In spite of research backing the CSC theory, there are many who believe that the stem cell model has not been adequately tested in most cancers. In January 2008, investigators identified a subpopulation enriched for human malignant melanoma-initiating cells defined by expression of the chemoresistance mediator ABCB5. Details reported in Nature by scientists from the Transplantation Research Center of Children's Hospital Boston and Brigham and Women's Hospital suggest that specific targeting of this tumorigenic minority population inhibits tumor growth.
ABCB5+ tumor cells detected in human melanoma patients showed a primitive molecular phenotype and correlate with clinical melanoma progression. In serial human-to-mouse xenotransplantation experiments, ABCB5+ melanoma cells possessed greater tumorigenic capacity than ABCB5-bulk populations and re-establish clinical tumor heterogeneity.
Additionally, Dr. Morrison and his team published a paper in the December 2008 issue of Nature showing that use of a standard immunodeficient mouse model, the NOD/SCID mouse, underestimates the frequency of tumorigenic human cancer cells. They showed that modified xenotransplantation assay conditions including the use of more highly immunocompromised NOD/SCID interleukin-2 receptor gamma chain null (IL2Rα<super>null</super>) mice can increase the detection of tumorigenic melanoma cells by several orders of magnitude.
Exemplifying the debate are the findings, published last June, of scientists at Stanford University’s Institute for Stem Cell Biology and Regenerative Medicine that a population of human melanoma cells developed into tumors in immunodeficient mice. The isolated cells originated at various sites and stages and were enriched for expression of the CD271+ bearing cells.
The CD271+ subset of cells was the tumor-initiating population in 90% of melanomas tested in the study, according to the researchers. However, melanoma did not develop after transplantation of isolated CD271- cells. The investigators also showed that tumors derived from these MTSC CD271+ transplanted human melanoma cells could metastasize in vivo.
Additionally, the CD271+ melanoma cells were found to lack expression of TYR, MART1, and MAGE in 86%, 69%, and 68% of melanoma patients, respectively. This helps to explain, according to the investigators, why T-cell therapies directed at these antigens usually result in only temporary tumor shrinkage.