Periostin involved in the activated hepatic stellate cells-induced progression of residual hepatocellular carcinoma after sublethal heat treatment: its role and potential for therapeutic inhibition

Rui Zhang,Xia-Hui Lin,Rong-Xin Chen,Jun Chen,Min Ma,Jie Chen,Dong-Mei Gao,Jie-Feng Cui

doi:10.1186/s12967-018-1676-3

Abstract

BackgroundIncomplete thermal ablation may induce invasiveness of hepatocellular carcinoma (HCC). Here, we investigated whether activated hepatic stellate cells (HSCs) would accelerate the progression of residual HCC after sublethal heat treatment, and thus sought to identify the potential targets.MethodsHepatocellular carcinoma cells were exposed to sublethal heat treatment and then cultured with the conditioned medium from activated HSCs (HSC-CM). The cell proliferation, migration, invasion and parameters of epithelial–mesenchymal transition (EMT) were analyzed. In vivo tumor progression of heat-treated residual HCC cells inoculated with activated HSCs was studied in nude mice.ResultsHSC-CM significantly enhanced the proliferation, motility, invasion, prominent EMT activation and decreased apoptosis of heat-exposed residual HCC cells. These increased malignant phenotypes were markedly attenuated by neutralizing periostin (POSTN) in HSC-CM. Furthermore, exogenous POSTN administration exerted the similar effects of HSC-CM on heat-treated residual HCC cells. POSTN induced the prominent activation of p52Shc and ERK1/2 via integrin β1 in heat-exposed residual HCC cells. Vitamin D analog calcipotriol blocked POSTN secretion from activated HSCs. Calcipotriol plus cisplatin significantly suppressed the activated HSCs-enhanced tumor progression of heat-treated residual HCC cells via the inhibited POSTN expression and the increased apoptosis.ConclusionsActivated HSCs promote the tumor progression of heat-treated residual HCC through the release of POSTN, which could be inhibited by calcipotriol. Calcipotriol plus cisplatin could be used to thwart the accelerated progression of residual HCC after suboptimal heat treatment.

Highlights

Incomplete thermal ablation may induce invasiveness of hepatocellular carcinoma (HCC)
As in our previous description [26], conditioned medium was collected from activated hepatic stellate cells (HSCs) (HSC-CM) and anti-human POSTN antibody (2.5 μg/mL) (Abcam, Cambridge, UK) was added into HSCs-derived condition medium (HSC-CM) to neutralize the activity of POSTN
HSC‐CM promotes proliferation, epithelial–mesenchymal transition (EMT), colony formation and decreases apoptosis of heat‐treated residual HCC cells As we previously described [26], 47.0 °C was chosen as IT50 to simulate the sublethal temperature at the tumor periphery during incomplete Radiofrequency ablation (RFA)

Summary

Introduction

Incomplete thermal ablation may induce invasiveness of hepatocellular carcinoma (HCC). Radiofrequency ablation (RFA) has been established as the standard care for unresectable early hepatocellular carcinoma (HCC) with complete response rates exceeding 90% [1, 2]. Due to its superiorities such as effectiveness, minimal invasiveness, safety and repeatability, RFA has been advocated to treat the patients with mediumlarge HCC [3, 4]. When RFA is used to treat HCC beyond 3 cm, local tumor recurrence is a common phenomenon because it is difficult for RFA to secure a sufficient safety margin in three dimensions to ablate microsatellite or microvascular invasion around the tumor [7]. Local tumor recurrence arises from those minimal or occult residual tumors. Rapid and aggressive tumor progression after incomplete RFA has been increasingly reported [8,9,10,11,12,13], albeit its mechanisms are not fully understood

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