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Activated hepatic stellate cells play pivotal roles in hepatocellular carcinoma cell chemoresistance and migration in multicellular tumor spheroids.

ABSTRACT: Most Hepatocellular carcinoma (HCC) are resistant to conventional chemotherapeutic agents and remain an unmet medical need. Recently, multiple studies on the crosstalk between HCC and their tumor microenvironment have been conducted to overcome chemoresistance in HCC. In this study, we formed multicellular tumor spheroids (MCTS) to elucidate the mechanisms of environment-mediated chemoresistance in HCC. We observed that hepatic stellate cells (HSCs) in MCTS significantly increased the compactness of spheroids and exhibited strong resistance to sorafenib and cisplatin relative to other types of stromal cells. Increased collagen 1A1 (COL1A1) expression was apparent in activated HSCs but not in fibroblasts or vascular endothelial cells in MCTS. Additionally, COL1A1 deficiency, which was increased by co-culture with HSCs, decreased the cell-cell interactions and thereby increased the therapeutic efficacy of anticancer therapies in MCTS. Furthermore, losartan, which can inhibit collagen I synthesis, attenuated the compactness of spheroids and increased the therapeutic efficacy of anticancer therapies in MCTS. Meanwhile, activated HSCs facilitated HCC migration by upregulating matrix metallopeptidase 9 (MMP9) in MCTS. Collectively, crosstalk between HCC cells and HSCs promoted HCC chemoresistance and migration by increasing the expression of COL1A1 and MMP9 in MCTS. Hence, targeting HSCs might represent a promising therapeutic strategy for liver cancer therapy.

SUBMITTER: Song Y

PROVIDER: S-EPMC5113076 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Activated hepatic stellate cells play pivotal roles in hepatocellular carcinoma cell chemoresistance and migration in multicellular tumor spheroids.

Song Yeonhwa Y Kim Se-Hyuk SH Kim Kang Mo KM Choi Eun Kyung EK Kim Joon J Seo Haeng Ran HR

Scientific reports 20161117

Most Hepatocellular carcinoma (HCC) are resistant to conventional chemotherapeutic agents and remain an unmet medical need. Recently, multiple studies on the crosstalk between HCC and their tumor microenvironment have been conducted to overcome chemoresistance in HCC. In this study, we formed multicellular tumor spheroids (MCTS) to elucidate the mechanisms of environment-mediated chemoresistance in HCC. We observed that hepatic stellate cells (HSCs) in MCTS significantly increased the compactnes ...[more]

PMID: 27853186

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Project description:Children with autism spectrum disorder (ASD) have significant difficulty in social functioning to include engaging in natural play with peers. Many children with ASD exhibit significantly less interactive play and more physiological stress during benign social encounters with same-age peers on a playground. Theatrical role-playing and performance with expert role models may provide a unique opportunity for children with ASD to learn to engage with other children in a safe, supportive environment. SENSE Theatre® is a peer-mediated, theater-based program aimed at improving social competence in youth with ASD. Previous studies have shown significant improvements in social and communication skills following SENSE Theatre® intervention. The current project examined play with novel peers and self-reported anxiety before and after participation in SENSE Theatre®. Participants included 77 children between 8 and 16 years with high-functioning (IQ ≥ 70) ASD. The combined sample of three cohorts was randomized to the experimental (EXP, N = 44) or waitlist control (WLC, N = 33) group. Participants in the EXP group received 40 h (10, 4-h sessions) of SENSE Theatre®. The Peer Interaction Paradigm (PIP), an ecologically valid measure of natural play, was administered before and after the intervention. Group Play and Self Play on the playground equipment during solicited (T4) and unsolicited (T1) play were used in the current study. The State Trait Anxiety Scale for Children (STAIC; Spielberger et al., 1983) was used to measure self-reported current and persistent anxiety, respectively. Following treatment, children in the EXP group engaged in significantly more Group Play with novel peers [F(2,73) = 7.78, p = 0.007] and much less Self Play [F(2,73) = 6.70, p = 0.01] during solicited play compared to the WLC group. Regression analysis revealed that pretreatment play and group status were significant predictors of solicited Group Play. Children in the EXP group reported significantly less Trait anxiety following intervention [F(2,71) = 6.87, p = 0.01]; however, State anxiety was comparable. Results corroborate previous findings of significant changes in social and play behavior in children with ASD following the peer-mediated, theater-based intervention. Acting and theatrical performance with supportive role models facilitates social engagement in everyday settings with novel peers and reductions in self-reported anxiety.

Dataset Information

Activated hepatic stellate cells play pivotal roles in hepatocellular carcinoma cell chemoresistance and migration in multicellular tumor spheroids.

Publications

Activated hepatic stellate cells play pivotal roles in hepatocellular carcinoma cell chemoresistance and migration in multicellular tumor spheroids.

Similar Datasets

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