Loss of Notch1 Signaling Leads to Skin Cancer in Mouse Model

Researchers using a line of genetically engineered mice lacking the Notch1 signaling protein in some skin cells have found that a state of persistent inflammation can lead to the generation of skin cancers from both normal cells and those lacking the Notch1 gene.

Investigators at Washington University School of Medicine (St. Louis, MO, USA) created a line of mice with both normal and Notch1 null skin cells. These animals developed thickened and inflamed patches of skin due to an increased number of blood vessels and local inflammation, which were a result of missing Notch1 signaling in some of the cells. Interestingly, these animals were prone to developing skin papillomas that originated from both normal and Notch 1 null skin cells. About 10% of these papillomas progressed to basal cell carcinomas.

While Notch1 is generally considered a tumor-suppressing gene in skin cells, Notch1 null patches of skin encouraged angiogenesis and the production of growth factors. The persistent expression of these factors provided cells with nutrients and proliferation signals that promoted tumor formation in the mutant skin tissue and in neighboring normal skin cells with active Notch1 signaling.

"The chronic skin condition in the mice led to the growth of skin tumors," said senior author Dr. Raphael Kopan, professor of developmental biology and dermatology at Washington University School of Medicine. "And what we learned from this process fit very well with the emerging realization that a tumor's surroundings play a critical role in its development. The study suggests that as researchers develop drugs, they should be mindful of their potential effect on the skin, particularly those that cause chronic damage to skin integrity. Studies like ours help define the range of possible complications in drug design and help tailor therapies to avoid them."

"It is very reasonable to assume that chronic wounds in a variety of tissues have similar characteristics," said Dr. Kopan. "The skin of these mice is easy to monitor and will give us the ability to further analyze tumor promotion and find answers that might apply to any chronic wound."

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Washington University School of Medicine