Reduced susceptibility to azoxymethane-induced aberrant crypt foci formation and colon cancer in growth hormone deficient rats

Objectives TO evaluate the role of GH in colon carcinogenesis, we examined the formation of aberiant crypt foci (ACFs) and tumor development in wild type (WT) and GH-deficient, spontaneous dwarf rats (SDRs) exposed to the carcinogen azoxymethane (AOM) Design: ACF were quanitfied by stereomicroscopy and tumor number and weights were recorded for each animal Cell proliferation Was measured by vincristine metaphase arrest. flow cytometry, and biomodeoxymidine (BidU) incorporation Apoptosis was measured by TUNEL staining and cleaved caspase-3 immunohistochemistry IGF-I was measured by radioimmunoassy (RIA) Hexokinase activity was measured by spectrophotometric assay. PARP cleavage. and IGF-IR, and p27(kip/cip) expression were measured by Western blotting. Results ACFs detected by stereomicroscopy were markedly induced (similar to 85%) in SDRs vs WT rats at 10, 25, and 28 weeks after AOM Tumor incidence, number, and weight also were reduced in SDR vs. WT animals AOM treatment increased cell proliferation in the distal colon (where tumors occur) of WT rats but not SDRs, and these changes corresponded to increased ACF and tumor formation Apoptosis rates were similar in AOM-treated WT and SDRs Alterations in serum IGF-I levels may contribute to differences in the proliferative response to AOM and decreased ACF formation in SDR vs WT rats Conclusions We conclude that early neoplastic lesions (ACFs) were reduced in GH-deficient animals This effect corresponds with differences in AOM-induced proliferation, but not apoptosis These data indicate that GH is required for the full effect of AOM oil colon ACF and tumor development. and that the SDR rat is a promising model for studies regarding the role of GH/IGF system in the initiation and promotion of colon cancer Published by Elsevier Ltd