Use of transgenic mouse models has demonstrated that polyamines play an essential role in the early promotional phase of pores and skin tumorigenesis

Use of transgenic mouse models has demonstrated that polyamines play an essential role in the early promotional phase of pores and skin tumorigenesis. have been shown to stimulate epidermal proliferation, alter keratinocyte differentiation status, increase neovascularization, and increase synthesis of extracellular matrix proteins in a manner similar to that seen in wound healing. It is becoming increasingly apparent that elevated polyamine levels activate not only epidermal cells but also underlying stromal cells in the skin to promote the development and progression of pores and skin tumors. The inhibition of polyamine biosynthesis offers potential to become an effective chemoprevention strategy for nonmelanoma pores and skin malignancy. at its earliest phases (Cockerell, 2000). Probably one of the most frequently used animal models for studying carcinogenesis inside a lining epithelium is the initiation-promotion model of tumorigenesis in mouse pores and skin. Whereas actinic keratoses are thought to be the benign precursor for human being SCCs, papillomas have been identified as benign precursors for murine SCCs. Papillomas are benign epidermal tumors seen very regularly after chemical carcinogen exposure, especially in two-stage carcinogenesis protocols in mouse pores and skin (Klein-Szanto, 1989). Murine papillomas are cauliflower-like constructions with a series of folds consisting of a central vascularized, connective cells core covered by a proliferative, stratified squamous epithelium and an abundant, orthokeratotic horny coating. Some papillomas regress, but others can progress to malignancy. Squamous cell carcinomas (SCC) can be induced in animals using UV light, ionizing radiation, or chemical carcinogens. In contrast to humans, mice have a strong predisposition to developing squamous cell carcinomas and appear to be relatively resistant to the development of BCCs. Following exposure to UV light or total carcinogens, mice can also develop keratoacanthomas (KA), which have a cup-shaped form having a horny central crater and epidermal edges that look like a continuation of the top third of hair follicles. Unlike human being KA, murine KA hardly ever regress and often convert to squamous carcinomas (Klein-Szanto, 1989). ODC and NonMelanoma Pores and skin Tumorigenesis Polyamines have long 1-Methylpyrrolidine been known to be associated with cell proliferation in both normal and neoplastic cells (Tabor and Tabor, 1984; Pegg, 1986; Pegg, 1988). Elevated levels of ODC and improved polyamines were in the beginning suspected to play a causal part in pores and skin tumorigenesis largely due to the early induction of ODC by tumor promoters (O’Brien, 1976; Gilmour (Bello-Fernandez (H?ltta (Shantz and Pegg, 1998), or an activated Ras or RhoA (Shantz and Pegg, 1998). In fact, c-Myc has been shown to transactivate ODC (Bello-Fernandez oncogene develop spontaneous keratoacanthomas and squamous cell carcinomas, whereas no tumors develop in the mono-transgenic mice (Smith tumor suppressor 1-Methylpyrrolidine gene and overexpressing 1-Methylpyrrolidine ODC in follicular cells (Tang induction of suprabasal epidermal ODC activity in ODCER transgenic mice raises both proliferation in the basal coating of the epidermis as well 1-Methylpyrrolidine as epidermal differentiation (Lan polymorphism (associated with higher ODC activity) and improved prostate malignancy risk in males who smoke or have high risk alleles of the androgen receptor gene (Visvanathan em et al. /em , 2004). Although there is no data in humans to suggest that some individuals may be at an elevated risk for nonmelanoma pores and skin cancer based on the presence of ODC polymorphic variants, an area for future studies is definitely whether chemoprevention using DFMO is definitely more efficacious if combined with screening for ODC polymorphic variants that may be associated with higher potential for ODC induction and improved malignancy risk (Guo em et al. /em , 2000). In addition, future studies using mouse strains with varying tumor reactions may identify human being genetic loci that change ODC-dependent enhanced susceptibility to skin tumorigenesis (Megosh em et al. /em , 2002; George em et al. /em , 2005). Despite these promising results in clinical trials for cancer prevention, there have been no published reports of polyamine-based chemotherapeutic trials for basal cell carcinomas or squamous cell carcinomas. In part, this may be due to the lack of success of DFMO as a global antitumor CALN agent in other tissue types since ODC inhibition leads to a compensatory increased cellular uptake of polyamines from the circulation which neutralizes the cytostatic effect of DFMO (Meyskens and Gerner, 1999). However, murine squamous cell carcinomas, with the exception of aggressive spindle cell carcinomas, show rapid tumor regression following treatment with high doses of DFMO (Chen em et al. /em , 2004)..