A prolonged and exaggerated wound response with elevated ODC activity mimics early tumor development

Abstract

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.

Polyamine-Blocking Therapy Reverses Immunosuppression in the Tumor Microenvironment

“…A single, topical, sub-threshold exposure to a carcinogen, then induction of epidermal ODC enzyme activity by topical treatment with the inducing agent 4-hydroxytamoxifen (4OHT), leads to rapid development of squamous cell carcinomas in transgenic mice (9). Wound repair following skin abrasion in ODC-ER transgenic mice is prolonged and characterized by exaggerated epidermal hyperplasia, persistent inflammation, and wound-induced tumors (10). …”

“…Smoldering, nonresolving inflammation characterizes the tumor microenvironment in which tumor infiltrating myeloid cells acquire M2 properties that promote cancer cell proliferation, stromal deposition, and angiogenesis and that inhibit adaptive immunity (45). Interestingly, we have shown previously that wound-induced skin tumor formation in ODC-ER transgenic mice is dependent on a polyamine-induced persistent inflammation following wounding (skin abrasion) (10). PBT may modulate the chronic, “smoldering” inflammation that characterizes many tumors by skewing tumor myeloid cell polarization from a M2 pro-tumor growth phenotype to a M1 pro-inflammatory phenotype.…”

“…A hallmark of tumorigenesis involves the induction of ornithine decarboxylase (ODC), the initial ratelimiting enzyme in polyamine biosynthesis (4, 5). Use of transgenic mouse models has demonstrated that increased ODC activity is sufficient to promote tumor development following low dose exposure to carcinogens, UV irradiation, or oncogene activation and wounding (6–10). It is commonly thought that tumorigenesis is promoted by elevated polyamine levels because they stimulate cellular proliferation and angiogenesis in tumors (9, 11–14).…”

Keratin-6 driven ODC expression to hair follicle keratinocytes enhances stemness and tumorigenesis by negatively regulating Notch

“…Hayes et al showed that elevated ODC stimulate the recruitment of bulge stem cells during the pathogenesis of skin cancer [8]. CK15 + and CD34 + cells in hair follicle mark keratinocytes with stem cell characteristics.…”

“…Over-expression of ODC has been demonstrated as an early event in the neoplastic transformation both in murine and human skin keratinocytes [4]. In this regard, employing various animal models of skin carcinogenesis and other epithelial tumors a direct link between increased ODC activity and promotion of neoplastic growth has also been established [7,8]. …”