Reduced susceptibility to azoxymethane-induced aberrant crypt foci formation and colon cancer in growth hormone deficient rats
| Autor: | Terry G. Unterman, Aleksandra Jovanovic Poole, R A Goodlad, Steven M. Swanson, Angela L. Tyner, R. Brooks Robey, Robert E. Carroll |
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| Jazyk: | angličtina |
| Rok vydání: | 2009 |
| Předmět: |
Male
medicine.medical_specialty Colon Endocrinology Diabetes and Metabolism Azoxymethane Apoptosis medicine.disease_cause Article Rats Sprague-Dawley chemistry.chemical_compound Endocrinology Internal medicine medicine Animals Carcinogen TUNEL assay Chemistry Cell growth Molecular biology digestive system diseases Rats Growth Hormone Colonic Neoplasms Carcinogens Disease Susceptibility Carcinogenesis Bromodeoxyuridine Aberrant crypt foci |
| Popis: | Objectives To evaluate the role of GH in colon carcinogenesis, we examined the formation of aberrant 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 quantified by stereomicroscopy and tumor number and weights were recorded for each animal. Cell proliferation was measured by vincristine metaphase arrest, flow cytometry, and bromodeoxyuridine (BrdU) incorporation. Apoptosis was measured by TUNEL staining and cleaved caspase-3 immunohistochemistry. IGF-I was measured by radioimmunoassay (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 reduced (∼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 on colon ACF and tumor development, and that the SDR rat is a promising model for studies regarding the role ofGH/IGF system in the initiation and promotion of colon cancer. |
| Databáze: | OpenAIRE |
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