Finding new tumor suppressor mechanisms
Animal lineages have evolved a diverse array of tumor suppressor mechanisms. Some of these mechanisms are conserved, while others are unique and are shaped by the species’ lifestyle and ecology. What then might be the strategies to identify such unique mechanisms? First, one can start with a long-lived and/or cancer resistant species. Next, establish cultures of primary cells from this species and observe the behavior of the cells and propensity for malignant transformation. One can try to introduce the known sets of mutational ‘hits’ into these cells such as inactivation of tumor suppressors and activation of oncogenes to see if additional hits, beyond what is known from human and mouse studies, are required for tumor formation. However, this strategy may override the unique mechanisms or result in tumor suppressive strategies that act upstream of the known tumor suppressors being overlooked. For example, in a species with extremely accurate DNA repair, mutational hits would not occur naturally and the forced inactivation of tumor suppressors would still lead to malignancy.
Another way to find novel tumor suppressor mechanisms is harder to define; one has to observe cell behavior and look for anything unusual. For example, this is how we found early contact inhibition (ECI) in the naked mole rat and concerted cell death (CCD) in the blind mole rat. Once the unique cellular phenotype is found, one can proceed to identify its molecular underpinnings. In addition to intrinsic cellular mechanisms, cancer resistant species may possess systemic mechanisms of tumor suppression, such as more efficient elimination of malignant cells by the immune system. Identification of such mechanisms is an exciting new avenue that requires working with the whole animal and maintaining animal colonies.
Mice and rats are staple models for cancer research. These animals are easy to maintain and are highly susceptible to cancer. Mouse genetic models have provided spectacular advances in our understanding of the process of tumorigenesis. However, mice and rats have less to offer for understanding the mechanisms of cancer resistance. In this Opinion article, we will discuss the progress achieved in identifying mechanisms of cancer resistance in ‘unconventional’ model organisms for cancer research. We argue that the studies of long-lived and cancer-resistant species of animals have the potential to bring about breakthroughs in cancer therapy and prevention. Studying these unconventional animal models may be less convenient, but ultimately very rewarding.
