Abstract
BackgroundAccelerated malignant behaviors induced by insufficient thermal ablation have been increasingly reported, however, the exact mechanisms are still unclear. Here, we investigated the importance of the extracellular matrix (ECM) in modulating the progression of residual hepatocellular carcinoma (HCC) after heat treatment.MethodsHeat-exposed residual HCC cells were cultured in different ECM gels. We used basement membrane gel (Matrigel) to simulate the normal microenvironment and collagen I to model the pathological stromal ECM. The alterations of morphology and parameters of proliferation, epithelial-mesenchymal transition (EMT) and stemness were analyzed in vitro and in vivo.ResultsIncreased collagen I deposition was observed at the periablational zone after incomplete RFA of HCC in a xenograft model. The markers of cell proliferation, EMT, motility and progenitor-like traits of heat-exposed residual HCC cells were significantly induced by collagen I as compared to Matrigel (p values all < 0.05). Importantly, collagen I induced the activation of ERK phosphorylation in heat-exposed residual HCC cells. ERK1/2 inhibitor reversed the collagen I-promoted ERK phosphorylation, cell proliferative, protrusive and spindle-like appearance of heat-treated residual HCC cells in vitro. Moreover, collagen I promoted the in vivo tumor progression of heat-exposed residual HCC cells, and sorafenib markedly reversed the collagen I-mediated protumor effects.ConclusionsOur findings demonstrate that collagen I could enhance the aggressive progression of residual HCC cells after suboptimal heat treatment and sorafenib may be a treatment approach to thwart this process.
Highlights
Accelerated malignant behaviors induced by insufficient thermal ablation have been increasingly reported, the exact mechanisms are still unclear
Collagen I deposit at the periablational zone A hepatocellular carcinoma (HCC) orthotopic animal model was subjected to partial radiofrequency ablation (RFA)
With the use of Sirius red staining, collagen deposit was significantly increased in residual HCC at the Collagen I promoted the malignant phenotypes of heatexposed residual HCC cells After exposed to sublethal heat treatment (47 °C for 10 min), HCC cells were seeded on the plates pre-coated with Matrigel gel or collagen I gel
Summary
Accelerated malignant behaviors induced by insufficient thermal ablation have been increasingly reported, the exact mechanisms are still unclear. We investigated the importance of the extracellular matrix (ECM) in modulating the progression of residual hepatocellular carcinoma (HCC) after heat treatment. Sublethal heat treatment induced residual HCC cells themselves displaying more malignant phenotypes [9,10,11]. Besides ECM remodeling, the other factors in post-RFA inflammation reaction influence the tumor progression after insufficient heat-treatment [14, 15]. Collagen I as one of most abundant ECM proteins has been associated with the increased aggressiveness of many solid tumors including HCC [18,19,20,21,22,23,24]. It is reasonable to hypothesize that the increased collagen I at periablation stroma would promote the malignant behaviors of residual tumors after insufficient heat treatment
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