Abstract
The malignant transformation of normal resident hepatic stem/progenitor cells has a critical role in hepatocarcinogenesis and the recurrence of hepatocellular carcinoma (HCC). We defined such hepatic progenitor cells as hepatoma-initiating cells. An efficient strategy is required to target and kill the hepatoma-initiating cells. We isolated extracellular microparticles (MPs) derived from apoptotic hepatic progenitor cells (HPCs) and tested their ability to inhibit hepatocarcinogenesis. Extracellular MPs were isolated from HPCs, hepatocytes and liver tumor cells. Their effects on tumor growth were investigated in rat primary HCC models, in which hepatocarcinogenesis is induced by diethylnitrosamine (DEN). The extracellular MPs derived from apoptotic HPCs, apoptotic hepatocytes and apoptotic liver tumor cells were similar in morphology, diameter and zeta potential. However, they had different antitumor effects. In DEN-exposed rats, only the MPs derived from apoptotic HPCs effectively inhibit hepatocarcinogenesis. In vitro and in vivo analyses confirmed that HPCs preferentially take up MPs derived from apoptotic HPCs compared to MPs from other liver cell types. Proteomic analysis of MPs from apoptotic HPCs showed enrichment of proteins involved in cell death pathways. Thus, HPC-derived MPs contain a death signal to induce the killing of hepatoma-initiating cells. Our findings provide evidence that a death signal encapsulated in HPC-derived extracellular microparticles can efficiently clear hepatoma-initiating cells and prevent hepatocarcinogenesis.Graphical
Highlights
Hepatocellular carcinoma (HCC), one of the most common malignant tumors, is an important health problem worldwide [1]
We found that the activation and malignant transformation of hepatic progenitor cells (HPCs) promote hepatocarcinogenesis and HCC recurrence [9,10,11,12]; we defined such HPCs as hepatoma-initiating cells
ApoHPCMPs, apoHep-MPs and apoLTC-MPs had a similar irregularly spherical morphology as observed by transmission electron microscopy (TEM) (Additional file 2: Fig. S2C). They had similar diameters of ~800 nm (Additional file 2: Fig. S2D) and similar zeta potentials of ~ − 17 mV (Additional file 2: Fig. S2E). To test whether these apoMPs have similar anticancer effects, we employed the diethylnitrosamine (DEN)induced primary HCC model in Sprague Dawley rats. 6 weeks of oral DEN treatment showed the obvious HPC activation (Additional file 2: Fig. S3), HPCs were labeled with an antibody against CK7 [23], and in our previous studies, we found that the activation and malignant transformation of HPCs promote hepatocarcinogenesis and HCC recurrence [9,10,11,12]
Summary
Hepatocellular carcinoma (HCC), one of the most common malignant tumors, is an important health problem worldwide [1]. We found that the activation and malignant transformation of HPCs promote hepatocarcinogenesis and HCC recurrence [9,10,11,12]; we defined such HPCs as hepatoma-initiating cells. Various nanoparticles, including lipid-based nanoparticles, metal-based nanoparticles, polymeric nanoparticles and dendrimers, have been used for targeted drug delivery in liver cancer treatment [13, 14]. These artificial nanoparticles may not be soluble in biological matrices, and they may possess potential toxicity. Extracellular microvesicles have attracted considerable attention as carriers of therapeutic reagents
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