title: Identification of liver cancer progenitors whose malignant progression depends on autocrine IL-6 signaling.
abstract: Hepatocellular carcinoma (HCC) is a slowly developing malignancy postulated to evolve from premalignant lesions in chronically damaged livers. However, it was never established that premalignant lesions actually contain tumor progenitors that give rise to cancer. Here, we describe isolation and characterization of HCC progenitor cells (HcPCs) from different mouse HCC models. Unlike fully malignant HCC, HcPCs give rise to cancer only when introduced into a liver undergoing chronic damage and compensatory proliferation. Although HcPCs exhibit a similar transcriptomic profile to bipotential hepatobiliary progenitors, the latter do not give rise to tumors. Cells resembling HcPCs reside within dysplastic lesions that appear several months before HCC nodules. Unlike early hepatocarcinogenesis, which depends on paracrine IL-6 production by inflammatory cells, due to upregulation of LIN28 expression, HcPCs had acquired autocrine IL-6 signaling that stimulates their in vivo growth and malignant progression. This may be a general mechanism that drives other IL-6-producing malignancies.
authors.affiliation: Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, University of California San Diego, School of Medicine, 9500 Gilman Drive, San Diego, CA 92093, USA.
authors.forename: Guobin
authors.initials: G
authors.lastname: He
authors.forename: Debanjan
authors.initials: D
authors.lastname: Dhar
authors.forename: Hayato
authors.initials: H
authors.lastname: Nakagawa
authors.forename: Joan
authors.initials: J
authors.lastname: Font-Burgada
authors.forename: Hisanobu
authors.initials: H
authors.lastname: Ogata
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Jiang
authors.forename: Shabnam
authors.initials: S
authors.lastname: Shalapour
authors.forename: Ekihiro
authors.initials: E
authors.lastname: Seki
authors.forename: Shawn E
authors.initials: SE
authors.lastname: Yost
authors.forename: Kristen
authors.initials: K
authors.lastname: Jepsen
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Frazer
authors.forename: Olivier
authors.initials: O
authors.lastname: Harismendy
authors.forename: Maria
authors.initials: M
authors.lastname: Hatziapostolou
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Iliopoulos
authors.forename: Atsushi
authors.initials: A
authors.lastname: Suetsugu
authors.forename: Robert M
authors.initials: RM
authors.lastname: Hoffman
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Tateishi
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Koike
authors.forename: Michael
authors.initials: M
authors.lastname: Karin
mesh_terms: D000818:Animals; D019898:Autocrine Communication; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D016174:Hepacivirus; D006526:Hepatitis C / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015850:Interleukin-6 / Q000378:metabolism*; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D014411:Neoplastic Stem Cells / Q000378:metabolism*
chemical_list: D015850:Interleukin-6