Characterization of aldehyde dehydrogenase isozymes in ovarian cancer tissues and sphere cultures

BMC Cancer

Yu-Ting Saw⁴  Junzheng Yang⁴  Shu-Kay Ng³  Shubai Liu⁴  Surendra Singh⁶  Margit Singh⁴  William R Welch¹  Hiroshi Tsuda²  Wing-Ping Fong⁵  David Thompson⁶  Vasilis Vasiliou⁶  Ross S Berkowitz⁴  Shu-Wing Ng⁴ 

[1] Department of Pathology, Brigham and Women’s Hospital, Boston, MA, 02115, USA

[2] Department of Obstetrics and Gynecology, School of Medicine, Keio University, Tokyo, 160-8582, Japan

[3] School of Medicine, Griffith Health Institute, Griffith University, Meadowbrook, QLD, 4131, Australia

[4] Department of Obstetrics/Gynecology and Reproductive Biology, Brigham and Women’s Hospital, Boston, MA, 02115, USA

[5] School of Life Sciences, The Chinese University of Hong Kong, Hong Kong, China

[6] Department of Pharmaceutical Sciences, University of Colorado Denver, Aurora, CO, 80045, USA

关键词: Tumor-type specific expression;    Sphere cultures;    Ovarian tumors;    Isozymes;    Aldehyde dehydrogenase;   

Others  :  1128595
DOI  :  10.1186/1471-2407-12-329

 received in 2012-04-09, accepted in 2012-07-18,  发布年份 2012

【 摘 要 】

Background

Aldehyde dehydrogenases belong to a superfamily of detoxifying enzymes that protect cells from carcinogenic aldehydes. Of the superfamily, ALDH1A1 has gained most attention because current studies have shown that its expression is associated with human cancer stem cells. However, ALDH1A1 is only one of the 19 human ALDH subfamilies currently known. The purpose of the present study was to determine if the expression and activities of other major ALDH isozymes are associated with human ovarian cancer and ovarian cancer sphere cultures.

Methods

Immunohistochemistry was used to delineate ALDH isozyme localization in clinical ovarian tissues. Western Blot analyses were performed on lysates prepared from cancer cell lines and ovarian cancer spheres to confirm the immunohistochemistry findings. Quantitative reverse transcription-polymerase chain reactions were used to measure the mRNA expression levels. The Aldefluor® assay was used to measure ALDH activity in cancer cells from the four tumor subtypes.

Results

Immunohistochemical staining showed significant overexpression of ALDH1A3, ALDH3A2, and ALDH7A1 isozymes in ovarian tumors relative to normal ovarian tissues. The expression and activity of ALDH1A1 is tumor type-dependent, as seen from immunohistochemisty, Western blot analysis, and the Aldefluor® assay. The expression was elevated in the mucinous and endometrioid ovarian epithelial tumors than in serous and clear cell tumors. In some serous and most clear cell tumors, ALDH1A1 expression was found in the stromal fibroblasts. RNA expression of all studied ALDH isozymes also showed higher expression in endometrioid and mucinous tumors than in the serous and clear cell subtypes. The expression of ALDH enzymes showed tumor type-dependent induction in ovarian cancer cells growing as sphere suspensions in serum-free medium.

Conclusions

The results of our study indicate that ALDH enzyme expression and activity may be associated with specific cell types in ovarian tumor tissues and vary according to cell states. Elucidating the function of the ALDH isozymes in lineage differentiation and pathogenesis may have significant implications for ovarian cancer pathophysiology.

【 授权许可】

   
2012 Saw et al.; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Altekruse S, Kosary C, Krapcho M, Neyman N, Aminou R, Waldron W, Ruhl J, Howlader N, Tatalovich Z, Cho H, et al.: SEER Cancer Statistics Review, 1975–2007. Bethesda, MD, USA :National Cancer Institue; 2010.
• [2]Jemal A, Siegel R, Xu J, Ward E: Cancer statistics, 2010. CA Cancer J Clin 2010, 60(5):277-300.
• [3]Bast RC, Boyer CM, Olt GJ, Berchuck A, Soper JT, Clarke-Pearson D, Xu FJ, Ramakrishnan S: Identification of marker for early detection of epithelial ovarian cancer. London, England: Chapman and Hall Medical; 1990.
• [4]Serov SF, Scullt RE: Histological typing of ovarian tumors. Geneva: World Health Organization; 1993.
• [5]Thor AD, Young RH, Clement PB: Pathology of the fallopian tube, broad ligament, peritoneum, and pelvic soft tissues. Hum Pathol 1991, 22(9):856-867.
• [6]McCluggage WG, Wilkinson N: Metastatic neoplasms involving the ovary: a review with an emphasis on morphological and immunohistochemical features. Histopathology 2005, 47(3):231-247.
• [7]Cambell IG, Morland S, Hitchcock A: Endometriosis and the relationship with ovarian cancer., vol. 5. Oxford: ISIS Medical Media Ltd; 1998.
• [8]DePriest PD, Banks ER, Powell DE, van Nagell JR, Gallion HH, Puls LE, Hunter JE, Kryscio RJ, Royalty MB: Endometrioid carcinoma of the ovary and endometriosis: the association in postmenopausal women. Gynecol Oncol 1992, 47(1):71-75.
• [9]Goff BA, Sainz de la Cuesta R, Muntz HG, Fleischhacker D, Ek M, Rice LW, Nikrui N, Tamimi HK, Cain JM, Greer BE, et al.: Clear cell carcinoma of the ovary: a distinct histologic type with poor prognosis and resistance to platinum-based chemotherapy in stage III disease. Gynecol Oncol 1996, 60(3):412-417.
• [10]Recio FO, Piver MS, Hempling RE, Driscoll DL: Lack of improved survival plus increase in thromboembolic complications in patients with clear cell carcinoma of the ovary treated with platinum versus nonplatinum-based chemotherapy. Cancer 1996, 78(10):2157-2163.
• [11]Itamochi H, Kigawa J, Sugiyama T, Kikuchi Y, Suzuki M, Terakawa N: Low proliferation activity may be associated with chemoresistance in clear cell carcinoma of the ovary. Obstet Gynecol 2002, 100(2):281-287.
• [12]Visvader JE, Lindeman GJ: Cancer stem cells in solid tumours: accumulating evidence and unresolved questions. Nat Rev Cancer 2008, 8(10):755-768.
• [13]Hermann PC, Huber SL, Herrler T, Aicher A, Ellwart JW, Guba M, Bruns CJ, Heeschen C: Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer. Cell Stem Cell 2007, 1(3):313-323.
• [14]Dalerba P, Dylla SJ, Park IK, Liu R, Wang X, Cho RW, Hoey T, Gurney A, Huang EH, Simeone DM, et al.: Phenotypic characterization of human colorectal cancer stem cells. Proc Natl Acad Sci U S A 2007, 104(24):10158-10163.
• [15]Wright MH, Calcagno AM, Salcido CD, Carlson MD, Ambudkar SV, Varticovski L: Brca1 breast tumors contain distinct CD44+/CD24- and CD133+ cells with cancer stem cell characteristics. Breast Cancer Res 2008, 10(1):R10. BioMed Central Full Text
• [16]Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY, Brooks M, Reinhard F, Zhang CC, Shipitsin M, et al.: The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 2008, 133(4):704-715.
• [17]Gupta PB, Fillmore CM, Jiang G, Shapira SD, Tao K, Kuperwasser C, Lander ES: Stochastic state transitions give rise to phenotypic equilibrium in populations of cancer cells. Cell 2011, 146(4):633-644.
• [18]Chaffer CL, Brueckmann I, Scheel C, Kaestli AJ, Wiggins PA, Rodrigues LO, Brooks M, Reinhardt F, Su Y, Polyak K, et al.: Normal and neoplastic nonstem cells can spontaneously convert to a stem-like state. Proc Natl Acad Sci U S A 2011, 108(19):7950-7955.
• [19]Dontu G, Abdallah WM, Foley JM, Jackson KW, Clarke MF, Kawamura MJ, Wicha MS: In vitro propagation and transcriptional profiling of human mammary stem/progenitor cells. Genes Dev 2003, 17(10):1253-1270.
• [20]Charafe-Jauffret E, Ginestier C, Iovino F, Wicinski J, Cervera N, Finetti P, Hur MH, Diebel ME, Monville F, Dutcher J, et al.: Breast cancer cell lines contain functional cancer stem cells with metastatic capacity and a distinct molecular signature. Cancer Res 2009, 69(4):1302-1313.
• [21]Bortolomai I, Canevari S, Facetti I, De Cecco L, Castellano G, Zacchetti A, Alison MR, Miotti S: Tumor initiating cells: Development and critical characterization of a model derived from the A431 carcinoma cell line forming spheres in suspension. Cell Cycle 2010, 9(6):1194-1206.
• [22]Mulholland DJ, Xin L, Morim A, Lawson D, Witte O, Wu H: Lin-Sca-1 + CD49fhigh stem/progenitors are tumor-initiating cells in the Pten-null prostate cancer model. Cancer Res 2009, 69(22):8555-8562.
• [23]Lukacs RU, Lawson DA, Xin L, Zong Y, Garraway I, Goldstein AS, Memarzadeh S, Witte ON: Epithelial stem cells of the prostate and their role in cancer progression. Cold Spring Harb Symp Quant Biol 2008, 73:491-502.
• [24]Alley MC, Scudiero DA, Monks A, Hursey ML, Czerwinski MJ, Fine DL, Abbott BJ, Mayo JG, Shoemaker RH, Boyd MR: Feasibility of drug screening with panels of human tumor cell lines using a microculture tetrazolium assay. Cancer Research 1988, 48(3):589-601.
• [25]Carpentino JE, Hynes MJ, Appelman HD, Zheng T, Steindler DA, Scott EW, Huang EH: Aldehyde dehydrogenase-expressing colon stem cells contribute to tumorigenesis in the transition from colitis to cancer. Cancer Res 2009, 69(20):8208-8215.
• [26]Charafe-Jauffret E, Ginestier C, Iovino F, Tarpin C, Diebel M, Esterni B, Houvenaeghel G, Extra JM, Bertucci F, Jacquemier J, et al.: Aldehyde dehydrogenase 1-positive cancer stem cells mediate metastasis and poor clinical outcome in inflammatory breast cancer. Clin Cancer Res 2010, 16(1):45-55.
• [27]Deng S, Yang X, Lassus H, Liang S, Kaur S, Ye Q, Li C, Wang LP, Roby KF, Orsulic S, et al.: Distinct expression levels and patterns of stem cell marker, aldehyde dehydrogenase isoform 1 (ALDH1), in human epithelial cancers. PLoS One 2010, 5(4):e10277.
• [28]Colombo F, Baldan F, Mazzucchelli S, Martin-Padura I, Marighetti P, Cattaneo A, Foglieni B, Spreafico M, Guerneri S, Baccarin M, et al.: Evidence of distinct tumour-propagating cell populations with different properties in primary human hepatocellular carcinoma. PLoS One 2011, 6(6):e21369.
• [29]van den Hoogen C, van der Horst G, Cheung H, Buijs JT, Lippitt JM, Guzman-Ramirez N, Hamdy FC, Eaton CL, Thalmann GN, Cecchini MG, et al.: High aldehyde dehydrogenase activity identifies tumor-initiating and metastasis-initiating cells in human prostate cancer. Cancer Res 2010, 70(12):5163-5173.
• [30]Buijs JT, van der Horst G, van den Hoogen C, Cheung H, de Rooij B, Kroon J, Petersen M, van Overveld PG, Pelger RC, van der Pluijm G: The BMP2/7 heterodimer inhibits the human breast cancer stem cell subpopulation and bone metastases formation. Oncogene 2011.
• [31]Marchitti SA, Brocker C, Stagos D, Vasiliou V: Non-P450 aldehyde oxidizing enzymes: the aldehyde dehydrogenase superfamily. Expert Opin Drug Metab Toxicol 2008, 4(6):697-720.
• [32]Jackson B, Brocker C, Thompson DC, Black W, Vasiliou K, Nebert DW, Vasiliou V: Update on the aldehyde dehydrogenase gene (ALDH) superfamily. Hum Genomics 2011, 5(4):283-303.
• [33]van den Hoogen C, van der Horst G, Cheung H, Buijs JT, Pelger RC, van der Pluijm G: The aldehyde dehydrogenase enzyme 7A1 is functionally involved in prostate cancer bone metastasis. Clin Exp Metastasis 2011, 28(7):615-625.
• [34]Marcato P, Dean CA, Pan D, Araslanova R, Gillis M, Joshi M, Helyer L, Pan L, Leidal A, Gujar S, et al.: Aldehyde dehydrogenase activity of breast cancer stem cells is primarily due to isoform ALDH1A3 and its expression is predictive of metastasis. Stem Cells 2011, 29(1):32-45.
• [35]Marchitti SA, Orlicky DJ, Brocker C, Vasiliou V: Aldehyde dehydrogenase 3B1 (ALDH3B1): immunohistochemical tissue distribution and cellular-specific localization in normal and cancerous human tissues. J Histochem Cytochem 2010, 58(9):765-783.
• [36]Marcato P, Dean CA, Giacomantonio CA, Lee PW: Aldehyde dehydrogenase: its role as a cancer stem cell marker comes down to the specific isoform. Cell Cycle 2011, 10(9):1378-1384.
• [37]Zhang Q, Taguchi A, Schliekelman M, Wong CH, Chin A, Kuick R, Misek DE, Hanash S: Comprehensive proteomic profiling of aldehyde dehydrogenases in lung adenocarcinoma cell lines. Int J Proteomics 2011, 2011:145010.
• [38]Landen CN, Goodman B, Katre AA, Steg AD, Nick AM, Stone RL, Miller LD, Mejia PV, Jennings NB, Gershenson DM, et al.: Targeting aldehyde dehydrogenase cancer stem cells in ovarian cancer. Mol Cancer Ther 2010, 12:3186-3199.
• [39]Wang YC, Yo YT, Lee HY, Liao YP, Chao TK, Su PH, Lai HC: ALDH1-Bright Epithelial Ovarian Cancer Cells Are Associated with CD44 Expression, Drug Resistance, and Poor Clinical Outcome. Am J Pathol 2012, 180(3):1159-1169.
• [40]Eirew P, Kannan N, Knapp DJ, Vaillant F, Emerman JT, Lindeman GJ, Visvader JE, Eaves CJ: Aldehyde Dehydrogenase Activity is a Biomarker of Primitive Normal Human Mammary Luminal Cells. Stem Cells 2011, 30(2):344-348.
• [41]Penumatsa K, Edassery SL, Barua A, Bradaric MJ, Luborsky JL: Differential expression of aldehyde dehydrogenase 1a1 (ALDH1) in normal ovary and serous ovarian tumors. J Ovarian Res 2010, 3:28. BioMed Central Full Text
• [42]Li H, Bitler BG, Vathipadiekal V, Maradeo ME, Slifker M, Creasy CL, Tummino PJ, Cairns P, Birrer MJ, Zhang R: ALDH1A1 Is a Novel EZH2 Target Gene in Epithelial Ovarian Cancer Identified by Genome-Wide Approaches. Cancer Prev Res (Phila) 2011, 5(3):484-491.
• [43]Huang KC, Park DC, Ng SK, Lee JY, Ni X, Ng WC, Bandera CA, Welch WR, Berkowitz RS, Mok SC, et al.: Selenium binding protein 1 in ovarian cancer. Int J Cancer 2006, 118(10):2433-2440.
• [44]Manzer R, Qamar L, Estey T, Pappa A, Petersen DR, Vasiliou V: Molecular cloning and baculovirus expression of the rabbit corneal aldehyde dehydrogenase (ALDH1A1) cDNA. DNA Cell Biol 2003, 22(5):329-338.
• [45]Lassen N, Bateman JB, Estey T, Kuszak JR, Nees DW, Piatigorsky J, Duester G, Day BJ, Huang J, Hines LM, et al.: Multiple and additive functions of ALDH3A1 and ALDH1A1: cataract phenotype and ocular oxidative damage in Aldh3a1(−/−)/Aldh1a1(−/−) knock-out mice. J Biol Chem 2007, 282(35):25668-25676.
• [46]Livak KJ, Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) Method. Methods 2001, 25(4):402-408.