Skin Cancer Starts When Tanning Goes Wrong in Mutated Stem Cells

Melanoma, a cancer of skin pigment cells called melanocytes, will strike an estimated 87,110 people in the U.S. in 2017, according to the Centers for Disease Control and Prevention. A fraction of those melanomas come from pre-existing moles, but the majority of them come from sources unknown — until now.

The origin of melanoma, one of the deadliest cancers, precedes the usual warning signs – the appearance of new or changing skin lesions. Melanoma actually begins in individual cells, most often in cells located in clear skin. But exactly which cells, under what circumstances, has been unclear. A group of scientists based at Cornell University now report that melanoma may arise from melanocyte stem cells (MCSCs), specifically, MCSCs that have become “melanoma competent” because they have accumulated a sufficient number of genetic mutations.

Merely acquiring a large enough mutational burden, however, is not enough for an MCSC to give rise to a melanoma. The MCSC must, in addition, be subjected to ultraviolet radiation strong enough to initiate a protective response—or, rather, a would-be protective response.

Ordinarily, the protective response initiated by ultraviolet (UV)-activated melanocytes involves the release of melanin, a pigment that shields the skin from the sun’s rays. In melanoma-competent MSCs, however, something else can happen: a sequence of events that results in melanoma.

This sequence of events was detailed in the journal Cell Stem Cell, in an article entitled “Melanocyte Stem Cell Activation and Translocation Initiate Cutaneous Melanoma in Response to UV Exposure.” The article not only delineates melanoma formation, highlighting the roles of mutational burden and UV stimulation, it also identifies a gene critical to melanomagenesis. Suppressing expression of this gene, the article’s authors suggest, could suppress melanomas of MSC origin.

“Here we employ mouse models to define the role of MCSCs as melanoma cells of origin, demonstrate that MCSC quiescence acts as a tumor suppressor, and identify the extrinsic environmental and molecular factors required for the critical early steps of melanoma initiation,” the article’s authors wrote. “Specifically, melanomas originate from melanoma-competent MCSCs upon stimulation by UVB, which induces MCSC activation and translocation via an inflammation-dependent process.”

The Cornell scientists used mice engineered with melanocyte stem cell mutations. One set of mice not only had these mutations but was also deprived of a particular gene, the Hgma2 gene. Hgma2 has been suspected of becoming expressed in the skin under UV radiation. When expressed, Hgma2 facilitates melanocyte stem cells movement from the base of skin hair follicles to the skin’s surface (the epidermis), where the cells release melanin.

The mice were given a very low dose of UV radiation, just enough to trigger a tanning response. Mice with tumor-causing mutations and the Hgma2 gene intact developed melanomas, but the mice with mutations and the deleted gene remained healthy.

“The chromatin-remodeling factor Hmga2 plays a critical role in UVB-mediated melanomagenesis,” the authors of the Cell Stem Cell article indicated. “Hmga2 in the skin microenvironment is required for UVB-mediated melanoma initiation.”

“If you had mutations that were sufficient for melanoma, everything would be fine until you went out and got a sunburn,” explained Andrew White, Ph.D., assistant professor of biomedical sciences at Cornell’s College of Veterinary Medicine, and senior author of the current study. “The stimuli that would normally just give you a tanning response could in fact start a melanoma instead.”

More study is needed to better understand the Hgma2 gene’s function.

“We have an actual mechanism, with Hgma2, that can be explored in the future and could be a way we can prevent melanomas from happening,” White said.