Research looks at melanocyte role in tumor formation

Human melanocytes may give rise to deadly tumors, according to Meenhard Herlyn, Ph.D., who presentated on the topic at The World Congress on Cancers of the Skin held in August/September in Vienna, Austria.

Dr. Herlyn“Melanocytes are located at the basement membrane that separates the epidermis from the dermis,” Dr. Herylyn explained. He is a professor of melanoma research at Wistar Institute in Philadelphia.

Dr. Herlyn says the turnover rate of melanocytes is slow, lasting from months to even years.

“They are also continuously exposed to DNA-damaging insults such as ultraviolet (UV) radiation,” he says. “However, melanocytes can generally repair damage quite efficiently.”

If the damage becomes too severe, melanocytes will express apoptosis markers and die. But a stem cell pool that resides in the dermis will survive to replenish the melanocytes.

“Those stem cells can differentiate into melanocytes, as well as into neuronal cells, smooth muscle cells or bone and cartilage,” Dr. Herlyn tells Dermatology Times. “These stem cells are not pigmented and can also be damaged by UVA, but less by UVB because that kind of light generally does not reach the dermis.”

The stem cells migrate from the dermis to the basement membrane zone.  As soon as they connect with keratinocytes, they mature to melanocytes,” Dr. Herlyn says. This connection is mediated by adhesion receptors (E-cadherin). “From then on, the keratinocytes in the basal layer dictate the growth rate of melanocytes, plus the expression of molecules on their surface,” he says.

In general, the shape of melanocytes is dictated by proteins in the basement membrane.

“Any disturbance of melanocytes may result in their removal from the basement membrane,” Dr. Herlyn says. “However, melanocytes try very hard to remain in the basement membrane zone because any removal will result in the cells activating apoptosis signals prior to death or they can be transformed through a combination of oncogenes and tumor suppressor gene mutations.”

Experimentally, transformation occurs most efficiently by viral oncogenes, according to Dr. Herlyn. “Still, viral oncogenes appear not to play any role in transformation to melanoma,” he says.

The cellular oncogenes that are detected the earliest in melanocytes, particularly in nonmalignant nevus cells, are mutated BRAF and NRAS. “But nevus cells can also carry mutations in the promoter region of the TERT genes,” Dr. Herlyn says. Furthermore, any combination of three to four oncogenes, or the downregulation or genetic inactivation of tumor suppressor genes, “can lead to malignant transformation,” Dr. Herlyn says. In some cases, only two mutations are sufficient for transformation.

Because approximately 80% of nevi carry a mutation of the BRAF oncogene, “there is always the possibility of cells acquiring additional mutations for transformation,” Dr. Herlyn says. “However, the dominant oncogenes, such as BRAF and NRAS, induce in melanocytes a state of senescence, which prevents melanocytes from further proliferation.”

This senescence can be overcome at an early stage, but not at a later stage, by which time the cells cannot be rescued.

“If the melanocytes are exposed to a tumor suppressor gene like CDKN2B or p15 at an early stage, malignant transformation can occur,” Dr. Herlyn says.

Overall, melanocytes “are in a precarious balance, due to their control by the keratinocytes and also their continuous exposure to DNA-damaging UV irradiation in the range of UVB and UVA,” Dr. Herlyn says.

Not surprisingly, melanocytes have “outstanding” mechanisms for repair, Dr. Herlyn says. “However, for individuals with specific genetic risk variance, this repair may be impaired or reduced,” he says. “Thus, we have begun to study those melanocytes that are derived from patients who have a moderate to high risk for developing melanoma.”

This is experimentally challenging, though, because most individuals are identified at an advanced age in life, “at a time when the melanocytes no longer readily proliferate,” Dr. Herlyn says. “Melanocytes isolated from the epidermis readily proliferate from birth to early adult, but after the age of 50 they are very difficult to study, due to their limited lifespan in culture.”

To overcome this limitation, melanocytes have been created by differentiating fibroblast or blood cells by using four transcription factors “that reprogram any cell to an induced pluripotent stem cell (iPS cell),” Dr. Herlyn says. “Such cells have embryonic stem-like characteristics, which at least theoretically allow them to be differentiated into any cell of the human body, including melanocytes.”

Laboratory models of melanocytes that are highly susceptible to transformation show that these melanocytes “have impaired responses to UV and to oncogenes, if their DNA is damaged,” Dr. Herlyn says. This knowledge will allow for the development of new strategies for prevention of deadly tumors in those individuals who are carriers of risk genes.