Induction of
ornithine decarboxylase (ODC), a key
enzyme in
polyamine biosynthesis, in ODC transgenic skin stimulates epidermal proliferation but not
hyperplasia, activates underlying stromal cells and promotes skin
tumorigenesis following a single subthreshold dose of a
carcinogen. Because chronic
wounds are a well-recognized risk factor for
skin cancer, we investigated the response to a tissue remodeling event in normal skin that is abraded to remove only the epidermal layer in K6/ODC transgenic (follicular ODC expression) and in inducible ODCER transgenic mice (suprabasal ODC expression). When regenerative epidermal
hyperplasia was resolved in normal littermates following abrasion, ODC transgenic mice exhibited progressive epidermal
hyperplasia with formation of benign
tumor growths and maintained an increased epidermal proliferation index and activation of translation-associated
proteins at abrasion sites. The epidermal
hyperplasia and
tumor-like growth was accompanied by activation of underlying stromal cells and prolonged infiltration of inflammatory cells. Treatment with the
anti-inflammatory agent dexamethasone did not reduce the high proliferative index in the regenerated epidermis but dramatically reduced the epidermal
hyperplasia and prevented the
wound-induced
tumor growths in abraded ODCER skin. Treatment with α-
difluoromethylornithine, a specific inhibitor of ODC activity, normalized the
wound response in transgenic mice and decreased
wound-induced
inflammation if administered from the time of abrasion but not if initiated 4 days following abrasion. These results suggest a role for
polyamines in prolonging
wound-associated
inflammation in addition to stimulating proliferation both of which are sufficient to sustain epidermal
hyperplasia and benign
tumor growth even in the absence of genetic damage.