Abstract
According to Berenblum’s two-stage hypothesis, the first stage in carcinogenesis is the production of benign premalignant lesions. Between this initiation stage and the formation of a malignant tumor there is often a long lag phase. We propose that this lag is caused by the delay in the formation of a new and rare tumor-specific antigen, which induces an immune response that stimulates tumor growth. Such tumor-specific antigens could arise as a result of a mutator-like phenotype, which is supposedly present in the benign initial stage of carcinogenesis. According to this hypothesis, the first stage lesion provides a weakly mutagenic environment conducive to the formation of the new antigen(s). If no such new antigens appear so there is no consequent immune response, it is argued that carcinogenesis would seldom if ever ensue.
Highlights
The phenomenon upon which this discussion is based is nicely summarized in a paper by Brash and Cairns [1], a short section of which is reproduced here: “
The incidence of lung cancer in smokers appears to be directly proportional to the number of cigarettes smoked per day [2], it is proportional to roughly the sixth power of the duration of smoking
When rats are continuously exposed to dietary carcinogens their incidence of cancer rises as the first or second power of dose rate but as a much higher power of time [3,4] . . . smokers keep their raised rate of lung cancer for many years after they have stopped smoking [5] . . . These numerous experiments suggest, that mutagenic carcinogens cause just one or two events and these are followed by steps that accumulate solely with the passage of time, driven perhaps by cell division [6]. . .”
Summary
The phenomenon upon which this discussion is based is nicely summarized in a paper by Brash and Cairns [1], a short section of which is reproduced here: “. In the present paper we review the probability that the frequently observed time lag in carcinogenesis is caused by the delay in the formation of a new tumor-specific antigen that, in turn, induces a tumor-stimulating immune response [7]. This tumorspecific antigen is postulated to arise as a result of a mutator-like phenotype that we postulate exists in the benign first stage of the carcinogenic mechanism [7,8]. We have previously published evidence suggesting that the primary role of the immune reaction in carcinogenesis is to stimulate rather than to inhibit cancer growth [15]. Perhaps one could inhibit tumor growth by drastically reducing the immune reaction
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