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Chronic Skin Condition May Lead to Tumor Growth
Posted: July 9, 2009
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Without Notch1, patches of the mice's skin developed abnormally and became thickened and inflamed. As the mice aged, benign tumors called papillomas formed. About 10% of these tumors spontaneously progressed to basal cell carcinoma, the most common type of skin cancer in people.
Importantly, further analysis showed that skin tumors had originated from both mutant and normal skin cells. Because normal cells contain active Notch1, they were not expected to form tumors, and that was an important clue that factors other than the missing Notch1 were responsible for tumor formation in skin. "Loss of Notch1 signaling in the mutant skin cells generated a wound-like environment in which both the mutant and normal skin cells became prone to cancer," Kopan says.
The research team showed that the mutant skin patches encouraged the growth of tiny blood vessels and production of growth factors that when expressed transiently help repair skin damage. The persistent expression of these factors provided cells with nutrients and proliferation signals that promoted tumor formation, Kopan says. Numerous immune cells secreting additional factors infiltrated the abnormal skin patches and adjacent cells, contributing to inflammation.
Recently, drugs that lower Notch1 activity have been used to manage Alzheimer's disease and to treat some forms of cancer, because, paradoxically, Notch1 can be a tumor promoter in tissues other than skin. Kopan says that his study shows that skin is very sensitive to reduction of Notch1 activity. The long-term use of such medications and others that compromise skin integrity could contribute to an increased likelihood of skin cancer, he says.
"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," Kopan says. "Studies like ours help define the range of possible complications in drug design and help tailor therapies to avoid them."