ALDH Activity Selectively Defines an Enhanced Tumor-Initiating Cell Population Relative to CD133 Expression in Human Pancreatic Adenocarcinoma

被引:210
作者
Kim, Michael P. [1 ]
Fleming, Jason B. [1 ]
Wang, Huamin [2 ]
Abbruzzese, James L. [3 ]
Choi, Woonyoung [4 ]
Kopetz, Scott [3 ]
McConkey, David J. [4 ]
Evans, Douglas B. [5 ]
Gallick, Gary E. [6 ]
机构
[1] Univ Texas MD Anderson Canc Ctr, Dept Surg Oncol, Houston, TX 77030 USA
[2] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA
[3] Univ Texas MD Anderson Canc Ctr, Dept Gastrointestinal Med Oncol, Houston, TX 77030 USA
[4] Univ Texas MD Anderson Canc Ctr, Dept Urol, Houston, TX 77030 USA
[5] Med Coll Wisconsin, Dept Surg, Milwaukee, WI 53226 USA
[6] Univ Texas MD Anderson Canc Ctr, Dept Genitourinary Med Oncol, Houston, TX 77030 USA
基金
美国国家卫生研究院;
关键词
CANCER STEM-CELLS; ALDEHYDE DEHYDROGENASE-ACTIVITY; BRAIN-TUMORS; IDENTIFICATION; GROWTH; MARKER;
D O I
10.1371/journal.pone.0020636
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Background: Multiple studies in recent years have identified highly tumorigenic populations of cells that drive tumor formation. These cancer stem cells (CSCs), or tumor-initiating cells (TICs), exhibit properties of normal stem cells and are associated with resistance to current therapies. As pancreatic adenocarcinoma is among the most resistant human cancers to chemo-radiation therapy, we sought to evaluate the presence of cell populations with tumor-initiating capacities in human pancreatic tumors. Understanding which pancreatic cancer cell populations possess tumor-initiating capabilities is critical to characterizing and understanding the biology of pancreatic CSCs towards therapeutic ends. Methodology/Principal Findings: We have isolated populations of cells with high ALDH activity (ALDH high) and/or CD133 cell surface expression from human xenograft tumors established from multiple patient tumors with pancreatic adenocarcinoma (direct xenograft tumors) and from the pancreatic cancer cell line L3.6pl. Through fluorescent activated cell sorting (FACs)-mediated enrichment and depletion of selected pancreatic cancer cell populations, we sought to discriminate the relative tumorigenicity of cell populations that express the pancreatic CSC markers CD133 and aldehyde dehydrogenase (ALDH). ALDH high and ALDH low cell populations were further examined for co-expression of CD44 and/or CD24. We demonstrate that unlike cell populations demonstrating low ALDH activity, as few as 100 cells enriched for high ALDH activity were capable of tumor formation, irrespective of CD133 expression. In direct xenograft tumors, the proportions of total tumor cells expressing ALDH and/or CD133 in xenograft tumors were unchanged through a minimum of two passages. We further demonstrate that ALDH expression among patients with pancreatic adenocarcinoma is heterogeneous, but the expression is constant in serial generations of individual direct xenograft tumors established from bulk human pancreatic tumors in NOD/SCID mice. Conclusions/Significance: We conclude that, in contrast to some previous studies, cell populations enriched for high ALDH activity alone are sufficient for efficient tumor-initiation with enhanced tumorigenic potential relative to CD133(+) and ALDH low cell populations in some direct xenograft tumors. Although cell populations enriched for CD133 expression may alone possess tumorigenic potential, they are significantly less tumorigenic than ALDH(high) cell populations. ALDH(high)/CD44(+)/CD24(+) or ALDH(low)/CD44(+)/CD24(+) phenotypes do not appear to significantly contribute to tumor formation at low numbers of inoculated tumor cells. ALDH expression broadly varies among patients with pancreatic adenocarcinoma and the apparent expression is recapitulated in serial generations of direct xenograft tumors in NOD/SCID. We have thus identified a distinct population of TICs that should lead to identification of novel targets for pancreatic cancer therapy.
引用
收藏
页数:11
相关论文
共 28 条
[1]   Prospective identification of tumorigenic breast cancer cells [J].
Al-Hajj, M ;
Wicha, MS ;
Benito-Hernandez, A ;
Morrison, SJ ;
Clarke, MF .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2003, 100 (07) :3983-3988
[2]   Glioma stem cells promote radioresistance by preferential activation of the DNA damage response [J].
Bao, Shideng ;
Wu, Qiulian ;
McLendon, Roger E. ;
Hao, Yueling ;
Shi, Qing ;
Hjelmeland, Anita B. ;
Dewhirst, Mark W. ;
Bigner, Darell D. ;
Rich, Jeremy N. .
NATURE, 2006, 444 (7120) :756-760
[3]  
Bruns Christiane J., 1999, Neoplasia (New York), V1, P50, DOI 10.1038/sj.neo.7900005
[4]   Identification of a primitive brain-derived neural stem cell population based on aldehyde dehydrogenase activity [J].
Corti, Stefania ;
Locatelli, Federica ;
Papadimitriou, Dimitra ;
Donadoni, Chiara ;
Salani, Sabrina ;
Del Bo, Roberto ;
Strazzer, Sandra ;
Bresolin, Nereo ;
Comi, Giacomo P. .
STEM CELLS, 2006, 24 (04) :975-985
[5]   CD133 Expression Defines a Tumor Initiating Cell Population in Primary Human Ovarian Cancer [J].
Curley, Michael D. ;
Therrien, Vanessa A. ;
Cummings, Christine L. ;
Sergent, Petra A. ;
Koulouris, Carolyn R. ;
Friel, Anne M. ;
Roberts, Drucilla J. ;
Seiden, Michael V. ;
Scadden, David T. ;
Rueda, Bo R. ;
Foster, Rosemary .
STEM CELLS, 2009, 27 (12) :2875-2883
[6]   Stem cell concepts renew cancer research [J].
Dick, John E. .
BLOOD, 2008, 112 (13) :4793-4807
[7]   Survival of the fittest: Cancer stem cells in therapeutic resistance and angiogenesis [J].
Eyler, Christine E. ;
Rich, Jeremy N. .
JOURNAL OF CLINICAL ONCOLOGY, 2008, 26 (17) :2839-2845
[8]   ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome [J].
Ginestier, Christophe ;
Hur, Min Hee ;
Charafe-Jauffret, Emmanuelle ;
Monville, Florence ;
Dutcher, Julie ;
Brown, Marty ;
Jacquemier, Jocelyne ;
Viens, Patrice ;
Kleer, Celina G. ;
Liu, Suling ;
Schott, Anne ;
Hayes, Dan ;
Birnbaum, Daniel ;
Wicha, Max S. ;
Dontu, Gabriela .
CELL STEM CELL, 2007, 1 (05) :555-567
[9]   Cancerous stem cells can arise from pediatric brain tumors [J].
Hemmati, HD ;
Nakano, I ;
Lazareff, JA ;
Masterman-Smith, M ;
Geschwind, DH ;
Bronner-Fraser, M ;
Kornblum, HI .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2003, 100 (25) :15178-15183
[10]   Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer [J].
Hermann, Patrick C. ;
Huber, Stephan L. ;
Herrler, Tanja ;
Aicher, Alexandra ;
Ellwart, Joachim W. ;
Guba, Markus ;
Bruns, Christiane J. ;
Heeschen, Christopher .
CELL STEM CELL, 2007, 1 (03) :313-323