The causes of cancer: implications for prevention and treatment.

The final clinical manifestation of cancer is a result of complex series of changes in a single cell. This review summarizes some of the new concepts and hypotheses that explain the evolution of cancers. The emphasis is on cancer as a disease of the stem cells within a tissue that undergo initiation as a result of mutational insult to one or more genes that are critical for cell growth. During the second stage (promotion stage) the initiated cells acquire proliferative capacity due to epigenetic changes, i.e., altered expression of genes whose products play a central role in signal transduction. This requires continued exposure to agents and events causing such changes. This stage is, therefore, reversible and the various components of this stage are central targets for the development of mechanism based anti-cancer drugs. During the stage of progression, the neoplastic lesions acquire additional genetic alterations and become clinically manifestable malignant neoplasms. At the biochemical and molecular level, neoplastic transformation involves aberrations in the expression and regulation of oncogenes, tumor suppression genes, transcription factors and components of the cell signal transduction cascades. The understanding of the various cellular biochemical and molecular events that metamorphose a normal cell into a cancer cell is central to the development of rational new drugs that are targeted against the various components. Such drugs in combination with the conventional chemotherapeutic agents that are currently used, provide a more effective control of cancer without the risk of toxic side effects.