Laminin-332 sustains chemoresistance and quiescence as part of the human hepatic cancer stem cell niche

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• 作者：Olivier Govaere¹ ; ^{olivier.govaere@med.kuleuven.be" class="auth_mail" title="E-mail the corresponding author} ; Jasper Wouters¹ ; Michaela Petz² ; Yves-Paul Vandewynckel³ ; Kathleen Van den Eynde¹ ; Anke Van den broeck⁴ ; Stefaan Verhulst⁵ ; Laurent Doll&eacute ; ⁵ ; Lies Gremeaux⁶ ; An Ceulemans¹ ; Frederik Nevens⁷ ; Leo A. van Grunsven⁵ ; Baki Topal⁴ ; Hugo Vankelecom⁶ ; Gianluigi Giannelli⁸ ; Hans Van Vlierberghe³ ; Wolfgang Mikulits² ; Mina Komuta¹ ; Tania Roskams¹
• 关键词：ABC ; ATP-binding cassette ; CC ; cholangiocellular carcinoma ; CSC ; cancer stem cell ; FFPE ; formalin-fixed paraffin-embedded ; FSC-A ; Forward Scatter Area ; HCC ; hepatocellular carcinoma ; HPC ; hepatic progenitor cell ; ITGA6 ; integrin alpha 6 ; K ; keratin ; Ln ; laminin ; MP ; main population ; pHH3 ; phosphorylated histone H3 ; pmTOR ; phosphorylated Mammalian Target of Rapamycin ; qPCR ; quantitative real-time PCR ; SP ; side population
• 刊名：Journal of Hepatology
• 出版年：2016
• 出版时间：March 2016
• 年：2016
• 卷：64
• 期：3
• 页码：609-617
• 全文大小：3144 K

文摘

Cancer stem cells (CSCs) are thought to be persistent in tumours due to their chemoresistance and to cause relapse and metastasis. Hepatic carcinomas displaying hepatic progenitor cell (HPC) features have been associated with a poor prognosis, though it remains unclear how CSCs relate to these different histological subtypes.

d="absSec_2">Methods

d="sp0015">Candidate CSCs were isolated using the side population (SP) technique from primary tissue samples diagnosed as keratin(K)19-negative or -positive hepatocellular carcinoma (HCC) or as combined hepatocellular/cholangiocarcinoma and analysed for gene and protein expression. The effect of laminin-332 was analysed m>in vitrom> by using HCC cell lines and m>in vivom> using a xenograft mouse model.

d="absSec_3">Results

d="sp0020">The size of the SP correlated with the degree of HPC features found in human hepatic cancer, and also showed an elevated mRNA expression of biliary/HPC markers and the extracellular matrix marker m>LAMC2m>, the gene encoding the laminin γ2-chain. Immunopositivity for the γ2-chain of laminin-332 was seen in the extracellular matrix surrounding small HPC-like tumour cells with a low proliferation rate. m>In vitrom>, laminin-332 increased K19 expression, phosphorylated mTOR and decreased phospho-histone H3 expression, indicating reduced cell mitosis. The effect of laminin-332 was enhanced upon mTORC1 inhibition and diminished when inhibiting mTORC1+C2. Resistance to doxorubicin and sorafenib treatment, and the SP fraction increased in the coated condition. m>In vivom>, laminin-332 reduced tumour growth and sustained K19 expression.

d="absSec_4">Conclusions

d="sp0025">In this study we identified a prominent role for laminin-332 as part of the specialised CSC niche in maintaining and supporting cell ‘stemness’, which leads to chemoresistance and quiescence.