Angiogenin Secretion From Hepatoma Cells Activates Hepatic Stellate Cells To Amplify A Self-Sustained Cycle Promoting Liver Cancer

Abstract

Hepatocellular carcinoma (HCC) frequently develops in a pro-inflammatory and pro-fibrogenic environment with hepatic stellate cells (HSCs) remodeling the extracellular matrix composition. Molecules secreted by liver tumors contributing to HSC activation and peritumoral stromal transformation remain to be fully identified. Here we show that conditioned medium from HCC cell lines, Hep3B and HepG2, induced primary mouse HSCs transdifferentiation, characterized by profibrotic properties and collagen modification, with similar results seen in the human HSC cell line LX2. Moreover, tumor growth was enhanced by coinjection of HepG2/LX2 cells in a xenograft murine model, supporting a HCC-HSC crosstalk in liver tumor progression. Protein microarray secretome analyses revealed angiogenin as the most robust and selective protein released by HCC compared to LX2 secreted molecules. In fact, recombinant angiogenin induced in vitro HSC activation requiring its nuclear translocation and rRNA transcriptional stimulation. Moreover, angiogenin antagonism by blocking antibodies or angiogenin inhibitor neomycin decreased in vitro HSC activation by conditioned media or recombinant angiogenin. Finally, neomycin administration reduced tumor growth of HepG2-LX2 cells coinjected in mice. In conclusion, angiogenin secretion by HCCs favors tumor development by inducing HSC activation and ECM remodeling. These findings indicate that targeting angiogenin signaling may be of potential relevance in HCC management.

Stromal fibroblast growth factor 2 reduces the efficacy of bromodomain inhibitors in uveal melanoma

“…Mice bearing UM001 xenograft tumors following subcutaneous injection of UM001 and LX-2 cells were treated with PLX51107 chow, AZD4547 or the combination of PLX51107 and AZD4547. LX-2 cells have been shown previously to not form into tumors in vivo (Amann et al, 2009;Barcena et al, 2015). Interestingly, PLX51107 increased UM001 tumor volume compared to controls ( Fig 8A).…”

Sevoflurane Protects Hepatocytes From Ischemic Injury by Reducing Reactive Oxygen Species Signaling of Hepatic Stellate Cells: Translational Findings Based on a Clinical Trial

“…The experimental approach is well established, and single-cell type-based assessment of intracellular signaling cascades is possible. 32,33 A second limitation emerges from the limitation of in vitro experiments using established cell lines. While Hep3B cells have hepatoma cell character, LX-2 cells are spontaneously immortalized cells.…”

Human angiogenin is a potent cytotoxin in the absence of ribonuclease inhibitor

“…Assays with H114N ANG, which is an inactive catalyst (Shapiro and Vallee 1989), demonstrated that cytotoxicity relies on catalytic activity. Moreover, the cytotoxicity of ANG is unaffected by neomycin, which blocks its localization to the nucleolus (Hu 1998;Bárcena et al 2015), suggesting that ANG acts elsewhere.…”