Abstract
Hepatic stellate cells (HSCs), a specialized stromal cytotype in the liver, have been demonstrated to actively contribute to hepatocellular carcinoma (HCC) development. However, the previous studies were performed using HSC cell lines, and the prognostic value of intratumoral HSCs (tHSCs) was unclear. Here we isolated tHSCs from fresh human HCC tissues, and analyzed the abilities of tHSCs to promote HCC progression by using in vitro assays for cell viability, migration and invasion as well as epithelial-mesenchymal transition (EMT) phenotype. 252 HCC patients who underwent hepatectomy were enrolled for analysis of tHSCs and E-cadherin expression in tumor tissues, and 55 HCC patients for analysis of tHSCs in tumor tissues and circulating tumor cells (CTCs) in blood. Prognostic factors were then identified. The results showed that coculture of tHSCs with HCC cells had a stronger effect on HCC cell viability, migration and invasion, accompanied with the acquisition of epithelial-mesenchymal transition (EMT) phenotype. In vivo cotransplantation of HCC cells with tHSCs into nude mice more efficiently promoted tumor formation and growth. Icaritin, a known apoptosis inducer of HSCs, was demonstrated to effectively inhibit tHSC proliferation in vitro and tHSC-induced HCC-promoting effects in vivo. Clinical evidence indicated that tHSCs were rich in 45% of the HCC specimens, tHSC-rich subtypes were negatively correlated either with E-cadherin expression in tumor tissues (r = -0.256, p < 0.001) or with preoperative CTCs in blood (r = -0.287, p = 0.033), and were significantly correlated with tumor size (p = 0.027), TNM staging (p = 0.018), and vascular invasion (p = 0.008). Overall and recurrence-free survival rates of tHSC-rich patients were significantly worse than those for tHSC-poor patients. Multivariate analysis revealed tHSC-rich as an independent factor for overall and recurrence-free survival. In conclusion, tHSCs provide a promising prognostic biomarker and a new treatment target for HCC.
Highlights
Tumor microenvironment is referred to as stroma, and basically consists of the extracellular matrix (ECM) and stromal cells [1]
The results showed that coculture of the prognostic value of intratumoral HSCs (tHSCs) with hepatocellular carcinoma (HCC) cells had a stronger effect on HCC cell viability, migration and invasion, accompanied with the acquisition of epithelial-mesenchymal transition (EMT) phenotype
There was an increase in PLC/PRF/5 cell growth after a 24hour incubation at different dilutions of tHSC-conditioned media (CM) (*p < 0.05), and tHSC-CM gave a greater proliferative capacity than did quiescent HSCs (qHSCs)-CM and activated HSCs (aHSCs)-CM in a dose- and time-dependent manner (Figure 1A and 1B, *p < 0.05). tHSC-CM caused a significant increase in PLC/PRF/5 cell migration than qHSCCM and aHSC-CM in wound healing assays (Figure 1C, *p < 0.05)
Summary
Tumor microenvironment is referred to as stroma, and basically consists of the extracellular matrix (ECM) and stromal cells [1]. The liver in particular consists of numerous specialized stromal cell types such as hepatic stellate cells (HSCs) and Kuffer cells. Due to the vast remodeling of the extracellular matrix (ECM) and altered expression of growth factors, activated HSCs provide the cellular basis for the establishment of hepatic fibrosis and cirrhosis [7]. Upon HCC development, HSCs are markedly recruited into the stroma, activated under the control of tumor cells, and represent the prevalent cell type of the stromal cells [8,9,10,11,12,13].
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
