Mechanisms of cancer resistance in long-lived mammals

Abstract

Cancer researchers have traditionally used the mouse and the rat as staple model organisms. These animals are very short-lived, reproduce rapidly and are highly prone to cancer. They have been very useful for modelling some human cancer types and testing experimental treatments; however, these cancer-prone species offer little for understanding the mechanisms of cancer resistance. Recent technological advances have expanded bestiary research to non-standard model organisms that possess unique traits of very high value to humans, such as cancer resistance and longevity. In recent years, several discoveries have been made in non-standard mammalian species, providing new insights on the natural mechanisms of cancer resistance. These include mechanisms of cancer resistance in the naked mole rat, blind mole rat and elephant. In each of these species, evolution took a different path, leading to novel mechanisms. Many other long-lived mammalian species display cancer resistance, including whales, grey squirrels, microbats, cows and horses. Understanding the molecular mechanisms of cancer resistance in all these species is important and timely, as, ultimately, these mechanisms could be harnessed for the development of human cancer therapies.

Figure 1. Evolution of anticancer mechanisms shaped by lifespan and body mass

(a) As species evolve a large body mass, their cancer risk increases due to the greater number of cells in the body that may acquire oncogenic mutations. To counteract this risk, large-bodied species, with body mass greater than 10 kg, evolved repression of somatic telomerase activity and replicative senescence as an additional tumor suppressor mechanism. Replicative senescence represents a late-acting barrier for tumor progression, since it allows the formation of small tumors prior to the activation of the telomere checkpoint. A long lifespan also increases the risk of cancer, and small (body mass less than 5 kg), long-lived species, which cannot tolerate the formation of small tumors, evolve telomere-independent tumor suppressor mechanisms. These mechanisms offset hyperplasia and manifest in slow cell proliferation in vitro. (b) Small- and large-bodied animals have a different tolerance to tumor size. Mouse and capybara are drawn to scale with a 3 g tumor. Such a tumor would likely affect fitness of a 30 g mouse but would be inconsequential for a 55 kg capybara. Part a reproduced with permission from Ref. , 2008 Seluanov, A. et al. Aging Cell © Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland 2008.

Figure 2. Anticancer mechanisms in the naked mole rat

Naked mole rat cells and tissues produce large quantities of high molecular mass hyaluronan (HMM-HA). HMM-HA interacts with CD44 receptors and triggers early contact inhibition (ECI) of naked mole rat fibroblasts via activation of p16^INK4A or the naked mole rat specific product of the INK4 locus, pALT. ECI provides protection from cancer by arresting the cell cycle at a low cell density and preventing hyperplasia. HMM-HA may also provide protection from metastasis by maintaining a stronger extracellular matrix. HMM-HA also acts as an antioxidant thereby reducing reactive oxygen species (ROS)-induced damage to nucleic acids and proteins. In addition, naked mole rats have a more stable epigenome than mouse cells, which can resist reprogramming by Yamanaka factors (Oct4, Sox2, Klf4 and Myc) and may similarly resist reprogramming associated with malignant transformation. Furthermore, naked mole rat cells have a unique ability to ‘sense’ the loss of a single tumor suppressor such as p53, RB or p19^ARF and undergo apoptosis or senescence.

Figure 3. Anticancer mechanisms in the blind mole rat

In response to hyperplasia caused by hyper-proliferation of cells in vitro or carcinogens in vivo, blind mole rat cells secrete interferon β (IFN β) that triggers concerted cell death by necrotic and apoptotic mechanisms. Concerted cell death serves as an efficient way to eliminate pre-malignant hyperplastic cells. Additionally, similarly to the naked mole rat, blind mole rat cells secrete abundant high molecular mass hyaluronan (HMM-HA). However, unlike naked mole rat cells, the blind mole rat cells do not display early contact inhibition (ECI). HMM-HA in the blind mole rat may contribute to cancer resistance by protecting the cells from reactive oxygen species (ROS)-induced damage. Blind mole rats express a dominant negative splice variant of heparanase that, together with HMM-HA, may contribute to stronger extracellular matrix (ECM) and prevent tumor growth and metastasis.

Figure 4. Anticancer mechanisms in the largest mammals, elephants and whales

Large animals have more cells in their bodies and statistically have a higher risk of developing malignancy. However, in reality, cancer incidence does not increase with the body mass of a species. This is because large animals have evolved additional tumor suppressor mechanisms. Elephants have evolved multiple copies of the TP53 gene (pseudogenes) that are associated with an increased apoptotic response. Anticancer mechanisms in the largest mammals, whales, are not yet known, but they do not involve TP53 duplications.

Figure 5. Developing anticancer treatments based on naturally evolved cancer resistance

Cancer resistance has evolved multiple times in mammals. Species that display cancer resistance include the largest mammals such as whales and elephants, subterranean long-lived mammals (the naked mole rat and the blind mole rat), long-lived squirrels and bats. The specific mechanisms differ and were shaped by species ecology, lifestyle, and body characteristics. These mechanisms are beginning to be understood. The known mechanisms include duplications of the TP53 gene in elephants, overproduction of high molecular mass hyaluronan (HMM-HA) in the naked mole rat, interferon-mediated concerted cell death in the blind mole rat, and reduced growth hormone (GH)–insulin-like growth factor 1 (IGF1) signaling and microRNA (miRNA) changes in bats. Once the molecular underpinnings of these mechanisms have been identified, they can be engineered in mice. For example, mice overexpressing the naked mole rat hyaluronan synthase gene can be generated. If these mouse models then show improved tumor resistance, pharmacological interventions can be developed to mimic the anticancer adaptations from cancer-resistant species in human patients. Question marks indicate anticancer adaptations for which the exact molecular mechanisms are unknown.