TY - JOUR

T1 - Notch signaling inhibits hepatocellular carcinoma following inactivation of the RB pathway

AU - Viatour, Patrick

AU - Ehmer, Ursula

AU - Saddic, Louis A

AU - Dorrell, Craig

AU - Andersen, Jesper Bøje

AU - Lin, Chenwei

AU - Zmoos, Anne-Flore

AU - Mazur, Pawel K

AU - Schaffer, Bethany E

AU - Ostermeier, Austin

AU - Vogel, Hannes

AU - Sylvester, Karl G

AU - Thorgeirsson, Snorri S

AU - Grompe, Markus

AU - Sage, Julien

PY - 2011/9/26

Y1 - 2011/9/26

N2 - Hepatocellular carcinoma (HCC) is the third cancer killer worldwide with >600,000 deaths every year. Although the major risk factors are known, therapeutic options in patients remain limited in part because of our incomplete understanding of the cellular and molecular mechanisms influencing HCC development. Evidence indicates that the retinoblastoma (RB) pathway is functionally inactivated in most cases of HCC by genetic, epigenetic, and/or viral mechanisms. To investigate the functional relevance of this observation, we inactivated the RB pathway in the liver of adult mice by deleting the three members of the Rb (Rb1) gene family: Rb, p107, and p130. Rb family triple knockout mice develop liver tumors with histopathological features and gene expression profiles similar to human HCC. In this mouse model, cancer initiation is associated with the specific expansion of populations of liver stem/progenitor cells, indicating that the RB pathway may prevent HCC development by maintaining the quiescence of adult liver progenitor cells. In addition, we show that during tumor progression, activation of the Notch pathway via E2F transcription factors serves as a negative feedback mechanism to slow HCC growth. The level of Notch activity is also able to predict survival of HCC patients, suggesting novel means to diagnose and treat HCC.

AB - Hepatocellular carcinoma (HCC) is the third cancer killer worldwide with >600,000 deaths every year. Although the major risk factors are known, therapeutic options in patients remain limited in part because of our incomplete understanding of the cellular and molecular mechanisms influencing HCC development. Evidence indicates that the retinoblastoma (RB) pathway is functionally inactivated in most cases of HCC by genetic, epigenetic, and/or viral mechanisms. To investigate the functional relevance of this observation, we inactivated the RB pathway in the liver of adult mice by deleting the three members of the Rb (Rb1) gene family: Rb, p107, and p130. Rb family triple knockout mice develop liver tumors with histopathological features and gene expression profiles similar to human HCC. In this mouse model, cancer initiation is associated with the specific expansion of populations of liver stem/progenitor cells, indicating that the RB pathway may prevent HCC development by maintaining the quiescence of adult liver progenitor cells. In addition, we show that during tumor progression, activation of the Notch pathway via E2F transcription factors serves as a negative feedback mechanism to slow HCC growth. The level of Notch activity is also able to predict survival of HCC patients, suggesting novel means to diagnose and treat HCC.

KW - Animals

KW - Carcinoma, Hepatocellular

KW - Cell Line

KW - Cell Proliferation

KW - E2F Transcription Factors

KW - Gene Expression Profiling

KW - Humans

KW - Liver Neoplasms

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Knockout

KW - Microarray Analysis

KW - Receptors, Notch

KW - Retinoblastoma Protein

KW - Signal Transduction

KW - Stem Cells

KW - Transcription, Genetic

U2 - 10.1084/jem.20110198

DO - 10.1084/jem.20110198

M3 - Journal article

C2 - 21875955

VL - 208

SP - 1963

EP - 1976

JO - The Journal of Experimental Medicine

JF - The Journal of Experimental Medicine

SN - 0022-1007

IS - 10

ER -