Melanoma Appears to Not Follow the Cancer Stem Cell Model

Scientists also report observing phenotypic plasticity among melanoma cells.

University of Michigan (U-M) researchers say that most types of melanoma cells can form malignant tumors. In addition, they found that melanoma tumor cells can change their appearance by switching various genes on and off, making the malignant cells a stealthy, shape-shifting target for researchers seeking new treatments.

The team, led by Sean Morrison, Ph.D., director of the U-M Center for Stem Cell Biology, notes that both findings fly in the face of the cancer stem cell model, which states that a handful of rare melanoma stem cells drive the formation, growth, and progression of malignant tumors in many cancers.

Details are published November 16 in Cancer Cell, and the paper is titled “Phenotypic Heterogeneity among Tumorigenic Melanoma Cells from Patients that Is Reversible and Not Hierarchically Organized.”

The research follows work reported by the Morrison lab in the December 4, 2008, edition of Nature showing that tumor-forming melanoma cells are not rare, as predicted by the cancer stem cell model. That paper suggested that at least one quarter of melanoma cells have the ability to form new tumors.

Dr. Morrison’s team believes that their most recent search of melanoma cells was exhaustive and says that it turned up nothing. They analyzed 44 subpopulations of human melanoma cells. All 44 had a similar ability to form tumors when transplanted into mice.

“Our results suggest that most melanoma cells are capable of driving disease progression and that it won’t be possible to cure patients by targeting rare sub-populations of cells,” says Dr. Morrison. “We think you need to kill all the cells.”

The study also found that tumor-forming melanoma cells have the ability to throw a genetic switch that changes the types of proteins expressed on the cells’ surface. The U-M group believes that this is the first research to present evidence for this type of pervasive phenotypic plasticity among melanoma cells.

“The fact that these markers are turned on and off by melanoma cells raises the possibility that melanoma cells may also turn on and off genes that regulate clinically important characteristics like drug resistance and metastatic ability,” Dr. Morrison remarks. “The ability to transition between various states may make melanoma more difficult to treat.”

The U-M team found that all tumor-forming melanoma cells gave rise to progeny with a variety of marker patterns, and all of those subpopulations retained the ability to form tumors. The marker changes appeared to be reversible, rather than being associated with a transition from tumor-forming to nontumor-forming states, as the cancer stem cell model would predict.