High infectious burden, low cancer incidence, and early malignancy in developing countries: a molecular hypothesis in term of the role of nitric oxide.

Nitric oxide (NO) is a neurotransmitter which plays a powerful role in the immune system: it kills bacteria, and, it also destroys the tumor cells. Specifically, immune system stimuli gamma interferon and lipopolysaccharide transmit signals to a macrophage nucleus causing the production of nitric oxide synthase, the enzyme that converts arginine to NO. The NO thus produced not only destroys bacteria but also attacks the tumor cells by inhibiting the energy-producing Krebs cycle, electron transport activity and DNA synthesis. People in developing countries who survive repeated childhood infections must be inferred to have robust microphage/NO systems and thus, also, a strong immunity against cancer--thence the low incidence of cancers in these countries. However, those unfortunate few in these countries who do develop cancer, despite a robust microphage/NO system, must be presumed to have a markedly virulent tumor development micro-environment (e.g., activation of tumor promotion genes, inactivation of tumor suppression genes, multiple mutations, etc.) that escapes even the particularly alert immune surveillance--thence the earlier (by about a decade) death by cancer in those countries. Thus the NO hypothesis put forward here simultaneously provides a mechanistic causation for (i) low cancer incidence in countries subjected to heavy infectious burdens, and (ii) the earlier occurrence (by about a decade) of major cancers in those countries when the immune surveillance, despite its robustness, fails to destroy the incipient formation of cancer cells.