File Download

There are no files associated with this item.

Supplementary

Conference Paper: The effect of tumor microenvironment on autophagy and sensitivity to targeted therapy in EGFR-mutated lung adenocarcinoma

TitleThe effect of tumor microenvironment on autophagy and sensitivity to targeted therapy in EGFR-mutated lung adenocarcinoma
Authors
Issue Date2014
Citation
The 21st Hong Kong International Cancer Congress (HKICC 2014), Hong Kong, 21 November 2014. How to Cite?
AbstractPurpose: Lung cancer is the top cancer killer worldwide. Tyrosine kinase inhibitors (TKIs), for example erlotinib, are commonly used to target epidermal growth factor receptor (EGFR)-mutated lung adenocarcinoma (ADC). Autophagy is a cellular response to stress, serving as a protective mechanism during anticancer therapy. The tumor microenvironment (TME) is composed of non-tumor cells that include fibroblasts. Our study aimed to investigate the effect of TME on autophagy and TKI sensitivity. Methods:  A model of TME was established by direct or indirect (transwell system) co-culture of HCC827 (EGFR exon 19-deleted lung ADC) and MRC-5 (human lung fibroblast) cells. Cell viability, apoptosis, autophagic proteins, epithelial-to-mesenchymal transition and cytokine (interleukin (IL)-6 and IL-8) expression were investigated. The effect of combined erlotinib/chloroquine treatment was studied in both a co-cultured in vitro model and HCC827 xenografts in nude mice. Results: Activation of MRC-5 cells with actin over-expression was evident when co-culturing with HCC827 cells. Direct co-culturing resulted in autophagy (p62 degradation) and cytokine storm (IL-6 and IL-8 production). Following cell sorting, autophagy and cytokine production were observed in both HCC827 and MRC-5 cells, with epithelial-to-mesenchymal transition (EMT) in HCC827 cells. Human recombinant IL-6 and IL-8 induced autophagy in homotypical HCC827 and MRC-5 cells. HCC827 cells became more sensitive to erlotinib upon co-culturing with MRC-5 cells, while the synergistic combination of erlotinib and chloroquine (autophagy inhibitor) was more pronounced in the presence of TME. Tumor growth was significantly suppressed with combined erlotinib/chloroquine compared with erlotinib in HCC827 xenografts. Conclusions:  A model of TME with MRC-5 fibroblasts induced autophagy, cytokine production and EMT in HCC827 lung ADC. Combined erlotinib/chloroquine remained synergistic in the presence of TME, with enhanced tumor suppression compared with erlotinib alone in a HCC827 xenograft model.
DescriptionCongress Theme: Translating Discoveries into Prevention and Cures
Persistent Identifierhttp://hdl.handle.net/10722/206849

 

DC FieldValueLanguage
dc.contributor.authorLi, Yen_US
dc.contributor.authorLam, SKen_US
dc.contributor.authorZheng, Cen_US
dc.contributor.authorLeung, LLen_US
dc.contributor.authorHo, JCMen_US
dc.date.accessioned2014-12-02T10:28:32Z-
dc.date.available2014-12-02T10:28:32Z-
dc.date.issued2014en_US
dc.identifier.citationThe 21st Hong Kong International Cancer Congress (HKICC 2014), Hong Kong, 21 November 2014.en_US
dc.identifier.urihttp://hdl.handle.net/10722/206849-
dc.descriptionCongress Theme: Translating Discoveries into Prevention and Curesen_US
dc.description.abstractPurpose: Lung cancer is the top cancer killer worldwide. Tyrosine kinase inhibitors (TKIs), for example erlotinib, are commonly used to target epidermal growth factor receptor (EGFR)-mutated lung adenocarcinoma (ADC). Autophagy is a cellular response to stress, serving as a protective mechanism during anticancer therapy. The tumor microenvironment (TME) is composed of non-tumor cells that include fibroblasts. Our study aimed to investigate the effect of TME on autophagy and TKI sensitivity. Methods:  A model of TME was established by direct or indirect (transwell system) co-culture of HCC827 (EGFR exon 19-deleted lung ADC) and MRC-5 (human lung fibroblast) cells. Cell viability, apoptosis, autophagic proteins, epithelial-to-mesenchymal transition and cytokine (interleukin (IL)-6 and IL-8) expression were investigated. The effect of combined erlotinib/chloroquine treatment was studied in both a co-cultured in vitro model and HCC827 xenografts in nude mice. Results: Activation of MRC-5 cells with actin over-expression was evident when co-culturing with HCC827 cells. Direct co-culturing resulted in autophagy (p62 degradation) and cytokine storm (IL-6 and IL-8 production). Following cell sorting, autophagy and cytokine production were observed in both HCC827 and MRC-5 cells, with epithelial-to-mesenchymal transition (EMT) in HCC827 cells. Human recombinant IL-6 and IL-8 induced autophagy in homotypical HCC827 and MRC-5 cells. HCC827 cells became more sensitive to erlotinib upon co-culturing with MRC-5 cells, while the synergistic combination of erlotinib and chloroquine (autophagy inhibitor) was more pronounced in the presence of TME. Tumor growth was significantly suppressed with combined erlotinib/chloroquine compared with erlotinib in HCC827 xenografts. Conclusions:  A model of TME with MRC-5 fibroblasts induced autophagy, cytokine production and EMT in HCC827 lung ADC. Combined erlotinib/chloroquine remained synergistic in the presence of TME, with enhanced tumor suppression compared with erlotinib alone in a HCC827 xenograft model.en_US
dc.languageengen_US
dc.relation.ispartof21st HKICC 2014en_US
dc.titleThe effect of tumor microenvironment on autophagy and sensitivity to targeted therapy in EGFR-mutated lung adenocarcinomaen_US
dc.typeConference_Paperen_US
dc.identifier.emailLam, SK: sklam77@hku.hken_US
dc.identifier.emailHo, JCM: jhocm@hku.hken_US
dc.identifier.authorityHo, JCM=rp00258en_US
dc.identifier.hkuros241620en_US

Export via OAI-PMH Interface in XML Formats


OR


Export to Other Non-XML Formats