ABSTRACT
Increased plasma IGF-1 has consistently been associated with a variety of human cancers, whereas reduced levels of IGF-1 are associated with increased lifespan in other species. However, the aforementioned relationships are correlational or are derived from animal models that are not specific for growth hormone/IGF-1 excess or deficiency. This study was designed to assess the effects of physiological changes in growth hormone and IGF-1 expression on dimethylbenzanthracine (DMBA)-induced mammary carcinogenesis. At 50 days of age, female heterozygous (dw/+) and growth hormone deficient dwarf (dw/dw) rats of the Lewis strain received a single dose of DMBA (80 micro g/g of body weight) via oral gavage. Animals were assigned to one of four experimental groups: a) heterozygous animals (normal size), b) dwarf animals administered vehicle, c) dwarf animals administered low levels of porcine growth hormone (50 micro g twice daily), and d) dwarf animals administered high levels of porcine growth hormone (200 micro g twice daily). At study termination, heterozygous animals exhibited a 70% incidence of mammary tumors, whereas no tumors were observed in saline-treated dwarf animals. Administration of either 100 micro g or 400 micro g growth hormone/day resulted in a dose dependent increase in incidence of mammary tumors (83 and 100%, respectively). Furthermore, heterozygous animals exhibited 1.5 +/- 0.25 tumors per tumor-bearing animal, whereas dwarf animals administered 100 micro g and 400 micro g growth hormone per day had 1.9 +/- 0.63 and 3.4 +/- 0.83 tumors per animal, respectively. The present study demonstrates that DMBA-induced carcinogenesis is dependent on critical plasma levels of growth hormone and IGF-1, and that growth hormone/IGF-1 deficient animals are resistant to DMBA-induced carcinogenesis.
Subject(s)
9,10-Dimethyl-1,2-benzanthracene , Carcinogens , Dwarfism/immunology , Dwarfism/metabolism , Growth Hormone/deficiency , Mammary Neoplasms, Experimental/chemically induced , Animals , Dwarfism/genetics , Female , Heterozygote , Immunity, Innate , Insulin-Like Growth Factor I/deficiency , Rats , Rats, Inbred Lew , Reference ValuesABSTRACT
The remarkable progress in understanding the genetic basis of life-span determination in invertebrates indicates that impairments in the insulin-insulin-like growth factor 1 (IGF-1) signaling cascade increase longevity. Similarities among insulin and IGF-1-like signaling pathways in invertebrates and mammals raise the possibility that modifications of these pathways may extend life span in mammals. Investigators using Ames, Snell, and growth hormone receptor knockout models have concluded that decreased growth hormone and IGF-1 are responsible for increased life span. In this review, we critique the dwarf models and, based on multiple endocrine deficiencies and developmental anomalies, conclude that these models may not be sufficient to assess the consequences of growth hormone or IGF-1 deficiency on either biological aging or life span. We attempt to resolve some of these issues by presenting an alternative animal model of growth hormone-IGF-1 deficiency. Finally, we propose an integrated explanation of growth hormone and IGF-1's contribution to the aging phenotype and life-span determination.
