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Targeting mTOR signaling for the prevention of progenitor‐derived hepatocellular carcinoma
Author(s) -
Sanders Jennifer A,
Brilliant Kate,
Francois Heather,
Mills David
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.872.7
Subject(s) - mtorc1 , progenitor cell , cancer research , pi3k/akt/mtor pathway , progenitor , carcinogenesis , hepatocellular carcinoma , biology , sirolimus , signal transduction , stem cell , microbiology and biotechnology , cancer , genetics , biochemistry
Progenitor cell activation occurs under conditions of severe liver injury and a subset of hepatocellular carcinomas (HCC) express progenitor cell markers. However, the signaling pathways involved in the initiation and progression of progenitor‐derived HCC have not been characterized. The objective of the present study was to characterize the effect of mTOR inhibition on the development and progression of progenitor‐marker positive hepatocellular carcinoma in an established rodent model. mTOR signaling was robustly activated during the early stages of preneoplastic foci development. However, activation of this pathway waned during the progression to persistent foci. To assess the functional role of mTORC1 in foci development and progression, the effect of the mTORC1 inhibitor, rapamycin, was studied. Rapamycin administration decreased the size of preneoplastic foci and the rate of cell proliferation within the foci at both early and late time points. These studies reveal a critical role for mTORC1 in the initiation of carcinogenesis therefore rapamycin may be an effective chemopreventative agent for progenitor‐derived HCC.