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SDEF: Preconceived Melanoma Pathogenesis Called Into Question


 

EXPERT ANALYSIS FROM SDEF HAWAII DERMATOLOGY SEMINAR

Clinical observation calls into question some of the preconceived notions about melanoma pathogenesis, according to Dr. James M. Grichnik.

The traditional model is that melanomas initially develop from differentiated melanocytes in the epidermis and then invade the dermis. This is largely based on pathologic features, said Dr. Grichnik, director of the melanoma program at Sylvester Cancer Comprehensive Center, and professor of dermatology at the University of Miami. Specifically, the lowest-risk melanoma in situ tumors are thought to remain in the epidermis, while higher-risk tumors invade the deeper dermal tissues.

However, there is a newer model of melanomagenesis that is based on stem cell biology, Dr. Grichnik said at the Hawaii Dermatology Seminar sponsored by Skin Disease Education Foundation (SDEF). The model suggests that stem cells in the dermis can become mature epidermal melanocytes, and that early epigenetic or genetic alterations leading to transformation may take place in the dermis rather than in the epidermis (J. Invest. Dermatol. 2008;128:2365-80).

Also, stem cell markers CD166, CD133, and nestin are expressed at significantly higher levels in melanoma compared to banal nevi. Nestin was found to be significantly increased in metastatic melanoma, compared with primary melanoma, suggesting this subpopulation of cells may be particularly virulent (Mod. Pathol. 2007;20:102-7).

The problem with tumor stem cell components, however, is that they may not have normal antigens, and components may escape into the lymph system rather than adhere to the lymph nodes.

"So, the immune system doesn't do a good job of catching them," Dr. Grichnik said, adding that tumors contain a heterogeneous population of cells. "They're trying to differentiate towards a normal pigment of cells, the melanocytes. Some of the heterogeneous population has the antigens that the immune system destroys, but the stem cell population doesn't."

Recognition of these pathways may lead to better diagnostic and therapeutic tools. A multiple treatment approach most likely will be needed.

"One approach is to destroy proliferative cells and another is to destroy the nonproliferative tumor stem cells," Dr. Grichnik said. "We'll have to develop therapies that are specific to the tumor stem cells."

Dr. Grichnik disclosed that he is a major shareholder and founder of DigitalDerm, and serves in a consultant role for Electro-Optical Systems and Spectral Image.

SDEF and this news organization are owned by Elsevier.

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