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Melanoma Stem Cells: Needle in the Haystack, or Mostly Hay?

Efforts to identify and study cells capable of initiating melanomas remain controversial.

Normal stem cells have functional properties that enable them to both renew themselves and produce differentiated cells that ultimately form organs, tissues, and entire organisms. Similarly, tumors can arise from single cells and also exhibit considerable heterogeneity. Cancer stem cells are not necessarily related to normal stem cells but have similar properties of self-renewal and the ability to form entire tumors. In some myeloid leukemias, for example, a hierarchical organization of cells includes rare cancer stem cells that proliferate slowly, giving rise to distinct, more differentiated clones that form the bulk of the tumor.¹ However, the cancer stem cell–driven hierarchy is not the only explanation of tumor heterogeneity. Tumors may also evolve through a sequence of acquired genetic changes in clone cells.

Tumor heterogeneity has very important therapeutic implications. For example, therapies that target rapidly proliferating cells but not the cancer stem cells that are the ultimate source of the malignancy are unlikely to be effective. Recent reports also demonstrate that reactivating such tumor suppressor pathways as p53 seems to affect only high-grade areas, reinforcing the notion that tumors are heterogeneous in composition and in response to therapies.^2,3

Melanoma stem cell research has been marked by controversy, with widely divergent findings regarding the prevalence of tumorigenic cells derived from human melanomas. Multiple research groups have reported finding markers of rare melanoma stem cells or tumor-initiating cells, including CD271⁴ and ABCB5.⁵ Their results support the idea that melanoma is organized as a hierarchy, and that markers distinguish the rare tumorigenic cells from nontumorigenic ones. These markers may have functional implications. ABCB5, for example, is a transporter that may confer resistance to immune attack and chemotherapy.^6,7

In contradistinction, another group has concluded that these markers are heterogeneously expressed across tumor cells as expected but fail to distinguish tumorigenic cells from nontumorigenic ones.⁸ These authors find that as many as 25% of cells isolated from melanomas are highly tumorigenic⁹ and that the observed heterogeneity can be explained by clonal evolution. In addition, they suggest that the same markers previously described as identifying melanoma-initiating cells may be heterogeneously and reversibly expressed.

Comment: It is not surprising that investigators have drawn such different conclusions about the characteristics of melanoma-initiating cells. Experimentally, the functional definition of a cancer stem cell or tumor-initiating cell is its ability to form a tumor in an immunocompromised mouse host. Different melanoma research groups have used mouse strains with different degrees of immunodeficiency and differ in their use of primary tumor cells versus more extensively cultured cells from human melanomas. These experiments are also extremely challenging technically.

So far, researchers have assessed only the ability of implanted cells to proliferate, without regard for microenvironmental factors, such as tissue stroma and immune cells. How tumorigenic melanoma cells actually contribute to tumor formation, progression, and metastasis (i.e., their ultimate behavior in humans) is also unknown. Controversy will continue until results from identical experimental systems can be independently validated and linked to the dynamics of tumor formation and progression in humans. The clinical implications are far reaching and will affect the rational design of future therapies.

— Kenneth Y. Tsai, MD, PhD

Published in Journal Watch Dermatology December 22, 2010

Citation(s):

1. Lapidot T et al. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature 1994 Feb 17; 367:645.

• Medline abstract (Free)

2. Feldser DM et al. Stage-specific sensitivity to p53 restoration during lung cancer progression. Nature 2010 Nov 25; 468:572.

• Medline abstract (Free)

3. Junttila MR et al. Selective activation of p53-mediated tumour suppression in high-grade tumours. Nature 2010 Nov 25; 468:567.

• Medline abstract (Free)

4. 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)

5. Schatton T et al. Identification of cells initiating human melanomas. Nature 2008 Jan 17; 451:345.

• Medline abstract (Free)

6. Frank NY et al. ABCB5-mediated doxorubicin transport and chemoresistance in human malignant melanoma. Cancer Res 2005 May 15; 65:4320.

• Original article (Subscription may be required)
• Medline abstract (Free)

7. Schatton T et al. Modulation of T-cell activation by malignant melanoma initiating cells. Cancer Res 2010 Jan 15; 70:697.

• Original article (Subscription may be required)
• Medline abstract (Free)

8. Quintana E et al. Phenotypic heterogeneity among tumorigenic melanoma cells from patients that is reversible and not hierarchically organized. Cancer Cell 2010 Nov 16; 18:510.

• Medline abstract (Free)

9. Quintana E et al. Efficient tumour formation by single human melanoma cells. Nature 2008 Dec 4; 456:593.

• Medline abstract (Free)

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