Aldehyde dehydrogenase activity selects for lung adenocarcinoma stem cells dependent on notch signaling

Sullivan, James P., Spinola, Monica, Dodge, Michael, Raso, Maria G., Behrens, Carmen, Gao, Boning, Schuster, Katja, Shao, Chunli, Larsen, Jill E., Sullivan, Laura A., Honorio, Sofia, Xie, Yang, Scaglioni, Pier P., DiMaio, J. Michael, Gazdar, Adi F., Shay, Jerry W., Wistuba, Ignacio I. and Minna, John D. (2010) Aldehyde dehydrogenase activity selects for lung adenocarcinoma stem cells dependent on notch signaling. Cancer Research, 70 23: 9937-9948. doi:10.1158/0008-5472.CAN-10-0881

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Author Sullivan, James P.
Spinola, Monica
Dodge, Michael
Raso, Maria G.
Behrens, Carmen
Gao, Boning
Schuster, Katja
Shao, Chunli
Larsen, Jill E.
Sullivan, Laura A.
Honorio, Sofia
Xie, Yang
Scaglioni, Pier P.
DiMaio, J. Michael
Gazdar, Adi F.
Shay, Jerry W.
Wistuba, Ignacio I.
Minna, John D.
Title Aldehyde dehydrogenase activity selects for lung adenocarcinoma stem cells dependent on notch signaling
Journal name Cancer Research   Check publisher's open access policy
ISSN 0008-5472
Publication date 2010-12-01
Sub-type Article (original research)
DOI 10.1158/0008-5472.CAN-10-0881
Open Access Status Not yet assessed
Volume 70
Issue 23
Start page 9937
End page 9948
Total pages 12
Place of publication Philadelphia, PA, United States
Publisher American Association for Cancer Research
Language eng
Formatted abstract
Aldehyde dehydrogenase (ALDH) is a candidate marker for lung cancer cells with stem cell-like properties. Immunohistochemical staining of a large panel of primary non–small cell lung cancer (NSCLC) samples for ALDH1A1, ALDH3A1, and CD133 revealed a significant correlation between ALDH1A1 (but not ALDH3A1 or CD133) expression and poor prognosis in patients including those with stage I and N0 disease. Flow cytometric analysis of a panel of lung cancer cell lines and patient tumors revealed that most NSCLCs contain a subpopulation of cells with elevated ALDH activity, and that this activity is associated with ALDH1A1 expression. Isolated ALDH+ lung cancer cells were observed to be highly tumorigenic and clonogenic as well as capable of self-renewal compared with their ALDH counterparts. Expression analysis of sorted cells revealed elevated Notch pathway transcript expression in ALDH+ cells. Suppression of the Notch pathway by treatment with either a γ-secretase inhibitor or stable expression of shRNA against NOTCH3 resulted in a significant decrease in ALDH+ lung cancer cells, commensurate with a reduction in tumor cell proliferation and clonogenicity. Taken together, these findings indicate that ALDH selects for a subpopulation of self-renewing NSCLC stem-like cells with increased tumorigenic potential, that NSCLCs harboring tumor cells with ALDH1A1 expression have inferior prognosis, and that ALDH1A1 and CD133 identify different tumor subpopulations. Therapeutic targeting of the Notch pathway reduces this ALDH+ component, implicating Notch signaling in lung cancer stem cell maintenance.
Keyword Tumor-initiating cells
Acute myeloid-leukemia
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: School of Medicine Publications
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Citation counts: TR Web of Science Citation Count  Cited 213 times in Thomson Reuters Web of Science Article | Citations
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Created: Fri, 04 Oct 2013, 23:43:27 EST by Jill Larsen on behalf of School of Medicine