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The Melanoma Stem Cell Controversy Continues

Melanoma-initiating cells that express CD271 may be unaffected by antimelanoma immunotherapy.

The cancer stem cell theory proposes that a small subset of cells in any given tumor represents an "immortal" pool that replenishes the larger tumor population. Efforts to demonstrate the existence of a melanoma stem cell have been rife with controversy, and studies conducted in the past 2 years have produced conflicting results.

Recently, stem cell researchers tested their hypothesis that should melanoma-initiating cells (MICs) exist, they would express primitive neural crest markers, such as the p75 nerve growth factor receptor CD271. The researchers found that many melanoma tumor specimens did in fact express CD271. In studies in mice, when cells were taken directly from patient specimens, CD271+ cells engrafted in 70% of the transplants compared with 7% of CD271– cells (P<0.0001). However, when specimens were allowed to further expand in animals prior to cell injection, tumors grew melanomas in 72% of tries involving CD271+ cells compared with 20% of tries with CD271– cells (P=0.0001). Although it may seem like a fine point, it does suggest that during the process of tumor propagation ex vivo, more cells gain the capacity to be tumorigenic — i.e., some of the results may be biased by an artifact of technique. The investigators also found that the CD271+ cells did not strongly express melanocyte differentiation antigens, such as TYR, MART1, and MAGEC1/MAGEC2, which are the current target antigens, unfortunately, of antimelanoma immunity strategies.

Comment: The melanoma stem cell debate has not ceased. Several interesting findings arise from this study. First, the association with CD271 establishes a developmental link between neural crest cells and melanomas, which has tremendous biological plausibility. Second, the use of fresh human specimens rather than cell lines puts a new spin on our understanding of how to analyze cancer stem cells; it is likely that the proportion of melanoma stem cells would vary as melanomas expand and, therefore, that the frequency with which MICs would be observed would change over time. Lastly, the clinical implications are a bit disturbing. If the stem cell population is unaffected by antimelanoma immunity, current immunotherapeutic approaches that rely on TYR, MART1 or MAGE as antigens may not be properly targeting the mother lode.

— Hensin Tsao, MD, PhD

Published in Journal Watch Dermatology July 30, 2010

Citation(s):

Boiko AD et al. Human melanoma-initiating cells express neural crest nerve growth factor receptor CD271. Nature 2010 Jul 1; 466:133.

• Medline abstract (Free)

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