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Aug 24, 2012

Enzyme Identifies Elusive Melanoma CSCs

  • Scientists appear to have identified a marker that defines melanoma cancer stem cells (CSC), the putative subtype of cancer cell that is capable of differentiating and self-renewing to drive cancer growth and metastasis. The University of Colorado Cancer Center-led team say the melanoma CSCs express high levels of aldehyde dehydrogenase (ALDH) activity, and primarily the ALDH1A1 and ALDH1A3 isoenzymes. ALDH had previously been identified as a stem cell marker in other cancer types, but not in melanoma.

    The researchers’ in vivo studies showed that ALDH-positive melanoma cells were more tumorigenic than ALDH-negative when transplanted in NOD/SCID mice and NSG mice, and were also more resistant to chemotherapeutic agents in vitro. Conversely, mice failed to develop tumors when implanted with ALDH-positive melanoma cells in which the ALDH1A gene had been knocked down using an siRNA. ALDH1A-silenced melanoma cells were also more sensitive to chemotherapy in vitro than those that were still capable of producing the enzyme.

    The team, led by Mayumi Fujita, M.D., and Yuchon Luo, went on to examine primary human melanoma tumors. They found that distinct subpopulations of ALDH+ cells generally made up about 0.1–0.2% of the overall tumor cell population. However, in samples of more aggressive metastatic melanoma, the relative numbers of of ALDH+ cells increased to 10% or more of the total tumor sample.

    When the researchers then looked more closely at pathways associated with ALDH production, they found that high levels of the enzyme were associated with overproduction of retinoic acid, which in turn impacts on genes involved in regulating cell survival, repair, and proliferation.

    Describing their results in Stem Cells, the authors say that as well as representing biomarkers for melanoma CSCs, the ALDH isoenzymes and the signaling pathways they trigger may present as a viable therapeutic target for the cancer. “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,” Dr. Fujita states. “Using a new drug to take away a melanoma stem cell’s chemoresistance could boost the effectiveness of existing drugs.”

    The University of Colorado team reports its findings in a paper titled “ALDH1A Isozymes are Markers of Human Melanoma Stem Cells and Potential Therapeutic Targets."


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