Cancer stem cells are defined by three abilities: differentiation, self-renewal and their ability to seed a tumor. These stem cells resist chemotherapy and many researchers posit their role in relapse. A University of Colorado Cancer Center study recently published in the journal Stem Cells, shows that melanoma cells with these abilities are marked by the enzyme ALDH, and imagines new therapies to target high-ALDH cells, potentially weeding the body of these most dangerous cancer creators.
"We've seen ALDH as a stem cell marker in other cancer types, but not in melanoma, and until now its function has been largely unknown," says the paper's senior author, Mayumi Fujita, MD, PhD, investigator at the CU Cancer Center and associate professor in the Department of Dermatology at the CU School of Medicine.
Fujita's group transplanted ALDH+ and ALDH- melanoma cells into animal models, showing the ALDH+ cells were much more powerfully tumorigenic. In the same ALDH+ cells, the group then silenced the gene that creates this protein, finding that with ALDH knocked down, melanoma cells died in cultures and lost their ability to form tumors in animal models. In cell cultures, silencing this ALDH gene also sensitized melanoma cells to existing chemotherapies. When the group explored human tumor samples, they found distinct subpopulations of these ALDH+ cells, which made up about 0.1-0.2 percent of patients' primary tumors. In samples of metastatic melanoma – the most aggressive form of the disease – the percentage of ALDH+ cells was greater, even over 10 percent in some tumors, further implying the powerful danger of these cells.
"In these same ALDH+ cells, we find the markers of stem cells are upregulated and those of cell differentiation are downregulated. In addition to these clues, ALDH+ cells generate the heterogeneous cell types seen in the original tumor," says Fujita, meaning that in addition to self-renewal and tumorigenesis, ALDH+ cells fulfill the third criteria for a cancer stem cell: the ability to differentiate.