Hepatic tumor–stroma crosstalk guides epithelial to mesenchymal transition at the tumor edge

Abstract

The tumor-stroma crosstalk is a dynamic process fundamental in tumor development. In hepatocellular carcinoma (HCC), the progression of malignant hepatocytes frequently depends on transforming growth factor (TGF)-b provided by stromal cells. TGF-b induces an epithelial to mesenchymal transition (EMT) of oncogenic Ras-transformed hepatocytes and an upregulation of platelet-derived growth factor (PDGF) signaling. To analyse the influence of the hepatic tumor-stroma crosstalk onto tumor growth and progression, we co-injected malignant hepatocytes and myofibroblasts (MFBs). For this, we either used in vitro-activated p19 ARF MFBs or in vivo-activated MFBs derived from physiologically inflamed livers of Mdr2/p19 ARF double-null mice. We show that co-transplantation of MFBs with Ras-transformed hepatocytes strongly enhances tumor growth. Genetic interference with the PDGF signaling decreases tumor cell growth and maintains plasma membranelocated E-cadherin and b-catenin at the tumor-host border, indicating a blockade of hepatocellular EMT. We further generated a collagen gel-based three dimensional HCC model in vitro to monitor the MFB-induced invasion of micro-organoid HCC spheroids. This invasion was diminished after inhibition of TGF-b or PDGF signaling. These data suggest that the TGF-b/PDGF axis is crucial during hepatic tumor-stroma crosstalk, regulating both tumor growth and cancer progression.

Cancer cells in epithelial-to-mesenchymal transition and tumor-propagating–cancer stem cells: distinct, overlapping or same populations

“…A TGF-b inhibitor inhibits tumorosphere formation by murine breast cancers and also tumor growth and metastasis (Bandyopadhyay et al, 2010). The EMT-inducing effect of TGF-b is mediated in transformed hepatocytes by the induction of growth factors in stromal myofibroblasts, which themselves cause EMT (van Zijl et al, 2009). In the RAS-RAF pathway, extracellular signal-regulated kinase 2 (ERK2) would specifically be involved in EMT induction but not ERK1 (Shin et al, 2010).…”

Acyclic Retinoid Targets Platelet-Derived Growth Factor Signaling in the Prevention of Hepatic Fibrosis and Hepatocellular Carcinoma Development

“…Moreover, recent reports suggested an interaction between PDGF signaling and Wnt/b-catenin signaling (25)(26)(27). We evaluated Wnt/b-catenin signaling in Pdgf-c Tg mice and showed by IHC staining that b-catenin was overexpressed in the submembrane at week 48 (Fig.…”

Tumor initiation and progression in hepatocellular carcinoma: risk factors, classification, and therapeutic targets

“…In HCC, the progression of malignant hepatocytes frequently depends on transforming growth factor (TGF)-beta provided by the stromal cells (fibroblasts, macrophages etc). This TGF-beta is one of the factors that can induce an Epithelial-to-Mesenchymal Transition (EMT) [80] . For different types of tumors it has been demonstrated that an EMT-switch is associated with a worse prognosis as seen in esophageal squamous cell carcinoom [81] , gastric cancer cells [82] bladder cancer [83] non-small cell lung cancer [84] and pancreas ductal adenomacarcinoma [85] .…”