STAGES IN CANCER DEVELOPMENT
Cancer may develop suddenly and result in rapid deterioration of the victim, or it may grow slowly for years. In most instances, the appearance of cancer is preceded by serial cellular changes termed stages.
Initiation and Promotion
A general characteristic of the development of cancer is the extended period of time between the initial exposure to a carcinogen and the appearance of a neoplasm. This period, known as the tumor induction time, is common to virtually every type of carcinogen. Beginning in the late 1940s, a number of investigators defined the early stages in the development, or natural history, of cancer. In a classical experiment performed on the skin of mice, a single application of an agent induced no neoplasms, but when it was followed by several applications of a second agent, termed the promoter, neoplasms developed. Initiation by the first agent is irreversible and, once imprinted in a cell, may be followed by promotion immediately, or months or even years later. Promoting agents themselves do not induce neoplasms, and unlike initiation, promotion is reversible: if the applications of the promoting agent are repeated at long, rather than short, intervals, no neoplasms result even though the total dose of the promoting agent in the two cases is the same. Promotion of neoplasms may be modulated by such factors as diet, hormones, environmental agents, and cell aging.
This two-stage process of initiation and promotion is a general phenomenon in the natural history of cancer development in many tissues. Some promoting agents exhibit tissue specificity; phenobarbital promotes only liver cancer, and saccharin appears to be specific for bladder neoplasia. In humans, alcoholic beverages, dietary fats, and many components in cigarette smoke are effective promoting agents.
Once a visible tumor has resulted from initiation and promotion, it may progress from a benign to a malignant form or from a low-grade malignancy to a rapidly growing, highly malignant cancer. Progression of a neoplasm occurs when a cell develops one or more significant abnormalities in one or more chromosomes and then grows and multiplies excessively. It is in the stage of progression that the activation of proto- and cellular oncogenes may be most readily demonstrated. In addition, it is in this stage that the elimination and/or inactivation of tumor suppressor genes can be demonstrated either by the specific loss or alteration of chromosomes or segments of chromosomes or through the study of genetic polymorphisms by recombinant DNA technology. A major component of tumor progression is metastasis, by which cells originating in the primary neoplasm can spread in a number of ways: through the bloodstream or lymphatic system, by direct implantation, or by surgical intervention, thereby establishing secondary growths. These metastatic growths, almost without exception, exhibit chromosomal abnormalities and usually lead to the death of the host. Although millions of cells metastasize from a primary neoplasm, only a fewÑthose with certain as yet undeciphered genetic capabilitiesÑestablish metastatic lesions in various sites.
Some neoplasms may "pause" and remain latent for years before continuing their progression to malignancy. Other neoplasms, even after they are well into the stage of progression and exhibit metastases, may stop growing, differentiate, and remain quiescent for the remaining life span of the host. An example of a neoplasm that may do this in humans is the neuroblastoma of the adrenal gland, a tumor that commonly arises during childhood.