Cancer Stem Cells

ALDH1A Isozymes are Markers of Human Melanoma Stem Cells and Potential Therapeutic Targets†‡§

  1. Yuchun Luo1,
  2. Katiuscia Dallaglio1,2,
  3. Ying Chen3,
  4. William A. Robinson4,
  5. Steven E. Robinson4,
  6. Martin D. McCarter5,
  7. Jianbin Wang6,
  8. Rene Gonzalez4,
  9. David C. Thompson7,
  10. David A. Norris1,8,
  11. Dennis R. Roop1,2,
  12. Vasilis Vasiliou3,
  13. Mayumi Fujita1,2,8,¶,*

Article first published online: 20 SEP 2012

DOI: 10.1002/stem.1193

Issue

STEM CELLS

STEM CELLS

Volume 30, Issue 10, pages 2100–2113, October 2012

Additional Information

How to Cite

Luo, Y., Dallaglio, K., Chen, Y., Robinson, W. A., Robinson, S. E., McCarter, M. D., Wang, J., Gonzalez, R., Thompson, D. C., Norris, D. A., Roop, D. R., Vasiliou, V. and Fujita, M. (2012), ALDH1A Isozymes are Markers of Human Melanoma Stem Cells and Potential Therapeutic Targets. STEM CELLS, 30: 2100–2113. doi: 10.1002/stem.1193

Author Information

  1. 1

    Department of Dermatology, University of Colorado Denver, Aurora, Colorado, USA

  2. 2

    Charles C Gates Center for Regenerative Medicine and Stem Cell Biology, University of Colorado Denver, Aurora, Colorado, USA

  3. 3

    Department of Pharmaceutical Sciences, University of Colorado Denver, Aurora, Colorado, USA

  4. 4

    Division of Medical Oncology, Department of Medicine, University of Colorado Denver, Aurora, Colorado, USA

  5. 5

    Department of Surgery, University of Colorado Denver, Aurora, Colorado, USA

  6. 6

    Department of Biochemistry and Molecular Genetics, and

  7. 7

    Clinical Pharmacy, University of Colorado Denver, Aurora, Colorado, USA

  8. 8

    Denver Veterans Affairs Medical Center, Denver, Colorado, USA

  1. Telephone: 303-724-4045; Fax: 303-724-4048

*Department of Dermatology, University of Colorado Denver, Mail Stop 8127, 12801 E. 17th Ave., Rm 4124, Aurora, Colorado 80045, USA

  1. †

    Author contributions: Y.L.: conception and design, collection and assembly of data, data analysis and interpretation, manuscript writing, and final approval of manuscript; K.D., Y.C., and J.W.: collection and assembly of data, data analysis and interpretation, and final approval of manuscript; W.A.R., S.E.R., M.D.M., and R.G.: provision of study material or patients and final approval of manuscript; D.C.T., D.A.N., D.R.R., and V.V.: data analysis and interpretation and final approval of manuscript; M.F.: conception and design, financial support, collection and assembly of data, data analysis and interpretation, manuscript writing, and final approval of manuscript.

  2. ‡

    Disclosure of potential conflicts of interest is found at the end of this article.

  3. §

    First published online in STEM CELLSEXPRESS August 7, 2012.

  4. Telephone: 303-724-4045; Fax: 303-724-4048

Publication History

  1. Issue published online: 20 SEP 2012
  2. Article first published online: 20 SEP 2012
  3. Accepted manuscript online: 7 AUG 2012 09:00AM EST
  4. Manuscript Accepted: 26 JUN 2012
  5. Manuscript Received: 28 FEB 2012

Funded by

  • NIH. Grant Number: CA125833
  • Veterans Affairs Merit Review Award
  • UCCC
  • Wendy Will Case Cancer Fund
  • Tadamitsu Cancer Research Fund
  • NEI. Grant Numbers: EY17963, EY11490

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Keywords:

  • Melanoma;
  • Cancer stem cells;
  • Tumor-initiating cells;
  • Aldehyde dehydrogenase;
  • Microarray analysis;
  • Molecular targeted therapy

Abstract

Although the concept of cancer stem cells (CSCs) is well-accepted for many tumors, the existence of such cells in human melanoma has been the subject of debate. In this study, we demonstrate the existence of human melanoma cells that fulfill the criteria for CSCs (self-renewal and differentiation) by serially xenotransplanting cells into nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice. These cells possess high aldehyde dehydrogenase (ALDH) activity with ALDH1A1 and ALDH1A3 being the predominant ALDH isozymes. ALDH-positive melanoma cells are more tumorigenic than ALDH-negative cells in both NOD/SCID mice and NSG mice. Biological analyses of the ALDH-positive melanoma cells reveal the ALDH isozymes to be key molecules regulating the function of these cells. Silencing ALDH1A by siRNA or shRNA leads to cell cycle arrest, apoptosis, decreased cell viability in vitro, and reduced tumorigenesis in vivo. ALDH-positive melanoma cells are more resistant to chemotherapeutic agents and silencing ALDH1A by siRNA sensitizes melanoma cells to drug-induced cell death. Furthermore, we, for the first time, examined the molecular signatures of ALDH-positive CSCs from patient-derived tumor specimens. The signatures of melanoma CSCs include retinoic acid (RA)-driven target genes with RA response elements and genes associated with stem cell function. These findings implicate that ALDH isozymes are not only biomarkers of CSCs but also attractive therapeutic targets for human melanoma. Further investigation of these isozymes and genes will enhance our understanding of the molecular mechanisms governing CSCs and reveal new molecular targets for therapeutic intervention of cancer. STEM Cells2012;30:2100–2113

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