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

Govaere, Olivier; Wouters, Jasper; Petz, Michaela; Vandewynckel, Yves-Paul; Eynde, Kathleen Van den; Broeck, Ann Van den; Verhulst, Stefaan; Dollé, Laurent; Gremeaux, Lies; Ceulemans, An; Nevens, Frederik; Grunsven, Leo A. van; Topal, Baki; Vankelecom, Hugo; Giannelli, Gianluigi; Vlierberghe, Hans Van; Mikulits, Wolfgang; Komuta, Mina; Roskams, Tania

doi:10.1016/j.jhep.2015.11.011

Cited by 113 publications

(109 citation statements)

References 34 publications

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“…In this milieu, Ln‐332 is distributed along the advancing edge of the tumor, correlated with a worse prognosis . In addition, Ln‐332 is expressed in the cancer stem cell niche, promoting the expression and maintenance of the stemness phenotype . This is also consistent with a recent study demonstrating that Ln‐332 and TGF‐β are correlated with overall survival in intrahepatic cholangiocarcinoma, while in HCC Ln‐332 cooperates with TGF‐β1, triggering the epithelial‐mesenchymal transition and promoting a more invasive and aggressive phenotype .…”

Section: Discussionsupporting

confidence: 89%

Hepatic stellate cells induce hepatocellular carcinoma cell resistance to sorafenib through the laminin‐332/α3 integrin axis recovery of focal adhesion kinase ubiquitination

et al. 2016

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Section: Discussionsupporting

confidence: 89%

Hepatic stellate cells induce hepatocellular carcinoma cell resistance to sorafenib through the laminin‐332/α3 integrin axis recovery of focal adhesion kinase ubiquitination

et al. 2016

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“…Our data supported that HAK-1B exhibited malignant features including higher invasive activity. In addition, Gorvaere et al recently reported that Laminin-332 induced K19 expression via mTORC2 signaling pathway, and Laminin-332 sustained chemoresistance including sorafenib of HCC cell line [26]. However, in our present study, the cytotoxicity of sorafenib or other drugs except for rapalogs was similar for both HAK-1A and HAK-1B cell lines (Table 1).…”

Section: Discussioncontrasting

confidence: 45%

Phosphorylation of mTOR Ser2481 is a key target limiting the efficacy of rapalogs for treating hepatocellular carcinoma

et al. 2016

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Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. Although recent studies facilitate the identification of crucial genes and relevant regulatory pathways, therapeutic approaches against advanced HCC are insufficiently effective. Therefore, we aimed here to develop potent therapeutics to provide a reliable biomarker for the therapeutic efficacy in patients with HCC. To this end, we first compared the cytotoxic effects of various anti-cancer drugs between well differentiated (HAK-1A) and poorly differentiated (HAK-1B) cell lines established from a single HCC tumor. Of various drug screened, HAK-1B cells were more sensitive by a factor of 2,000 to the mTORC1 inhibitors (rapalogs), rapamycin and everolimus, than HAK-1A cells. Although rapalogs inhibited phosphorylation of mTOR Ser2448 in HAK-1A and HAK-1B cells, phosphorylation of mTOR Ser2481 was specifically inhibited only in HAK-1B cells. Silencing of Raptor induced apoptosis and inhibited the growth of only HAK-1B cells. Further, three other cell lines established independently from the tumors of three patients with HCC were also approximately 2,000-fold times more sensitive to rapamycin, which correlated closely with the inhibition of mTOR Ser2481 phosphorylation by rapamycin. Treatment with everolimus markedly inhibited the growth of tumors induced by poorly differentiated HAK-1B and KYN-2 cells and phosphorylation of mTOR Ser2481 in vivo. To our knowledge, this is the first study showing that the phosphorylation of mTOR Ser2481 is selectively inhibited by rapalogs in mTORC1-addicted HCC cells and may be a potential reliable biomarker for the therapeutic efficacy of rapalogs for treating HCC patients.

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“…Specifically, genetically distinct subclones together with developmental pathways and epigenetic modifications can contribute to functional heterogeneity and chemoresistance 65 . Furthermore, the tumour microenvironment, composed of cancer-associated macrophages, fibroblasts and vascular cells and functioning as a specialized CSC niche, contributes to the maintenance of stemness and chemoresistance [65][66][67] .…”

Section: Cancer Stem Cellsmentioning

confidence: 99%

Cholangiocarcinoma: current knowledge and future perspectives consensus statement from the European Network for the Study of Cholangiocarcinoma (ENS-CCA)

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et al. 2016

Nat Rev Gastroenterol Hepatol

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

Abstract: 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.

Cited by 113 publications

References 34 publications

Hepatic stellate cells induce hepatocellular carcinoma cell resistance to sorafenib through the laminin‐332/α3 integrin axis recovery of focal adhesion kinase ubiquitination

Hepatic stellate cells induce hepatocellular carcinoma cell resistance to sorafenib through the laminin‐332/α3 integrin axis recovery of focal adhesion kinase ubiquitination

Phosphorylation of mTOR Ser2481 is a key target limiting the efficacy of rapalogs for treating hepatocellular carcinoma

Cholangiocarcinoma: current knowledge and future perspectives consensus statement from the European Network for the Study of Cholangiocarcinoma (ENS-CCA)

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