Identification of Liver Cancer Progenitors Whose Malignant Progression Depends on Autocrine IL-6 Signaling

Abstract

SUMMARY Hepatocellular carcinoma (HCC) is a slowly developing malignancy postulated to evolve from pre-malignant 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.

PBX3 is targeted by multiple miRNAs and is essential for liver tumour-initiating cells

“…Although exactly how TICs emerge remains elusive, accumulating evidence demonstrates that TICs may be the oncogenic derivatives of normal-tissue stem or progenitor cells, or arise from acquisition of stem cell properties by more differentiated cells as a result of transformation-associated genetic or epigenetic reprogramming [5][6][7][8][9][10] . Furthermore, recent studies indicate that CSC phenotypes can reversibly turn on and off spontaneously or with the variation of their microenvironment niches [11][12][13][14] .…”

β-Arrestin1 enhances hepatocellular carcinogenesis through inflammation-mediated Akt signalling

“…TNF-a is one of the most important proinflammatory factors with numerous biological properties, such as apoptosis, proliferation and differentiation, and it contributes to carcinogenesis in various inflammatory conditions such as chronic viral hepatitis as well as alcoholic and non-alcoholic fatty liver diseases [29][30][31] . Administration of DEN or CCl 4 to mice induces liver injury following hepatitis 6,27 . Experimentally, in DEN-or CCl 4 -induced mouse hepatitis models, inflammation enhances TNF-a to promote liver tumorigenesis 32 .…”

“…TNF-a, one of the most important proinflammatory cytokines, is produced predominantly by Kupffer cells and in part by neutrophils or hepatocytes during inflammatory responses; this cytokine is critical for maintenance of chronic inflammation 2 . The increased production of TNF-a may, in turn, augment the activation of inflammatory cells and mediate the release of inflammation factors, such as interleukin-1 (IL-1), IL-6 and intercellular adhesion molecule 6 . TNF-a has pleiotropic functions in inflammatory progression depending on cell type or biological context 7 .…”

Hepatocyte-specific Bid depletion reduces tumor development by suppressing inflammation-related compensatory proliferation

“…with 25 mg/kg BW DEN (Sigma-Aldrich, St. Louis, MO, USA). 38 Acute effects of DEN were studied using 8-week-old Bid Δhep and Bid flo/flo mice that were injected i.p. with 100 mg/kg BW DEN.…”