Melanoma Stem Cells Characterized by High Aldehyde Dehydrogenase Activity

Cancer researchers have unequivocally identified a population of stem cells in melanoma tumors that are characterized by high aldehyde dehydrogenase (ALDH) activity.

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 the present study, which was published in the August 7, 2012, online edition of the journal Stem Cells, investigators at the University of Colorado School of Medicine (Aurora, USA) demonstrated the existence of human melanoma cells that fulfill the criteria for CSCs (self-renewal and differentiation).

The investigators established the existence of a CSC population by serially xenotransplanting cells into NOD/SCID mice. These cells were found to possess high aldehyde dehydrogenase (ALDH) activity with ALDH1A1 and ALDH1A3 being the predominant ALDH isozymes.

ALDH-positive melanoma cells were more tumorigenic than ALDH-negative cells in both NOD/SCID mice and NSG mice. Biological analyses of the ALDH-positive melanoma cells revealed the ALDH isozymes to be key molecules regulating the function of these cells. Silencing ALDH1A by siRNA (small interfering RNA) or shRNA (short hairpin RNA) led to cell cycle arrest, apoptosis, and decreased cell viability in vitro and reduced tumorigenesis in vivo. ALDH-positive melanoma cells were more resistant to chemotherapeutic agents, and silencing ALDH1A by siRNA sensitized melanoma cells to drug-induced cell death.

In human tumor samples, ALDH+ cells made up about 0.1%-0.2% of patients’ primary tumors. In samples of metastatic melanoma - the most aggressive form of the disease - the percentage of ALDH+ cells was greater, over 10% in some tumors.

The investigators examined the molecular signatures of ALDH-positive CSCs from patient-derived tumor specimens. The signatures of melanoma CSCs included retinoic acid (RA)-driven target genes with RA response elements and genes associated with stem cell function.

“We have seen ALDH as a stem cell marker in other cancer types, but not in melanoma, and until now its function has been largely unknown,” said senior author, Dr. Mayumi Fujita, associate professor of dermatology at the University of Colorado School of Medicine. “In these same ALDH+ cells, we find the markers of stem cells are upregulated and those of cell differentiation are downregulated. In addition to these clues, ALDH+ cells generate the heterogeneous cell types seen in the original tumor. Our hope is that we can intervene in this signaling, either at the level of ALDH or elsewhere in the pathway, especially to resensitize cells to chemotherapy. Using a new drug to take away a melanoma stem cell’s chemoresistance could boost the effectiveness of existing drugs.”

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University of Colorado School of Medicine