TY - JOUR
T1 - Label-retaining liver cancer cells are relatively resistant to sorafenib
AU - Xin, Hong Wu
AU - Ambe, Chenwi M.
AU - Hari, Danielle M.
AU - Wiegand, Gordon W.
AU - Miller, Tyler C.
AU - Chen, Jin Qiu
AU - Anderson, Andrew J.
AU - Ray, Satyajit
AU - Mullinax, John E.
AU - Koizumi, Tomotake
AU - Langan, Russell C.
AU - Burka, Douglas
AU - Herrmann, Michelle A.
AU - Goldsmith, Paul K.
AU - Stojadinovic, Alexander
AU - Rudloff, Udo
AU - Thorgeirsson, Snorri S.
AU - Avital, Itzhak
PY - 2013/12/1
Y1 - 2013/12/1
N2 - Objective: The standard therapy for advanced hepatocellular carcinoma (HCC) is sorafenib, with most patients experiencing disease progression within 6 months. 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-aktmurine-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.
AB - Objective: The standard therapy for advanced hepatocellular carcinoma (HCC) is sorafenib, with most patients experiencing disease progression within 6 months. 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-aktmurine-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.
UR - https://www.scopus.com/pages/publications/84887458286
U2 - 10.1136/gutjnl-2012-303261
DO - 10.1136/gutjnl-2012-303261
M3 - Article
AN - SCOPUS:84887458286
SN - 0017-5749
VL - 62
SP - 1777
EP - 1786
JO - Gut
JF - Gut
IS - 12
ER -
