Distinct pathways of genomic progression to benign and malignant tumors of the liver.

Distinct pathways of genomic progression to benign and malignant tumors of the liver. Research Abstract Details 

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Distinct pathways of genomic progression to benign and malignant tumors of the liver. Abstract Text:

Aaron D Tward,Kirk D Jones,Stephen Yant,Siu Tim Cheung,Sheung Tat Fan,Xin Chen,Mark A Kay,Rong Wang,J Michael Bishop,

We used several of the genetic lesions commonly associated with human liver tumors to reconstruct genetic progression to hepatocellular carcinoma and adenoma in mouse models. We initiated tumorigenesis with a transgene of the protooncogene MET or by hydrodynamic transfection of MET in combination with other genes into the livers of adult animals. Hepatocellular carcinoma in both instances arose from cooperation between MET and constitutively active versions of beta-catenin. In contrast, adenomas were produced by cooperation between MET and defective signaling through the transcription factor HNF1alpha. Prompted by these findings, we uncovered a coincidence between activation of the protein-tyrosine kinase encoded by MET and activating mutations of beta-catenin in a subset of human hepatocellular carcinomas. Inactivation of MET transgenes led to regression of hepatocellular carcinomas despite the persistence of activated beta-catenin. The tumors eventually recurred in the absence of MET expression, however, presumably after the occurrence of one or more events that cooperated with activated beta-catenin in lieu of MET. These results offer insight into hepatic tumorigenesis, provide mouse models that should be useful in the further study of hepatic tumorigenesis and for preclinical testing, and identify a subset of human hepatocellular carcinomas that may be susceptible to combination therapy directed against Met and the Wnt signaling pathway.

Distinct pathways of genomic progression to benign and malignant tumors of the liver. Publishing Authors By Initials

AD Tward,KD Jones,S Yant,ST Cheung,ST Fan,X Chen,MA Kay,R Wang,JM Bishop,

For similar proteins: armadillo domain proteins: beta catenin research abstracts see: proteins: armadillo domain proteins: beta catenin research

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Distinct pathways of genomic progression to benign and malignant tumors of the liver. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: Proceedings of the National Academy of Sciences of

VOLUME: 104

Page Numbers: 14771-6

Journal Abbreviation: Proc. Natl. Acad. Sci. U.S.A.

ISSN: 0027-8424

DAY: 4

MONTH: 09

YEAR: 2007

Distinct pathways of genomic progression to benign and malignant tumors of the liver. Information

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LANGUAGE: eng

NlmUniqueID: 7505876

Distinct pathways of genomic progression to benign and malignant tumors of the liver. Keywords Mesh Terms:

KEYWORDS: beta Catenin

MESH TERMS: genetics

Chemical & Substance for Abstract: Distinct pathways of genomic progression to benign and malignant tumors of the liver. Information

Substance Name: Proto-Oncogene Proteins c-met

Registry Number: EC 2.7.1.112

Grant and Affiliation Information for Distinct pathways of genomic progression to benign and malignant tumors of the liver.

AFFILIATION: G. W. Hooper Foundation and Department of Microbiology and Immunology, University of California, San Francisco, CA 94143, USA. atward@partners.org

Country: United States

AGENCY: United States PHS

GRANT: K01 096774

ACRONYM: DK

MEDLINETA: Proc Natl Acad Sci U S A

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