Reply to Bredberg: The voice of the whale

As stated in Bredberg's letter (1), most tumors are, indeed, monoclonal. This does not mean, however, that the neoplastic change occurs in a single step. It is now well recognized that tumors evolve by multiple genetic and epigenetic changes that affect regulatory pathways of cell division, apoptosis, and differentiation (2). Given that many pathways can change in a cancer-favoring direction, the fact that cancer affects only one-third of humanity is surprising. Multiple mechanisms must have evolved to nip incipient cancers in the bud. They include DNA repair and the triggering of apoptosis in cells with unrepaired DNA and in cells driven by illegitimate activation towards a proliferating mode.

These protective mechanisms are genetically variable. This explains part of the variation in cancer susceptibility. It fails to explain, however, why disseminated cancer cells so rarely grow into metastasis or why the same type of tumor, e.g., carcinoma of the prostate, remains latent in some patients and progresses in others.

As suggested in my article (3), systemic mechanisms may have evolved that inhibit the growth of incipient or disseminated neoplastic cells. They may act at the level of microenvironmental control. They may explain the low incidence of cancer in some feral strains of mice and in the rabbit and the guinea pig. If acting at the systemic level, as Bredberg's letter (1) asserts, they may have a similar impact in small and large animals, including the whale.