Peto's Paradox and the evolution of cancer suppression

Aleah Caulin, University of Pennsylvania

Cancer is a consequence of multicellularity. Multicellular organisms must control their somatic cell growth in order to maintain homeostasis within the body. Thus, tumor suppression mechanisms had to evolve to ensure the success of multicellular life. The challenge of suppressing cancer dramatically increases with larger bodies and longer lifespans. Based on the probability of carcinogenesis for an individual cell, we expect lifetime risk of cancer to scale with body size and lifespan. The fact that this expected correlation has not been observed empirically is known as Peto's Paradox. Cancer rates across multicellular animals only vary on the order of two-fold even though animal sizes vary by a million-fold. The general explanation for this is that large, long-lived animals are somehow more resistant to carcinogenesis than small, short-lived animals. How they accomplish this cancer suppression has yet to be elucidated. We have begun to test hypotheses to resolve Peto's Paradox. We have computationally analyzed the copy number of cancer-associated genes across mammals of various sizes and have explored an analytical model of colorectal cancer in order to understand what parameter space allows – for example, for a mouse, human and whale to have roughly the same lifetime risk of cancer. In the future, the analytical model will be supplemented with a high-performance computational model of carcinogenesis that can take into account spatial interactions and the inherent dependencies between related cells in a tumor as it evolves. Understanding how large, long-lived organisms suppress cancer may provide the foundation for improved cancer prevention in humans.

Abstract Author(s): Aleah F. Caulin, Shane T. Jensen, Carlo C. Maley