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1078-0432.CCR-13-3292.Full-Text.Pdf Published OnlineFirst June 6, 2014; DOI: 10.1158/1078-0432.CCR-13-3292 Clinical Cancer Biology of Human Tumors Research Essential Role of Aldehyde Dehydrogenase 1A3 for the Maintenance of Non–Small Cell Lung Cancer Stem Cells Is Associated with the STAT3 Pathway Chunli Shao1,2, James P. Sullivan3,4, Luc Girard1,2,7, Alexander Augustyn1,2, Paul Yenerall1,2, Jaime Rodriguez-Canales5, Hui Liu5, Carmen Behrens5, Jerry W. Shay6, Ignacio I. Wistuba5, and John D. Minna1,2,7,8 Abstract Purpose: Lung cancer stem cells (CSC) with elevated aldehyde dehydrogenase (ALDH) activity are self- renewing, clonogenic, and tumorigenic. The purpose of our study is to elucidate the mechanisms by which lung CSCs are regulated. Experimental Design: A genome-wide gene expression analysis was performed to identify genes þ À differentially expressed in the ALDH versus ALDH cells. RT-PCR, Western blot analysis, and Aldefluor assay were used to validate identified genes. To explore the function in CSCs, we manipulated their expression followed by colony and tumor formation assays. þ Results: We identified a subset of genes that were differentially expressed in common in ALDH cells, þ À among which ALDH1A3 was the most upregulated gene in ALDH versus ALDH cells. shRNA-mediated knockdown of ALDH1A3 in non–small cell lung cancer (NSCLC) resulted in a dramatic reduction in ALDH activity, clonogenicity, and tumorigenicity, indicating that ALDH1A3 is required for tumorigenic properties. þ In contrast, overexpression of ALDH1A3 by itself it was not sufficient to increase tumorigenicity. The ALDH À cells also expressed more activated STAT3 than ALDH cells. Inhibition of STAT3 or its activator EZH2 þ genetically or pharmacologically diminished the level of ALDH cells and clonogenicity. Unexpectedly, ALDH1A3 was highly expressed in female, never smokers, well-differentiated tumors, or adenocarcinoma. ALDH1A3 low expression was associated with poor overall survival. Conclusions: Our data show that ALDH1A3 is the predominant ALDH isozyme responsible for ALDH activity and tumorigenicity in most NSCLCs, and that inhibiting either ALDH1A3 or the þ STAT3 pathway are potential therapeutic strategies to eliminate the ALDH subpopulationinNSCLCs. Clin Cancer Res; 20(15); 1–13. Ó2014 AACR. Introduction breast cancer pleural effusions, accumulating evidence has The "cancer stem cell (CSC)" model proposes that tumor supported the existence of CSCs in many solid tumors, progression, drug resistance, metastasis, and relapse after which share important characteristics with embryonic and therapy may be driven by a subset of cells within a tumor normal tissue stem cells, such as self-renewal capability and representing a functionally important example of intratu- the competency to undergo differentiation (3). In non– mor heterogeneity (1, 2). Since the discovery of CSCs in small cell lung cancers (NSCLC), several populations of CSCs have been identified and characterized by the expres- sion of CSC markers, including CD133, CD44, aldehyde Authors' Affiliations: 1Hamon Center for Therapeutic Oncology Research, dehydrogenase (ALDH), and Side Population (SP; refs. 4– 2 3 Simmons Comprehensive Cancer Center, Massachusetts General Hos- 7). Ho and colleagues showed that as few as 1,000 isolated pital and 4Harvard Medical School, Boston, Massachusetts; 5Department of Translational Molecular Pathology, University of Texas M.D. Anderson SP cells from 6 lung cancer lines could generate xenograft À Cancer Center, Houston; Departments of 6Cell Biology, 7Pharmacology, tumors in NOD/SCID mice, whereas the bulk of the SP 8 and Internal Medicine, University of Texas Southwestern Medical Center, tumor cells could not (5). Eramo and colleagues found that Dallas, Texas þ CD133 subpopulations in some NSCLC and small cell Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). lung cancer (SCLC) tumors are self-renewing and highly tumorigenic and are capable of efficiently propagating the Corresponding Author: John D. Minna, The University of Texas South- in vitro in vivo western Medical Center, 6000 Harry Hines Blvd., Dallas, TX 75390-8593. disease both and (8). However several follow- Phone: 214-648-4900; Fax: 214-648-4940; E-mail: up studies using SP and CD133 as identifiers of lung CSCs [email protected] indicated these markers frequently identify non-CSC sub- doi: 10.1158/1078-0432.CCR-13-3292 populations, signifying a need for more reliable methods to Ó2014 American Association for Cancer Research. identify and isolate lung CSCs (9, 10). www.aacrjournals.org OF1 Downloaded from clincancerres.aacrjournals.org on September 27, 2021. © 2014 American Association for Cancer Research. Published OnlineFirst June 6, 2014; DOI: 10.1158/1078-0432.CCR-13-3292 Shao et al. igenicity in mouse xenograft models (28–30). Thus, we Translational Relevance investigated which ALDH isozyme was associated with the The malignant phenotype appears driven by a sub- NSCLC stem cell subpopulation and whether there was a þ population of cancer stem cells (CSC), which self-renew, connection between such ALDH cells and the STAT3 differentiate, and contribute to drug resistance and pathway. metastasis. Our group and others have identified CSCs In this study, we characterized the expression profile of þ À in non–small cell lung cancers (NSCLC) by their ALDH and ALDH tumor cells in a panel of NSCLC lines enhanced aldehyde dehydrogenase (ALDH) activity and and found the expression of ALDH1A3 to be the most þ þ found that the ALDH subpopulation contains highly commonly elevated of all ALDH isozymes in the ALDH tumorigenic and clonogenic cells. Here, we show that NSCLC subpopulations. We found that knockdown of one of the 19 ALDH isozymes, ALDH1A3, is responsible ALDH1A3 significantly reduces the clonogenicity, tumori- for ALDH activity in a majority of NSCLCs despite genicity, and ALDH activity of lung cancer cells. Following oncogenotype, functionally required for lung CSC sur- this, we were able to show the STAT3 pathway is more þ À vival, and that pSTAT3 is tightly linked to ALDH1A3 activated in ALDH cells than in ALDH lung cancer cells activity. Inhibition of ALDH1A3 or STAT3 attenuated þ and inhibition of the STAT3 pathway also impaired the ALDH1A3 expression, ALDH lung cancer cells, and maintenance of lung CSCs. Together, the data show that tumor cell clonogenicity. Collectively, our findings indi- ALDH1A3 is functionally important for the malignant cate that ALDH1A3 expression and STAT3 pathway behavior of NSCLCs and that ALDH1A3 and STAT3 are activation are essential for the maintenance of NSCLC promising therapeutic targets for NSCLC through their þ CSCs, and that both ALDH1A3 and the STAT3 pathway significant role in the ALDH subpopulation of tumor cells. are rational therapeutic targets for eliminating NSCLC stem cells. Materials and Methods Cell culture All NSCLC lines used in this study were obtained from More recently, elevated ALDH activity has been employ- the Hamon Cancer Center Collection (University of Texas ed as a CSC marker in multiple tumor types (11–13). We Southwestern Medical Center, Dallas, TX) and main- þ and others have identified a subpopulation of ALDH tained in RPMI-1640 (Life Technologies) supplemented NSCLC cells with increased malignant behavior in many with 5% fetal calf serum at 37 C in a humidified atmo- tumor cell lines and patient samples using the flow cyto- sphere containing 5% CO2 and 95% air. All cell lines have metry-based Aldefluor assay (6, 14, 15). Similar to findings been DNA fingerprinted using the PowerPlex 1.2 kit þ in other types of cancers, ALDH tumor cells isolated from (Promega) and are found mycoplasma free using the patient lung tumors and lung cancer cell lines are enriched e-Myco kit (Boca Scientific). in highly tumorigenic and clonogenic cells which are capable of self renewal (6, 16–18). Of the 19 isozymes in Aldefluor assay and FACS this family, class one aldehyde dehydrogenases (ALDH1) The Aldefluor assay (Stem Cell Technologies) was used to are frequently associated with alcohol metabolism, reti- profile and sort cells based on ALDH activity as previously þ À noic acid synthesis, drug resistance, and stem cell homeo- described (14). ALDH and ALDH cells were sorted by BD stasis (19–21). Recently, expression of the ALDH1A1 iso- Aria (BD Biosciences) cell sorters and the purity was usually zyme was shown to be a biomarker of poor prognosis in >90% confirmed by post-sort analyses. Flow cytometric tumors of the breast, colon, ovary, and lung (22–24). How- profiling was performed on a FACScan flow cytometer (BD ever, additional evidence in metastatic breast and colon Biosciences) and analyzed using FlowJo software (Treestar). cancers implicated another ALDH isozyme, ALDH1A3, and other class one ALDH isozymes as putative CSC Colony formation assay markers (18, 25, 26). Therefore, a thorough understanding Anchorage-dependent (liquid) and -independent (soft of the expression and function of the role of specific ALDH agar) colony formation assays were done as described isozymes in lung CSCs is necessary for clinical translation (14). The inhibitors used in the study were Stattic (Calbio- of CSCs identified by ALDH activity in lung cancer. chem), Ruxolitinib (LC Laboratories), and GSK126 STAT3 was originally identified as acute phase response (Xcessbio). factor that bound to IL6 response elements within the promoter region of various acute phase response genes. Microarray analysis þ À Cytokines and growth factors
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