PMID- 10216129
OWN - NLM
STAT- MEDLINE
DCOM- 19990519
LR  - 20240513
IS  - 0270-9139 (Print)
IS  - 0270-9139 (Linking)
VI  - 29
IP  - 5
DP  - 1999 May
TI  - Overexpression of C-NEU and C-MET during rat liver cholangiocarcinogenesis: A 
      link between biliary intestinal metaplasia and mucin-producing 
      cholangiocarcinoma.
PG  - 1453-62
AB  - Based on limited but compelling immunohistochemical data demonstrating individual 
      overexpression of the tyrosine kinase growth factor receptors, c-erbB-2 and 
      c-met, in significant percentages of human cholangiocarcinoma (ChC), we 
      investigated if combined overexpression of both c-neu, the rat homologue of 
      c-erbB-2, and c-met, the receptor for hepatocyte growth factor/scatter factor 
      (HGF/SF), might represent a characteristic, early event associated with 
      furan-induced cholangiocarcinogenesis in rat liver. Specifically, through the use 
      of immunohistochemistry, in situ hybridization (ISH), and Western and Northern 
      blotting, we found that both c-neu and c-met are prominently overexpressed in 
      intestinal metaplastic lesions in early putative precancerous cholangiofibrotic 
      tissue formed in the livers of rats after 6 weeks of furan treatment when 
      compared with normal and hyperplastic intrahepatic biliary epithelia. We further 
      demonstrated that c-neu and c-met are concordantly overexpressed in neoplastic 
      glandular epithelia in later-developed primary "intestinal-type" of ChC formed in 
      the livers of furan-treated rats, as well as in subsequently derived 
      transplantable mucin-producing tumors. Overexpression of c-neu and c-met 
      correlated with increased proliferating cell nuclear antigen (PCNA)-labeling 
      indices, which were determined to be three to four times higher in intestinal 
      metaplastic glands in precancerous cholangiofibrotic tissue and in neoplastic 
      glands in the primary "intestinal type" of ChC than in hyperplastic bile ductular 
      structures within either cholangiofibrotic or bile duct-ligated (BDL) livers. The 
      c-neu and c-met receptor proteins overexpressed in different in vivo passages of 
      a transplantable ChC each contained immunoreactive phosphotyrosines, indicating 
      an activated state. However, we did not detect evidence of either gene 
      amplification of c-neu or c-met or of a common transmembrane-activating mutation 
      in c-neu expressed in transplantable ChC. Our findings indicate that altered 
      expression of c-neu and c-met occurs relatively early in the process of 
      furan-induced cholangiocarcinogenesis in rat liver and may play a potentially 
      important role in its pathogenesis. They further indicate a common alteration in 
      tyrosine kinase growth factor receptor expression linking early putative 
      precancerous intestinal metaplastic lesions in liver to later-developed 
      mucin-producing biliary cancer.
FAU - Radaeva, S
AU  - Radaeva S
AD  - Department of Pathology, Medical College of Virginia Campus of Virginia 
      Commonwealth University, Richmond, VA 23298-0297, USA.
FAU - Ferreira-Gonzalez, A
AU  - Ferreira-Gonzalez A
FAU - Sirica, A E
AU  - Sirica AE
LA  - eng
GR  - 5 R01 CA 39225/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Hepatology
JT  - Hepatology (Baltimore, Md.)
JID - 8302946
RN  - 0 (Furans)
RN  - 0 (Mucins)
RN  - 0 (Proliferating Cell Nuclear Antigen)
RN  - 0 (RNA, Messenger)
RN  - EC 2.7.10.1 (Proto-Oncogene Proteins c-met)
RN  - EC 2.7.10.1 (Receptor, ErbB-2)
RN  - UC0XV6A8N9 (furan)
SB  - IM
MH  - Animals
MH  - Bile Ducts/metabolism/pathology
MH  - Biliary Tract/pathology
MH  - Cholangiocarcinoma/chemically induced/*metabolism/pathology
MH  - Furans
MH  - In Situ Hybridization
MH  - Intestines/pathology
MH  - Liver/metabolism
MH  - Liver Neoplasms/chemically induced/*metabolism/pathology
MH  - Male
MH  - Metaplasia
MH  - Mucins/*biosynthesis
MH  - Neoplasm Transplantation
MH  - Proliferating Cell Nuclear Antigen/metabolism
MH  - Proto-Oncogene Proteins c-met/genetics/*metabolism
MH  - RNA, Messenger/metabolism
MH  - Rats
MH  - Rats, Inbred F344
MH  - Receptor, ErbB-2/genetics/*metabolism
MH  - Reference Values
EDAT- 1999/04/27 00:00
MHDA- 1999/04/27 00:01
CRDT- 1999/04/27 00:00
PHST- 1999/04/27 00:00 [pubmed]
PHST- 1999/04/27 00:01 [medline]
PHST- 1999/04/27 00:00 [entrez]
AID - S0270913999002232 [pii]
AID - 10.1002/hep.510290524 [doi]
PST - ppublish
SO  - Hepatology. 1999 May;29(5):1453-62. doi: 10.1002/hep.510290524.