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


METHODS
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 ( approximately 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 of GH/IGF system in the initiation and promotion of colon cancer.
Carroll
Robert E
RE
Department of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA. rcarroll@uic.edu
Goodlad
Robert A
RA
Poole
Aleksandra J
AJ
Tyner
Angela L
AL
Robey
R Brooks
RB
Swanson
Steven M
SM
Unterman
Terry G
TG
D000818:Animals; D017209:Apoptosis; D001397:Azoxymethane / Q000633:toxicity*; D002273:Carcinogens / Q000633:toxicity*; D003106:Colon / Q000473:pathology*; D003110:Colonic Neoplasms / Q000139:chemically induced* / Q000473:pathology; D004198:Disease Susceptibility; D013006:Growth Hormone / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley
D002273:Carcinogens; D013006:Growth Hormone; D001397:Azoxymethane