Role of nitric oxide in angiogenesis and tumor progression in head and neck cancer

J Natl Cancer Inst. 1998 Apr 15;90(8):587-96. doi: 10.1093/jnci/90.8.587.


Background: Angiogenesis (formation of new blood vessels) is associated with tumor growth and metastasis in patients with solid tumors, including those of the head and neck. Nitric oxide (NO) production may contribute to these processes. We assessed the role of the NO pathway in angiogenesis and tumor progression in patients with head and neck cancer.

Methods: Biochemical assays were used to measure NO synthase (NOS) activity and cyclic guanosine monophosphate (cGMP) levels in specimens of tumor and normal mucosa obtained from 27 patients. Microvessels in tumor specimens were identified by CD-31-specific immunohistochemical staining. Associations between microvessel densities, levels of NOS, and cGMP were examined by use of two-sided statistical tests. Tumor specimens and human squamous carcinoma A-431 cells were grown as explants on the corneas of rabbits, and the effect of the NOS inhibitor N(omega)-nitro-L-arginine-methyl ester (L-NAME) was tested.

Results: Levels of total NOS, inducible NOS, and cGMP were higher in tumor specimens than in specimens of normal mucosa (all P<.0001). Tumor specimens from patients with lymph node metastases presented a higher total NOS activity (P = .005) and were markedly more vascularized than tumor specimens from patients with no lymph node involvement (P = .0002). Microvessel density at the tumor edge was an independent predictor of metastasis for this series of patients (odds ratio = 1.19; 95% confidence interval = 1.07-2.89; P = .04). A-431 cells and tumor specimens exhibiting high levels of NOS activity induced angiogenesis in the rabbit cornea assay; when NO production was blocked, tumor angiogenesis and growth were repressed.

Conclusions: The NO pathway appears to play a key role in tumor angiogenesis and spread in patients with head and neck cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Carcinoma, Squamous Cell / enzymology
  • Carcinoma, Squamous Cell / metabolism*
  • Carcinoma, Squamous Cell / pathology*
  • Cyclic GMP / metabolism
  • Disease Progression
  • Enzyme Inhibitors / pharmacology
  • Female
  • Fluorescent Antibody Technique
  • Head and Neck Neoplasms / enzymology
  • Head and Neck Neoplasms / metabolism*
  • Head and Neck Neoplasms / pathology*
  • Humans
  • Lymphatic Metastasis
  • Male
  • Middle Aged
  • Multivariate Analysis
  • NG-Nitroarginine Methyl Ester / pharmacology
  • Neoplasm Staging
  • Neovascularization, Pathologic / metabolism*
  • Nitric Oxide / antagonists & inhibitors
  • Nitric Oxide / metabolism*
  • Nitric Oxide Synthase / antagonists & inhibitors
  • Nitric Oxide Synthase / metabolism*
  • Nitric Oxide Synthase Type II
  • Polymerase Chain Reaction / methods
  • Transcription, Genetic
  • Tumor Cells, Cultured


  • Enzyme Inhibitors
  • Nitric Oxide
  • NOS2 protein, human
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type II
  • Cyclic GMP
  • NG-Nitroarginine Methyl Ester