Hypersensitivity to contact inhibition provides a clue to cancer resistance of naked mole-rat

Abstract

The naked mole-rat is the longest living rodent with a maximum lifespan exceeding 28 years. In addition to its longevity, naked mole-rats have an extraordinary resistance to cancer as tumors have never been observed in these rodents. Furthermore, we show that a combination of activated Ras and SV40 LT fails to induce robust anchorage-independent growth in naked mole-rat cells, while it readily transforms mouse fibroblasts. The mechanisms responsible for the cancer resistance of naked mole-rats were unknown. Here we show that naked mole-rat fibroblasts display hypersensitivity to contact inhibition, a phenomenon we termed ''early contact inhibition.'' Contact inhibition is a key anticancer mechanism that arrests cell division when cells reach a high density. In cell culture, naked mole-rat fibroblasts arrest at a much lower density than those from a mouse. We demonstrate that early contact inhibition requires the activity of p53 and pRb tumor suppressor pathways. Inactivation of both p53 and pRb attenuates early contact inhibition. Contact inhibition in human and mouse is triggered by the induction of p27 Kip1 . In contrast, early contact inhibition in naked mole-rat is associated with the induction of p16 Ink4a . Furthermore, we show that the roles of p16 Ink4a and p27 Kip1 in the control of contact inhibition became temporally separated in this species: the early contact inhibition is controlled by p16 Ink4a , and regular contact inhibition is controlled by p27 Kip1 . We propose that the additional layer of protection conferred by two-tiered contact inhibition contributes to the remarkable tumor resistance of the naked mole-rat.longevity ͉ p16Ink4a ͉ p53 ͉ pRb ͉ tumor suppressor

Molecular evolution of the hyaluronan synthase 2 gene in mammals: implications for adaptations to the subterranean niche and cancer resistance

“…This is a process whereby cell growth occurring when cells come into contact with each other, or with the extracellular matrix, is arrested at much lower densities than in the mouse. Contact inhibition is lost in cancer cells, and the loss of ECI makes cells more susceptible to malignant transformation [6]. ECI is controlled by the interaction of HA with the CD44 -NF2 pathway, which mediates contact inhibition [3].…”

Cancer resistance in the blind mole rat is mediated by concerted necrotic cell death mechanism

“…Naked mole rat cells proliferate slowly in culture and display hypersensitivity to contact inhibition (14). Abrogation of ECI makes naked mole rat cells more prone to malignant transformation.…”

“…Our previous studies of another long-lived subterranean rodent, the naked mole rat (Heterocaphalus glaber), identified a novel anticancer mechanism termed early contact inhibition (ECI) (14). Naked mole rat cells proliferate slowly in culture and display hypersensitivity to contact inhibition (14).…”

Annals of morphology. Atavisms: Phylogenetic lazarus?

“…According to Hartl et al [2010] the protein product Myc of the cellular c-myc proto-oncogene is the central part of a cellular transcription regulator network controlling expression of about 15% of all human genes involved in cell growth, proliferation, differentiation, metabolism, and apoptosis, and that deregulation of c-myc gene with increased levels of myc occurs in about 30% of all human cancers. Davies and Lineweaver [2011] consider cancer an "atavistic condition" due to genetic/epigenetic malfunction that "unlocks" (derepresses) an $1 BY-old ancient "tool kit" of pre-existing adaptations, re-establishing dominance of an earlier layer of genes that controlled loose-knit colonies of partially differentiated cells -"similar to tumors," cancer then being an actual or potential burden of all metazoans in whom adult cells proliferate, except perhaps for the naked mole rat [Suluanov et al, 2009].…”