TY - JOUR
T1 - Cell proliferation and regulation of negative growth factors in mouse liver foci
AU - Moser, Glenda J.
AU - Wolf, Douglas C.
AU - Harden, Rebekah
AU - Standeven, Andrew M.
AU - Mills, Jeremy
AU - Jirtle, Randy L.
AU - Goldsworthy, Thomas L.
PY - 1996/9/1
Y1 - 1996/9/1
N2 - Foci of altered hepatocytes are preneoplastic lesions capable of progressing to hepatocellular carcinomas. To characterize the growth of preneoplastic hepatic lesions, size of hepatic foci was analyzed with regard to growth factor regulation and hepatocyte proliferation in focal and non-focal hepatocytes. Twelve-day-old female B6C3F1 mice were initiated with a single dose of the potent mutagen N-nitrosodiethylamine (DEN) (5 mg/kg body weight). Beginning at 6 weeks of age, mice were exposed for 16 weeks to 2038 p.p.m. unleaded gasoline (UG) vapor or 1 p.p.m. ethinyl estradiol (EE) in the diet. Analysis of hepatic foci demonstrated that UG significantly increased, but EE significantly decreased the size of DEN-initiated foci. Hepatic labeling index (LI), as measured by the incorporation of 5-bromo-2'-deoxyuridine, was similar in non-focal hepatocytes at 16 weeks in all groups (0.4-0.8%) and greatly increased in hepatic foci. Hepatocyte LI was significantly increased in DEN/UG foci (29%, n = 41) and significantly decreased in DEN/EE foci (6%, n = 23) relative to DEN/control focal hepatocytes (18%, n = 25). The mean LI of foci correlated with the focal size differences observed in the treatment groups. Immunohistochemical analysis with antibodies directed to the negative growth regulator transforming growth factor-beta1 (TGF-β1) demonstrated a consistent decrease of TGF-β1 in DEN/Ct and DEN/UG hepatic foci relative to non-lesion hepatocytes. Similar results were seen with mannose 6-phosphate/insulin-like growth factor-II receptor (M6P/IGF-II R), which facilitates activation of latent TGF β1. In contrast, only 50% of DEN/EE foci had decreased levels of TGF-β1 and M6P/IGF-II R relative to non-focal hepatocytes. These data suggest that proliferative responses observed in hepatic foci may be correlated with foci size. In contrast, chemically induced proliferative responses in non-focal hepatocytes after subchronic exposure cannot necessarily be used to predict proliferative effects in preneoplastic cell populations. Furthermore, these studies suggest that hepatic foci may occur by M6P/IGF-II R enhancing activation of latent TGF-β1 in non-focal hepatocytes but not in the focal hepatocytes, thereby affording focal hepatocytes a selective growth advantage.
AB - Foci of altered hepatocytes are preneoplastic lesions capable of progressing to hepatocellular carcinomas. To characterize the growth of preneoplastic hepatic lesions, size of hepatic foci was analyzed with regard to growth factor regulation and hepatocyte proliferation in focal and non-focal hepatocytes. Twelve-day-old female B6C3F1 mice were initiated with a single dose of the potent mutagen N-nitrosodiethylamine (DEN) (5 mg/kg body weight). Beginning at 6 weeks of age, mice were exposed for 16 weeks to 2038 p.p.m. unleaded gasoline (UG) vapor or 1 p.p.m. ethinyl estradiol (EE) in the diet. Analysis of hepatic foci demonstrated that UG significantly increased, but EE significantly decreased the size of DEN-initiated foci. Hepatic labeling index (LI), as measured by the incorporation of 5-bromo-2'-deoxyuridine, was similar in non-focal hepatocytes at 16 weeks in all groups (0.4-0.8%) and greatly increased in hepatic foci. Hepatocyte LI was significantly increased in DEN/UG foci (29%, n = 41) and significantly decreased in DEN/EE foci (6%, n = 23) relative to DEN/control focal hepatocytes (18%, n = 25). The mean LI of foci correlated with the focal size differences observed in the treatment groups. Immunohistochemical analysis with antibodies directed to the negative growth regulator transforming growth factor-beta1 (TGF-β1) demonstrated a consistent decrease of TGF-β1 in DEN/Ct and DEN/UG hepatic foci relative to non-lesion hepatocytes. Similar results were seen with mannose 6-phosphate/insulin-like growth factor-II receptor (M6P/IGF-II R), which facilitates activation of latent TGF β1. In contrast, only 50% of DEN/EE foci had decreased levels of TGF-β1 and M6P/IGF-II R relative to non-focal hepatocytes. These data suggest that proliferative responses observed in hepatic foci may be correlated with foci size. In contrast, chemically induced proliferative responses in non-focal hepatocytes after subchronic exposure cannot necessarily be used to predict proliferative effects in preneoplastic cell populations. Furthermore, these studies suggest that hepatic foci may occur by M6P/IGF-II R enhancing activation of latent TGF-β1 in non-focal hepatocytes but not in the focal hepatocytes, thereby affording focal hepatocytes a selective growth advantage.
UR - http://www.scopus.com/inward/record.url?scp=0029789688&partnerID=8YFLogxK
U2 - 10.1093/carcin/17.9.1835
DO - 10.1093/carcin/17.9.1835
M3 - Article
C2 - 8824503
AN - SCOPUS:0029789688
SN - 0143-3334
VL - 17
SP - 1835
EP - 1840
JO - Carcinogenesis
JF - Carcinogenesis
IS - 9
ER -