Activation of carcinogenesis
Activation of carcinogenesis
Increased replicative DNA synthesis and subsequent cell division is important in each of the stages of carcinogenesis. Two possible mechanisms have been proposed for the induction of cancer. In one, an increase in DNA synthesis and mitosis by a nongenotoxic carcinogen may induce mutations in dividing cells through misrepair. With continual cell division, mutations will result in an initiated preneoplastic cell that may clonally expand to a neoplasm. In addition, nongenotoxic agents may serve to stimulate the selective clonal growth of already “spontaneously initiated cells”. In maintaining cell number within a tissue, an equilibrium exists between cell proliferation and cell death. The cancer process thus is a result of an imbalance between cell growth and death. Endogenous and exogenous factors that influence DNA damage, cell growth, and cell death contribute to carcinogenesis. Experimental evidence supports an important role for reactive oxygen species in the cancer process. Increases in reactive oxygen in the cell, through either physiological modification or through chemical carcinogen exposure, contribute to the carcinogenesis processes. This may be via genotoxic effects resulting in oxidative DNA adducts or through modification of gene expression.
The universal nature of radiation as a carcinogen relates to a specific characteristic of ionizing radiation that differentiates it from chemical toxic agents or other physical carcinogens, which are usually tissue specific in their action. This is its ability to penetrate cells and to deposit energy within them in a random fashion, unaffected by the usual cellular barriers presented to chemical agents. All cells in the body are thus susceptible to damage by ionizing radiation; the amount of damage will be related to the physical parameters that determine the radiation dose received by the particular cells or tissue.
Hormone-related cancers, namely breast, endometrium, ovary, prostate, testis, thyroid and osteosarcoma, share a unique mechanism of carcinogenesis. Endogenous and exogenous hormones drive cell proliferation, and thus the opportunity for the accumulation of random genetic errors. The emergence of a malignant phenotype depends on a series of somatic mutations that occur during cell division.
Oxidative stress can occur through overproduction of reactive oxygen and nitrogen species through either endogenous or exogenous insults. Important to carcinogenesis, the unregulated or prolonged production of cellular oxidants has been linked to mutation (induced by oxidant-induced DNA damage), as well as modification of gene expression. In particular, signal transduction pathways, including AP-1 and NFkB, are known to be activated by reactive oxygen species, and they lead to the transcription of genes involved in cell growth regulatory pathways.