Reduced incidence and delayed occurrence of fatal neoplastic diseases in growth hormone receptor/binding protein knockout mice

Abstract

Although studies of Ames and Snell dwarf mice have suggested possible important roles of the growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis in aging and age-related diseases, the results cannot rule out the possibility of other hormonal changes playing an important role in the life extension exhibited by these dwarf mice. Therefore, growth hormone receptor/binding protein (GHR/BP) knockout (KO) mice would be valuable animals to directly assess the roles of somatotropic axis in aging and age-related diseases because the primary hormonal change is due to GH/IGF-1 deficiency. Our pathological findings showed GHR/BP KO mice to have a lower incidence and delayed occurrence of fatal neoplastic lesions compared with their wild-type littermates. These changes of fatal neoplasms are similar to the effects observed with calorie restriction and therefore could possibly be a major contributing factor to the extended life span observed in the GHR/BP KO mice.

Figure 1.

Percentage of tumor-bearing mice in GHR/BP KO group and their WT littermates. The percentage of mice with tumor(s) per group (the tumor-bearing mice) is shown. GHR/BP = growth hormone receptor/binding protein; KO = knockout; WT = wild type.

Figure 2.

Tumor burden in GHR/BP KO mice and their WT littermates. The average number of different types of tumors in mice (the tumor burden) from each group is shown. The values for the tumor burden represent the mean ± SEM for 19 GHR/BP KO and 30 WT mice. GHR/BP = growth hormone receptor/binding protein; KO = knockout; WT = wild type. *The value was significantly different (p < .05) from that of WT mice.

Figure 3.

Mortality by neoplastic lesions in GHR/BP KO mice and their WT littermates. Kaplan–Meier survival curves for fatal neoplastic lesions in GHR/BP KO mice and their WT littermates are shown. GHR/BP = growth hormone receptor/binding protein; KO = knockout; WT = wild type.

Figure 4.

Severity of adenocarcinoma in GHR/BP KO mice and their WT littermates. The severity of adenocarcinoma was graded as follows: Grade 1, primary site only; Grade 2, primary site and intraorgan or one other organ metastasis; Grade 3, metastasis to two to three organs; and Grade 4, metastasis to more than four organs or Grade 3 + additional pathology, for example, pleural effusion, ascites, and subcutaneous edema. The average severity of adenocarcinoma in mice from each group is shown. GHR/BP = growth hormone receptor/binding protein; KO = knockout; WT = wild type. *The value was significantly different (p < .05) from that of WT mice.

Figure 5.

Severity of glomerulonephritis in GHR/BP KO mice and their WT littermates. The severity of the glomerulonephritis was scored using the criteria as follows: Glomerulonephritis was graded in the order of increasing severity: Grade 0, no lesions; Grade 1, minimal change in glomeruli (minimal glomerulosclerosis); Grade 2, Grade 1 with a few (less than 10) casts in renal tubules; Grade 3, Grade 1 with more than 10 casts in renal tubules; and Grade 4, Grade 3 with interstitial fibrosis. The average severity of glomerulonephritis in mice from each group is shown (a). *The value was significantly different (p < .05) from that of WT mice. (b) and (c) show the histopathology of kidney in GHR/BP KO (b: Grade 0) and WT (c: Grade 3) mice. GHR/BP = growth hormone receptor/binding protein; KO = knockout; WT = wild type.

Figure 6.

Disease burden in GHR/BP KO mice and their WT littermates. The average disease burden per mouse is the total number of pathological changes of any type found in individual mice from each group (a). The values for the disease burden represent the mean ± SEM for 19 GHR/BP KO and 30 WT mice (a). *The value was significantly different (p < .05) from that of WT mice. The disease burden of each mouse at death was also compared (b). The closed triangle and continuous line represent WT littermates, and the open circle and dashed line represent GHR/BP KO mice. The GHR/BP KO mice showed slower rates of accumulated histopathological changes than their WT littermates. GHR/BP = growth hormone receptor/binding protein; KO = knockout; WT = wild type.