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Nitric oxide, a mediator of inflammation, suppresses tumorigenesis

S Perwez Hussain1, Glennwood E Trivers, Lorne J Hofseth

  • 1Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892-4255, USA.

Cancer Research
|October 7, 2004
PubMed

Insights

Nitric oxide (NO*) production, regulated by NOS2 and p53, suppresses cancer development. Genetic studies in mice reveal that NO* deficiency accelerates lymphoma and sarcoma formation, highlighting its tumor-suppressive role.

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • Inflammation is a known driver of cancer development.
  • Nitric oxide synthase 2 (NOS2) produces nitric oxide (NO*), a key inflammatory mediator.
  • The tumor suppressor protein p53 regulates NO* production by inhibiting NOS2.

Purpose of the Study:

  • To investigate the cooperative roles of NO* and p53 in tumorigenesis using a genetic approach.
  • To determine if NO* and p53 interaction influences cancer development and progression.

Main Methods:

  • Cross-breeding of mice with specific genetic deficiencies in p53 and NOS2 (p53-/-NOS2-/-, p53-/-NOS2+/-, p53+/-NOS2-/-, p53+/-NOS2+/-).
  • Monitoring tumor development (lymphomas, sarcomas) in genetically modified mouse models.
  • Assessing spleen and thymus for apoptotic index, proliferation index, death receptor ligands (CD95-L, TRAIL), and p21(waf1) expression.
  • Measuring cytokine levels (interleukin 10) in deficient mice.

Main Results:

  • Lymphomas developed more rapidly in mice lacking functional NOS2 and/or p53 compared to controls.
  • Sarcomas and lymphomas also showed accelerated development in mice with combined p53 and NOS2 deficiencies.
  • Mice lacking both p53 and NOS2 exhibited increased anti-inflammatory interleukin 10 production.
  • p53-/-NOS2+/+ mice displayed higher apoptosis and lower proliferation with increased expression of death receptor ligands and p21(waf1) compared to double knockout mice.

Conclusions:

  • NO* plays a critical role in suppressing tumorigenesis.
  • p53 and NO* cooperate in regulating tumor development.
  • NO* deficiency exacerbates cancer progression, particularly in the context of p53 dysfunction.

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