Peto's Paradox: evolution's prescription for cancer prevention

Abstract

The evolution of multicellularity required the suppression of cancer. If every cell has some chance of becoming cancerous, large, long-lived organisms should have an increased risk of developing cancer compared with small, short-lived organisms. The lack of correlation between body size and cancer risk is known as Peto's paradox. Animals with 1000 times more cells than humans do not exhibit an increased cancer risk, suggesting that natural mechanisms can suppress cancer 1000 times more effectively than is done in human cells. Because cancer has proven difficult to cure, attention has turned to cancer prevention. In this review, similar to pharmaceutical companies mining natural products, we seek to understand how evolution has suppressed cancer to develop ultimately improved cancer prevention in humans.

Figure 1. Alternative pathways to cancer hallmarks

(a) Assume that the ancestor of a large, long-lived organism has two pathways initiated by cytokines (triangles) such that if either one is disrupted the result is a hallmark of cancer. We illustrate this concept with cell proliferation; however this could be replaced with any of the hallmarks. A large organism could decrease its risk of cancer by evolving redundant copies of tumor suppressor genes (squares) (b) or by removing proto-oncogenes (circles) and tumor suppressor genes to eliminate an entire pathway (c) so that there are fewer carcinogenic loci in the genome that are vulnerable to mutation. This option might be constrained by selective pressures on the remaining pathways to produce the adaptive phenotypes that had been encoded in the deleted pathway.

Figure I. Estimated probability of colorectal cancer by age 90 based on the number of cells in the colon

The probability of getting colorectal cancer at a certain age was calculated with the equation p = 1-(1-(1-(1-u)^d)^k)^Nm [71] where u is the mutation rate per gene per division, d is the number of stem cell divisions since birth, k is the number of rate limiting mutations required for cancer to occur, N is the number of effective stem cells per crypt and m is the number of crypts per colon [71]. Parameter values are listed in Table S1. This shows that assuming all other parameters are equal, larger animals should have a much greater lifetime risk of cancer when compared to smaller organisms. Blue dots for mouse, human and whale indicate the estimated risk of colon cancer occurring within 90 years of life given the approximate number of cells in a human colon, 1,000 times fewer cells to represent the mouse, and 1,000 times more cells to represent the whale. The estimate for 1,000 times smaller than a human (e.g. a mouse) is still barely above zero even after 90 years. In reality, a mouse only lives a maximum of 4 years [35], so based on this equation they should never get colorectal cancer. The red dot indicates the lifetime risk of colon cancer according to the American Cancer Society which is about 5.3% for men and women averaged together [10].