Editors' ChoiceCancer

The importance of staying small

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Science Translational Medicine  08 Mar 2017:
Vol. 9, Issue 380, eaam9860
DOI: 10.1126/scitranslmed.aam9860

Abstract

Long-lived and cancer-resistant adult dwarf rodents have enhanced DNA repair capacity due to decreased GH/IGF-1 signaling during peripubertal development.

Dietary and hormonal status during the formative peripubertal period of development have lasting impacts on cancer susceptibility, metabolism, and life expectancy, a paradigm known as the Developmental Origins of Health and Disease (DOHAD). Humans with growth hormone (GH) insensitivity due to mutations in growth hormone receptor (GHR), referred to as Laron syndrome, have short stature but are resistant to the development of diabetes and cancer during adulthood. Likewise, rodents lacking GH/IGF-1 signaling due to improper development of the anterior pituitary are smaller than their wild-type counterparts but display increased cancer resistance, metabolic fitness, and extreme longevity. Early life and peripubertal GH supplementation of these dwarf rodents greatly diminishes these health benefits in adulthood. Despite the dramatic changes in life span and health status of these animals, the anticancer contributions of decreased GH/IGF-1 signaling during the period surrounding sexual maturation are not well understood.

A key factor of cancer development is the accumulation of DNA mutations resulting in aberrant expression or activity of tumor suppressors and oncogenes. Boosting DNA repair efficiency and cellular resistance under stress is a potent mechanism to prevent oncogenesis. In a study by Podlutsky et al., the authors determined the molecular mechanisms behind cellular stress resistance and tumor development in the cells of GH-deficient rodents. The authors found that cultured primary fibroblasts from these long-lived animals had increased DNA repair capacity after exposure to ionizing radiation–induced damage compared with their wild-type counterparts. Importantly, treatment with GH in early life abolished this phenotype, but inducing GH/IGF-1 signaling in later adulthood had no effect on DNA repair capacity. Mechanistically, the lack of GH/IGF-1 signaling during the peripubertal period increased the basal and ionizing radiation–induced expression of critical DNA repair and stress response genes.

This study provides functional and molecular evidence for the increase in cellular stress resistance found in GH/IGF-1 signaling-deficient dwarf rodents and helps explain the extraordinary cancer resistance and longevity in these animals. It also shows the need for future studies examining how dietary and hormonal status during a short, but critical, period in young people’s lives can permanently change their future health and well-being.

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