Our greatest successes in fighting
cancer derive from the identification and removal or inactivation of carcinogenic substances, and from the identification and removal of pre-malignant lesions. In comparison, our successes at treating already formed
malignancies have been minimal. Therefore, emphasis should be put in identifying and removing pre-malignant lesions, and in the identification and removal of those agents that cause or contribute to
cancer development. It is important to target initiators, co-
carcinogens and promoters, since by removing any one of them,
tumor growth may be prevented. Identification of these agents is difficult. Epidemiological studies largely study
cancer after it has occurred. It would be preferable to identify potential carcinogenic substances at an earlier stage before they have caused a large number of
malignancies and thus become identifiable by epidemiology. During the past three decades, we have accumulated an impressive amount of evidence concerning molecular pathways that when altered contribute to malignant growth. It is time that we start applying this knowledge to the identification of human
carcinogens. Here, we review the molecular changes that are required for
carcinogenesis and propose some criteria that, in the absence of epidemiological evidence, can be used to identify agents that cause or contribute to human
cancer development. In the absence of epidemiological evidence, a given agent should be considered a human
carcinogen when: (1) the agent causes or contributes to the development of
tumors in animals that are of the same type as those
tumors associated with exposure to the agent in humans; (2) the agent transforms or contributes to the transformation of human cells in culture and these cells are of the same type from which associated human
malignancies arise; (3) there is molecular evidence that the agent interferes with one or more key molecular pathways in human cells which leads to the formation of human
cancer.