carcinogenesis; metabolism; nitric oxide; nitric oxide synthase; prognosis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Review

MeSH terms

  • Disease Progression
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Neoplasms / metabolism*
  • Nitric Oxide / metabolism*
  • Nitric Oxide Synthase Type II / metabolism
  • Prognosis
  • Reactive Nitrogen Species / metabolism*
  • Signal Transduction
  • Tumor Microenvironment

Substances

  • Reactive Nitrogen Species
  • Nitric Oxide
  • NOS2 protein, human
  • Nitric Oxide Synthase Type II