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Reversing the intractable nature of pancreatic cancer by selectively targeting ALDH-high, therapy-resistant cancer cells

Authors
 Sang Kyum Kim ; Honsoul Kim ; Dae-Sik Lim ; Hoguen Kim ; Gou Young Koh ; Chaeuk Chung ; Tackhoon Kim ; Tae-shin Kim ; Da-hye Lee 
Citation
 PLoS One, Vol.8(10) : e78130, 2013 
Journal Title
 PLoS One 
ISSN
 1932-6203 
Issue Date
2013
Abstract
Human pancreatic ductal adenocarcinoma (PDAC) is a cancer with a dismal prognosis. The efficacy of PDAC anticancer therapies is often short-lived; however, there is little information on how this disease entity so frequently gains resistance to treatment. We adopted the concept of cancer stem cells (CSCs) to explain the mechanism of resistance and evaluated the efficacy of a candidate anticancer drug to target these therapy-resistant CSCs. We identified a subpopulation of cells in PDAC with CSC features that were enriched for aldehyde dehydrogenase (ALDH), a marker expressed in certain stem/progenitor cells. These cells were also highly resistant to, and were further enriched by, treatment with gemcitabine. Similarly, surgical specimens from PDAC patients showed that those who had undergone preoperative chemo-radiation therapy more frequently displayed cancers with ALDH strongly positive subpopulations compared with untreated patients. Importantly, these ALDH-high cancer cells were sensitive to disulfiram, an ALDH inhibitor, when tested in vitro. Furthermore, in vivo xenograft studies showed that the effect of disulfiram was additive to that of low-dose gemcitabine when applied in combination. In conclusion, human PDAC-derived cells that express high levels of ALDH show CSC features and have a key role in the development of resistance to anticancer therapies. Disulfiram can be used to suppress this therapy-resistant subpopulation.
URI
http://ir.ymlib.yonsei.ac.kr/handle/22282913/88645
DOI
10.1371/journal.pone.0078130
Appears in Collections:
1. 연구논문 > 1. College of Medicine > Dept. of Pathology
1. 연구논문 > 1. College of Medicine > Dept. of Radiology
Yonsei Authors
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