Genomic instability in cancer.

Solid tumours have abnormal, deficient vascular and lymphatic systems. As a result, perfusion within these malignancies is inadequate and chaotic, and the cancers contain regions that are transiently and chronically exposed to low pH, severe hypoxia and nutrient deprivation. These microenvironmental inadequacies are present from the earliest point in the development of solid tumours, and are fully established while the neoplasms are still microscopic. Exposures to acidic and hypoxic environments have been shown to produce a wide range of cytogenetic changes. These include increases in mutation frequencies; deficits in DNA repair; DNA overreplication and gene amplification; the induction of chromosomal fragile sites, triggering genomic rearrangements; and changes in gene expression. Moreover, exposure of cells to adverse microenvironments such as those in solid tumours selects for cells which have defects in the structure or expression of the genes that normally regulate cell proliferation. The genetic changes and selection pressures induced by hypoxia may be critical in causing the development of the genomic instability and genetic heterogeneity which is characteristic of solid tumours and in fostering the evolution of relatively benign cell populations in solid tumours to increasingly malignant, increasingly aggressive phenotypes.