Large mammals must evolve efficient ways to suppress cancer in order to become large. Being large means having more cells, any of which could undergo potentially cancerous mutations. In order for cetaceans such as the large whales to exist at all, they must employ much more effective anti-cancer strategies than those found in humans. If we can identify those strategies, then perhaps they might form the basis for novel cancer therapies. Given the state of this research, it is still too early to say whether this is a plausible near future opportunity, or whether it will turn out to require to great a degree of biological engineering to accomplish over the next few decades.
Despite the generally increased cancer risk in large, long-lived organisms, cetaceans, among the largest and longest-living mammals, appear to possess a counteracting mechanism. Nevertheless, the genetic basis underlying this mechanism remains poorly understood. The p53 pathway serves as an ideal target for studying the mechanisms behind cancer resistance, as most cancer types have evolved strategies to circumvent its suppressive functions. Here, comparative genetic analysis of 73 genes involved in the p53 pathway in cetaceans was undertaken to explore the potential anticancer mechanisms behind natural longevity.
Results showed that long-lived species contained three positively selected genes (APAF1, CASP8, and TP73) and three duplicated genes (IGFBP3, PERP, and CASP3) related to apoptosis regulation. Additionally, the evolutionary rates of three genes associated with angiogenesis (SERPINE1, CD82, and TSC2) showed a significant relationship with longevity quotient (LQ) and maximum lifespan (MLS), suggesting angiogenesis inhibition as another potential strategy protecting cetaceans from cancer. Interestingly, several positively selected tumor suppressor genes with high copy numbers were correlated with body size in the large-bodied and long-lived cetacean lineages, corroborating Peto's paradox, which posits no link between cancer incidence and body size or longevity across species.
In conclusion, we identified several candidate genes that may confer cancer resistance in cetaceans, providing a new avenue for further research into the mechanisms of lifespan extension.