Label-retaining liver cancer cells are relatively resistant to sorafenib

被引：94

作者：

Xin, Hong-Wu ^{[1
]}

Ambe, Chenwi M. ^{[1
]}

Hari, Danielle M. ^{[1
]}

Wiegand, Gordon W. ^{[1
]}

Miller, Tyler C. ^{[1
]}

Chen, Jin-Qiu ^{[2
]}

Anderson, Andrew J. ^{[1
]}

Ray, Satyajit ^{[1
]}

Mullinax, John E. ^{[1
]}

Koizumi, Tomotake ^{[1
]}

Langan, Russell C. ^{[1
]}

Burka, Douglas ^{[1
]}

Herrmann, Michelle A. ^{[2
]}

Goldsmith, Paul K. ^{[2
]}

Stojadinovic, Alexander ^{[3
,4
]}

Rudloff, Udo ^{[1
]}

Thorgeirsson, Snorri S. ^{[5
]}

Avital, Itzhak ^{[1
,4
,6
]}

机构：

[1] NCI, Surg Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA

[2] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA

[3] Walter Reed Natl Mil Med Ctr, Div Surg Oncol, Dept Surg, Bethesda, MD USA

[4] Uniformed Serv Univ Hlth Sci, Dept Surg, Bethesda, MD 20814 USA

[5] NCI, Expt Carcinogenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA

[6] Bon Secours Canc Inst, Richmond, VA 23230 USA

来源：

GUT | 2013年 / 62卷 / 12期

关键词：

Cancer; Cell Proliferation; Drug Resistance; Hepatocellular Carcinoma; Stem Cells; ADVANCED HEPATOCELLULAR-CARCINOMA; MULTIKINASE INHIBITOR; MYELOID-LEUKEMIA; STEM-CELLS; PROLIFERATION; APOPTOSIS; DIVISION;

D O I：

10.1136/gutjnl-2012-303261

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

摘要：

Objective The standard therapy for advanced hepatocellular carcinoma (HCC) is sorafenib, with most patients experiencing disease progression within 6months. Label-retaining cancer cells (LRCC) represent a novel subpopulation of cancer stem cells (CSC). The objective was to test whether LRCC are resistant to sorafenib. Methods We tested human HCC derived LRCC and non-LRCC before and after treatment with sorafenib. Results LRCC derived from human HCC are relatively resistant to sorafenib. The proportion of LRCC in HCC cell lines is increased after sorafenib while the general population of cancer cells undergoes growth suppression. We show that LRCC demonstrate improved viability and toxicity profiles, and reduced apoptosis, over non-LRCC. We show that after treatment with sorafenib, LRCC upregulate the CSC marker aldehyde dehydrogenase 1 family, wingless-type MMTV-integration-site family, cell survival and proliferation genes, and downregulate apoptosis, cell cycle arrest, cell adhesion and stem cells differentiation genes. This phenomenon was accompanied by non-uniform activation of specific isoforms of the sorafenib target proteins extracellular-signal-regulated kinases and v-akt-murine-thymoma-viral-oncogene homologue (AKT) in LRCC but not in non-LRCC. A molecular pathway map for sorafenib treated LRCC is proposed. Conclusions Our results suggest that HCC derived LRCC are relatively resistant to sorafenib. Since LRCC can generate tumours with as few as 10 cells, our data suggest a potential role for these cells in disease recurrence. Further investigation of this phenomenon might provide novel insights into cancer biology, cancer recurrence and drug resistance with important implications for the development of novel cancer therapies based on targeting LRCC.

引用

页码：1777 / 1786

页数：10