Ideas in pathology. Pivotal role of increased cell proliferation in human carcinogenesis.

Cancer develops secondary to multiple genetic events. Each time a cell divides there is a rare chance that a genetic error related to the carcinogenic process will occur. Thus, environmental agents or disease processes that produce sustained increased cell proliferation can enhance the likelihood of cancer development by providing additional cell divisions, each with an opportunity for spontaneous genetic error. Studies of hereditary cancers and of various DNA-damaging agents, such as radiation and certain viruses and chemicals, have provided insight into identification of the essential genes, but many examples of carcinogenesis in humans do not involve direct DNA damage. Also, most preneoplastic lesions in human carcinogenesis show increased proliferation compared with normal tissues, whether from increased mitotic rate, blocked differentiation, prolonged cell survival, or other mechanisms. Selected examples of proliferation-related carcinogenesis are described, including certain infectious agents, defective immune surveillance, hormonal imbalances, chronic inflammatory-regenerative processes, and exposure to various chemicals. A common biologic mechanism for these diverse stimuli is increased cell proliferation as a prelude to cancer. This mechanism seems essential to the genesis of many cancers in humans.