RESUMEN
Ultraviolet B (UVB) light is the major environmental carcinogen contributing to non-melanoma skin cancer (NMSC) development. There are over 3.5 million NMSC diagnoses in two million patients annually, with men having a 3-fold greater incidence of squamous cell carcinoma (SCC) compared with women. Chronic inflammation has been linked to tumorigenesis, with a key role for the cyclooxygenase-2 (COX-2) enzyme. Diclofenac, a COX-2 inhibitor and non-steroidal anti-inflammatory drug, currently is prescribed to patients as a short-term therapeutic agent to induce SCC precursor lesion regression. However, its efficacy as a preventative agent in patients without evidence of precursor lesions but with significant UVB-induced cutaneous damage has not been explored. We previously demonstrated in a murine model of UVB-induced skin carcinogenesis that when exposed to equivalent UVB doses, male mice had lower levels of inflammation but developed increased tumor multiplicity, burden and grade compared with female mice. Because of the discrepancy in the degree of inflammation between male and female skin, we sought to determine if topical treatment of previously damaged skin with an anti-inflammatory COX-2 inhibitor would decrease tumor burden and if it would be equally effective in the sexes. Our results demonstrated that despite observed sex differences in the inflammatory response, prolonged topical diclofenac treatment of chronically UVB-damaged skin effectively reduced tumor multiplicity in both sexes. Unexpectedly, tumor burden was significantly decreased only in male mice. Our data suggest a new therapeutic use for currently available topical diclofenac as a preventative intervention for patients predisposed to cutaneous SCC development before lesions appear.
Asunto(s)
Carcinoma de Células Escamosas/prevención & control , Inhibidores de la Ciclooxigenasa 2/administración & dosificación , Diclofenaco/administración & dosificación , Neoplasias Inducidas por Radiación/prevención & control , Neoplasias Cutáneas/prevención & control , Carga Tumoral/efectos de los fármacos , Rayos Ultravioleta/efectos adversos , Administración Tópica , Animales , Carcinoma de Células Escamosas/etiología , Carcinoma de Células Escamosas/patología , Ciclooxigenasa 2/química , Ciclooxigenasa 2/metabolismo , Femenino , Técnicas para Inmunoenzimas , Masculino , Ratones , Ratones Pelados , Clasificación del Tumor , Neoplasias Inducidas por Radiación/etiología , Neoplasias Inducidas por Radiación/patología , Neoplasias Cutáneas/etiología , Neoplasias Cutáneas/patología , Carga Tumoral/efectos de la radiaciónRESUMEN
In immunocompromised individuals, such as organ transplant recipients, the risk of cutaneous squamous cell carcinoma (SCC) is increased 60-250 fold, and there is an increased likelihood to develop aggressive, metastatic SCC. An understanding of the genes involved in SCC tumorigenesis is critical to prevent SCC-associated morbidity and mortality. Mouse models show that different immunosuppressive drugs lead to SCCs varying in size, number, and malignant potential. In this study, we used mouse models that mimic adult transplant recipients to study the effect of immunosuppressive drugs and UV light on SCC development. UV-induced tumors from six treatment groups, control, tacrolimus (Tac), rapamycin (Rap), cyclosporin (CsA), mycophenolate mofetil (MMF), and Rap plus CsA, were evaluated by array comparative genomic hybridization. Mouse SCCs appear to show similar genomic aberrations as those reported in human SCCs and offer the ability to identify genomic changes associated with specific and combinatorial effects of drugs. Fewer aberrations were seen in tumors of mice treated with MMF or Rap. Tumors from Tac-treated animals showed the highest number of changes. Calcineurin inhibitors (Tac and CsA) did not cluster together by their genomic aberrations, indicating their contribution to UV mediated carcinogenesis may be through different pathways. The combination treatment (Rap plus CsA) did not cluster with either treatment individually, suggesting it may influence SCC tumorigenesis via a different mechanism. Future studies will identify specific genes mapping to regions of aberration that are different between treatment groups to identify target pathways that may be affected by these drugs.
Asunto(s)
Carcinoma de Células Escamosas/genética , Aberraciones Cromosómicas , Inmunosupresores/toxicidad , Neoplasias Inducidas por Radiación/genética , Neoplasias Cutáneas/genética , Rayos Ultravioleta , Análisis de Varianza , Animales , Carcinoma de Células Escamosas/inducido químicamente , Carcinoma de Células Escamosas/metabolismo , Hibridación Genómica Comparativa , Modelos Animales de Enfermedad , Femenino , Dosificación de Gen , Humanos , Huésped Inmunocomprometido , Ratones , Ratones Pelados , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Neoplasias Inducidas por Radiación/metabolismo , Análisis de Secuencia por Matrices de Oligonucleótidos , Neoplasias Cutáneas/inducido químicamente , Neoplasias Cutáneas/metabolismoRESUMEN
The American Cancer Society reports the incidence of squamous cell carcinoma in males to be thrice the incidence in females. This increased squamous cell carcinoma incidence has been attributed to men accumulating more sun exposure and using less sun protection than women. To date, there have been no controlled studies examining the effect of gender on skin tumor development following equal doses of UVB. Gender differences in UVB-induced skin carcinogenesis were examined using the Skh-1 mouse model. After chronic exposure to equal doses of UVB, male mice developed tumors earlier and had more tumors than female mice; tumors in male mice tended to be larger, and the total tumor burden was greater than in females. In addition, tumors in males were of more advanced histologic grade compared with those of female mice. To evaluate the contribution of differences in inflammation and DNA damage to differences in skin carcinogenesis, male and female Skh-1 mice were exposed once to 2,240 J/m(2) UVB and examined 48 h after exposure. Surprisingly, male mice developed less of an inflammatory response, as determined by skin fold thickness and myeloperoxidase activity, compared with females. Interestingly, male mice showed more cutaneous oxidative DNA damage than the females and lower antioxidant levels. These results show a gender bias in skin carcinogenesis and suggest that the gender difference in tumor development is more influenced by the extent of oxidative DNA damage and antioxidant capacities than by inflammatory response.
Asunto(s)
Transformación Celular Neoplásica/efectos de la radiación , Daño del ADN , Neoplasias Cutáneas/etiología , Piel/efectos de la radiación , Animales , Antioxidantes/metabolismo , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Transformación Celular Neoplásica/patología , Femenino , Inflamación/genética , Inflamación/metabolismo , Inflamación/patología , Masculino , Ratones , Factores Sexuales , Piel/patología , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/patologíaRESUMEN
SCOPE: UV exposure is a risk factor for keratinocyte carcinoma (KC) while critical for endogenous vitamin D production. We investigated dietary modulation of skin and serum 25-hydroxyvitamin D3 (25OHD3 ) and its C-3 epimer (C3epi) in a mouse model of KC. C3epi is an under-investigated metabolite of vitamin D with respect to its biological implications. METHODS AND RESULTS: Male and female Skh-1 mice were supplemented with 25, 150 or 1000 IU/kg diet vitamin D3 for 25 weeks, with some exposed to UV light. Skin and serum vitamin D metabolites were quantitated using HPLC-MS/MS (n = 3 per dose/sex/UV treatment). Serum and skin 25OHD3 and C3epi significantly increased with dose (P<0.0001), but with different response patterns. UV exposure significantly attenuated serum, but not skin, levels of both metabolites (P<0.001, P = 0.0287), while up-regulating expression of renal Cyp24a1 (P < 0.01). A dose by sex interaction trended toward significance with serum and skin levels of C3epi, wherein male mice attained higher levels of C3epi with higher dietary vitamin D3 . This reflected a similar, but non-significant pattern in average tumor size. CONCLUSION: The complex relationship between vitamin D and KC requires further investigation. This study provides insight into modulation of local and systemic vitamin D status with dietary supplementation.
Asunto(s)
Colecalciferol/administración & dosificación , Colecalciferol/sangre , Dieta , Piel/química , Animales , Suplementos Dietéticos , Relación Dosis-Respuesta a Droga , Femenino , Masculino , Ratones , Espectrometría de Masas en Tándem , Rayos Ultravioleta/efectos adversos , Regulación hacia Arriba , Vitamina D3 24-Hidroxilasa/genética , Vitamina D3 24-Hidroxilasa/metabolismoRESUMEN
To mitigate melanoma risk, sunscreen use is widely advocated; yet, the ability of sunscreens to prevent melanoma remains controversial. Here, we test the tenet that sunscreens limit melanoma risk by blocking ultraviolet radiation (UV)-induced DNA damage using murine models that recapitulate the genetics and spontaneous evolution of human melanoma. We find that a single, non-erythematous dose of UV dramatically accelerates melanoma onset and increases tumor multiplicity in mice carrying an endogenous, melanocyte-specific NRas61R allele. By contrast, transient UV exposure does not alter tumor onset in mice lacking p16INK4a or harboring an NRas12D allele. To block the rapid onset of melanoma cooperatively caused by UV and NRas61R , we employed a variety of aerosol sunscreens. While all sunscreens delayed melanoma formation and blocked UV-induced DNA damage, differences in aerosol output (i.e., amount applied/cm2 ) caused variability in the cancer preventative efficacy of products with identical sunburn protection factor (SPF) ratings.
Asunto(s)
Carcinogénesis/patología , Carcinogénesis/efectos de la radiación , Melanoma/tratamiento farmacológico , Melanoma/patología , Mutación/genética , Neoplasias Cutáneas/tratamiento farmacológico , Protectores Solares/uso terapéutico , Rayos Ultravioleta , Proteínas ras/genética , Aerosoles , Animales , Codón/genética , Daño del ADN , Supervivencia sin Enfermedad , Relación Dosis-Respuesta en la Radiación , Ratones Endogámicos C57BL , Neoplasias Cutáneas/patología , Factor de Protección SolarRESUMEN
Prolonged tomato consumption can mitigate ultraviolet (UV) light induced sunburn via unknown mechanisms. Dietary carotenoids distributed to skin are hypothesized to protect skin against UV-induced damage, although other phytochemicals may play a role. We hypothesize that tomato consumption would protect against skin cancer. SKH-1 hairless and immunocompetent mice (n = 180) were fed AIN-93G or AIN-93G + 10% tangerine or red tomato powder for 35 weeks. From weeks 11-20, mice (n = 120) were exposed to 2240 J/m2 UV-B light, 3x/week, and tumors were tracked weekly. Control mice were fed the same diets but not exposed to UV. Tumor number was significantly lower in male mice consuming red tomato diets (1.73 ± 0.50, P = 0.015) or pooled tomato diets (2.03 ± 0.45, P = 0.017) compared to controls (4.04 ± 0.65). Carotenoid levels in plasma and skin were quantitated, with total lycopene higher in skin of tangerine fed animals despite a lower dose. Metabolomic analyses elucidated compounds derived from tomato glycoalkaloids (including tomatidine and hydroxylated-tomatidine) as significantly different metabolites in skin after tomato exposure. Here, we describe that tomato consumption can modulate risk for keratinocyte carcinomas; however, the role of the newly identified specific phytochemicals possibly responsible for this action require further investigation.
Asunto(s)
Productos Biológicos/administración & dosificación , Metabolómica/métodos , Neoplasias Cutáneas/prevención & control , Solanum lycopersicum/química , Rayos Ultravioleta/efectos adversos , Animales , Productos Biológicos/farmacocinética , Carotenoides/sangre , Cromatografía Líquida de Alta Presión , Modelos Animales de Enfermedad , Licopeno/sangre , Masculino , Ratones , Extractos Vegetales/administración & dosificación , Extractos Vegetales/uso terapéutico , Neoplasias Cutáneas/sangre , Neoplasias Cutáneas/etiología , Neoplasias Cutáneas/metabolismo , Espectrometría de Masas en TándemRESUMEN
Chronic exposure to UV light, the primary cause of skin cancer, results in the induction of high levels of cyclooxygenase-2 (COX-2) expression in the skin. The involvement of COX-2 in the carcinogenesis process is mediated by its enzymatic product, prostaglandin E(2) (PGE(2)). PGE(2) has been shown to have a variety of activities that can contribute to tumor development and growth. The effects of PGE(2) on different cell types are mediated by four E prostanoid (EP) receptors, EP(1)-EP(4). While recent studies have demonstrated the importance of EP(1) in the development of colon and breast cancer, the extent of EP(1) involvement in the cutaneous photocarcinogenesis process is unknown. This study found that topical treatment with celecoxib or the specific EP(1) antagonist ONO-8713 decreased acute UVB-induced inflammation in the skin and significantly reduced the number of tumors per mouse following 25 weeks of UVB exposure and topical treatment. This study suggests that drugs designed to block EP(1) may have the potential to be used as anti-inflammatory and/or chemopreventive agents that reduce the risk of skin cancer development.
Asunto(s)
Dermatitis/etiología , Receptores de Prostaglandina E/antagonistas & inhibidores , Receptores de Prostaglandina E/fisiología , Neoplasias Cutáneas/etiología , Piel/efectos de la radiación , Rayos Ultravioleta , Animales , Celecoxib , Cinamatos/uso terapéutico , Inhibidores de la Ciclooxigenasa/uso terapéutico , Dermatitis/tratamiento farmacológico , Femenino , Queratinocitos/química , Ratones , Ratones Pelados , Pirazoles/uso terapéutico , Receptores de Prostaglandina E/análisis , Subtipo EP1 de Receptores de Prostaglandina E , Piel/patología , Neoplasias Cutáneas/tratamiento farmacológico , Sulfonamidas/uso terapéutico , Proteína p53 Supresora de Tumor/análisisRESUMEN
Immune-suppressed organ transplant recipients (OTRs) can develop catastrophic squamous cell carcinoma (SCC), characterized by multiple primary tumors, extensive body surface area involvement, or metastases. There are currently no curative systemic therapies available. We previously showed that IL-22 enhances SCC proliferation. Herein, we examined links between cyclosporine (CSA), IL-22, and SCC in patients, cell lines, and mice with UV light-induced SCC. Eighteen of 114 OTRs developed catastrophic SCC, which was strongly associated with CSA treatment. We found that CSA drives T cell polarization toward IL-22-producing T22 cells, and CSA treatment increased IL-22 receptor in SCC cells. SCC tissue from OTRs showed increased expression of IL-22RA1. CSA potentiated rescue by IL-22 of serum-starved SCC cells; treatment of SCC cells with IL-22 and CSA increased both their migratory and invasive capacity. In a UV-induced model of SCC in SKH-1 immunocompetent mice, treatment with anti-IL-22 antibody reduced tumor number and tumor burden. We found that catastrophic SCC in OTRs is associated with CSA use, which may be acting by favoring T22 polarization. Since anti-IL-22 antibody administration decreased tumor number and tumor burden in vivo, blockade of the IL-22 axis may be developed as a viable therapeutic option for catastrophic SCC.
Asunto(s)
Carcinoma de Células Escamosas/inducido químicamente , Ciclosporina/farmacología , Inmunosupresores/farmacología , Interleucinas/metabolismo , Neoplasias Cutáneas/inducido químicamente , Animales , Línea Celular Tumoral , Humanos , Ratones , Receptores de Interleucina/metabolismo , Interleucina-22RESUMEN
SCOPE: UVB exposure, a major factor in the development of skin cancer, has differential sex effects. Tomato product consumption reduces the intensity of UVB-induced erythema in humans, but the mechanisms are unknown. METHODS AND RESULTS: Four-week-old SKH-1 hairless mice (40 females, 40 males) were divided into two feeding groups (control or with 10% tangerine tomatoes naturally rich in UV-absorbing phytoene and phytofluene) and two UV exposure groups (with or without UV). After 10 weeks of feeding, the UV group was exposed to a single UV dose and sacrificed 48 h later. Blood and dorsal skin samples were taken for carotenoid analysis. Dorsal skin was harvested to assess sex and UV effects on carotenoid deposition, inflammation (skinfold thickness, myeloperoxidase levels), and DNA damage (cyclobutane pyrimidine dimers, p53). Females had significantly higher levels of both skin and blood carotenoids relative to males. UV exposure significantly reduced skin carotenoid levels in females but not males. Tomato consumption attenuated acute UV-induced increases in CPD in both sexes, and reduced myeloperoxidase activity and percent p53 positive epidermal cells in males. CONCLUSION: Tangerine tomatoes mediate acute UV-induced skin damage in SKH-1 mice via reduced DNA damage in both sexes, and through reduced inflammation in males.
Asunto(s)
Carotenoides/metabolismo , Daño del ADN/efectos de la radiación , Solanum lycopersicum , Animales , Carotenoides/farmacología , Daño del ADN/efectos de los fármacos , Dermatitis/dietoterapia , Dermatitis/genética , Eritema/dietoterapia , Eritema/etiología , Femenino , Masculino , Ratones Pelados , Factores Sexuales , Piel/patología , Piel/efectos de la radiación , Proteína p53 Supresora de Tumor/metabolismo , Rayos Ultravioleta/efectos adversosRESUMEN
Standard chemotherapeutic agents used for the treatment of pre-cancerous skin lesions and non-melanoma skin cancers are not completely effective. Several studies have suggested that repeated inflammatory sunburn reactions, which include the induction of cyclooxygenase-2 (COX-2) and the subsequent production of prostaglandins, play a role in skin cancer development. COX-2 inhibition has been demonstrated to be a potent means of preventing skin cancer development in mice; however, COX-2 inhibitors alone are not effective as chemotherapeutic agents. Data in a variety of cancer types suggest greater efficacy in treating tumors with combination chemotherapies. Therefore, we hypothesized that a combination of the chemotherapeutic agent 5-fluorouracil (5-FU) and the COX-2 inhibitor and anti-inflammatory drug celecoxib would act synergistically to regress tumors in a murine model of ultraviolet light B- (UVB-) induced carcinogenesis. We found that topical treatment with 5-FU and celecoxib together was up to 70% more effective in reducing the number of UVB-induced skin tumors than 5-FU treatment alone. Our data suggest that more effective chemotherapy regimens can be developed to treat the millions of pre-cancerous and cancerous skin lesions that arise every year, which could ultimately lead to a significant reduction in costs and cosmetic defects (scarring) associated with surgical interventions.
Asunto(s)
Antimetabolitos Antineoplásicos/farmacología , Inhibidores de la Ciclooxigenasa/farmacología , Fluorouracilo/farmacología , Neoplasias Cutáneas/tratamiento farmacológico , Sulfonamidas/farmacología , Administración Tópica , Animales , Celecoxib , División Celular/efectos de los fármacos , Dinoprostona/metabolismo , Sinergismo Farmacológico , Quimioterapia Combinada , Femenino , Ratones , Ratones Pelados , Pirazoles , Piel/metabolismo , Piel/patología , Piel/efectos de la radiación , Neoplasias Cutáneas/patología , Rayos Ultravioleta/efectos adversosRESUMEN
ΔNp63α, a proto-oncogene, is up-regulated in non-melanoma skin cancers and directly regulates the expression of both Vitamin D receptor (VDR) and phosphatase and tensin homologue deleted on chromosome ten (PTEN). Since ΔNp63α has been shown to inhibit cell invasion via regulation of VDR, we wanted to determine whether dietary Vitamin D3 protected against UVB induced tumor formation in SKH-1 mice, a model for squamous cell carcinoma development. We examined whether there was a correlation between dietary Vitamin D3 and ΔNp63α, VDR or PTEN expression in vivo in SKH-1 mice chronically exposed to UVB radiation and fed chow containing increasing concentrations of dietary Vitamin D3. Although we observed differential effects of the Vitamin D3 diet on ΔNp63α and VDR expression in chronically irradiated normal mouse skin as well as UVB induced tumors, Vitamin D3 had little effect on PTEN expression in vivo. While low-grade papillomas in mice exposed to UV and fed normal chow displayed increased levels of ΔNp63α, expression of both ΔNp63α and VDR was reduced in invasive tumors. Interestingly, in mice fed high Vitamin D3 chow, elevated levels of ΔNp63α were observed in both local and invasive tumors but not in normal skin suggesting that oral supplementation with Vitamin D3 may increase the proliferative potential of skin tumors by increasing ΔNp63α levels.
Asunto(s)
Carcinoma de Células Escamosas/genética , Colecalciferol/farmacología , Fosfoproteínas/genética , Neoplasias Cutáneas/genética , Transactivadores/genética , Rayos Ultravioleta , Animales , Carcinoma de Células Escamosas/patología , Proliferación Celular/efectos de los fármacos , Proliferación Celular/genética , Proliferación Celular/efectos de la radiación , Dieta , Progresión de la Enfermedad , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de la radiación , Masculino , Ratones , Ratones Pelados , Fosfohidrolasa PTEN/genética , Receptores de Calcitriol/genética , Piel/efectos de los fármacos , Piel/metabolismo , Piel/patología , Piel/efectos de la radiación , Neoplasias Cutáneas/patologíaRESUMEN
SCOPE: Broccoli sprouts are a rich source of glucosinolates, a group of phytochemicals that when hydrolyzed, are associated with cancer prevention. Our objectives were to investigate the metabolism, distribution, and interconversion of isothiocyanates (ITCs) in mice fed thermally processed broccoli sprout powders (BSPs) or the purified ITC sulforaphane. METHODS AND RESULTS: For 1 wk, mice were fed a control diet (n = 20) or one of four treatment diets (n = 10 each) containing nonheated BSP, 60°C mildly heated BSP, 5-min steamed BSP, or 3 mmol purified sulforaphane. Sulforaphane and erucin metabolite concentrations in skin, liver, kidney, bladder, lung, and plasma were quantified using HPLC-MS/MS. Thermal intensity of BSP processing had disparate effects on ITC metabolite concentrations upon consumption. Mild heating generally resulted in the greatest ITC metabolite concentrations in vivo, followed by the nonheated and steamed BSP diets. We observed interconversion between sulforaphane and erucin species or metabolites, and report that erucin is the favored form in liver, kidney, and bladder, even when only sulforaphane is consumed. CONCLUSION: ITC metabolites were distributed to all tissues analyzed, suggesting the potential for systemic benefits. We report for the first time tissue-dependent ratio of sulforaphane and erucin, though further investigation is warranted to assess biological activity of individual forms.
Asunto(s)
Anticarcinógenos/metabolismo , Brassica/química , Suplementos Dietéticos , Manipulación de Alimentos , Isotiocianatos/metabolismo , Brotes de la Planta/química , Animales , Anticarcinógenos/administración & dosificación , Anticarcinógenos/aislamiento & purificación , Suplementos Dietéticos/análisis , Femenino , Liofilización , Alimentos Funcionales/análisis , Glucosa/análogos & derivados , Glucosa/análisis , Glucosa/metabolismo , Glucosinolatos/análisis , Glucosinolatos/metabolismo , Calor , Imidoésteres/análisis , Imidoésteres/metabolismo , Isotiocianatos/administración & dosificación , Isotiocianatos/sangre , Isotiocianatos/aislamiento & purificación , Riñón/crecimiento & desarrollo , Riñón/metabolismo , Hígado/crecimiento & desarrollo , Hígado/metabolismo , Ratones Pelados , Especificidad de Órganos , Oximas , Sulfuros/sangre , Sulfuros/metabolismo , Sulfóxidos , Tiocianatos/sangre , Tiocianatos/metabolismo , Vejiga Urinaria/crecimiento & desarrollo , Vejiga Urinaria/metabolismo , Aumento de PesoRESUMEN
UNLABELLED: Macrophage migration inhibitory factor (MIF) is a homotrimeric proinflammatory cytokine implicated in chronic inflammatory diseases and malignancies, including cutaneous squamous cell carcinomas (SCC). To determine whether MIF inhibition could reduce UVB light-induced inflammation and squamous carcinogenesis, a small-molecule MIF inhibitor (CPSI-1306) was utilized that disrupts homotrimerization. To examine the effect of CPSI-1306 on acute UVB-induced skin changes, Skh-1 hairless mice were systemically treated with CPSI-1306 for 5 days before UVB exposure. In addition to decreasing skin thickness and myeloperoxidase (MPO) activity, CPSI-1306 pretreatment increased keratinocyte apoptosis and p53 expression, decreased proliferation and phosphohistone variant H2AX (γ-H2AX), and enhanced repair of cyclobutane pyrimidine dimers. To examine the effect of CPSI-1306 on squamous carcinogenesis, mice were exposed to UVB for 10 weeks, followed by CPSI-1306 treatment for 8 weeks. CPSI-1306 dramatically decreased the density of UVB-associated p53 foci in non-tumor-bearing skin while simultaneously decreasing the epidermal Ki67 proliferation index. In addition to slowing the rate of tumor development, CPSI-1306 decreased the average tumor burden per mouse. Although CPSI-1306-treated mice developed only papillomas, nearly a third of papillomas in vehicle-treated mice progressed to microinvasive SCC. Thus, MIF inhibition is a promising strategy for prevention of the deleterious cutaneous effects of acute and chronic UVB exposure. IMPLICATIONS: Macrophage migration inhibitory factor is a viable target for the prevention of UVB-induced cutaneous SSCs.
Asunto(s)
Carcinoma de Células Escamosas/tratamiento farmacológico , Oxidorreductasas Intramoleculares/antagonistas & inhibidores , Isoxazoles/administración & dosificación , Factores Inhibidores de la Migración de Macrófagos/antagonistas & inhibidores , Morfolinas/administración & dosificación , Neoplasias Inducidas por Radiación/tratamiento farmacológico , Neoplasias Cutáneas/tratamiento farmacológico , Animales , Apoptosis/efectos de los fármacos , Carcinoma de Células Escamosas/patología , Daño del ADN/efectos de los fármacos , Daño del ADN/efectos de la radiación , Femenino , Oxidorreductasas Intramoleculares/genética , Factores Inhibidores de la Migración de Macrófagos/genética , Ratones , Neoplasias Inducidas por Radiación/genética , Neoplasias Inducidas por Radiación/patología , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Proteína p53 Supresora de Tumor/genética , Rayos UltravioletaRESUMEN
Epidemiological studies support a link between cumulative sun exposure and cutaneous squamous cell carcinoma (SCC) development. However, the presumed effects of extended ultraviolet light B (UVB) exposure on tumorigenesis in the sexes have not been formally investigated. We examined differences in ultimate tumorigenesis at 25 weeks in mice exposed to UVB for either 10 or 25 weeks. Additionally, we investigated the effect of continued UVB exposure on the efficacy of topical treatment with anti-inflammatory (diclofenac) or antioxidant (C E Ferulic or vitamin E) compounds on modulating tumorigenesis. Vehicle-treated mice in the 25-week UVB exposure model exhibited an increased tumor burden and a higher percentage of malignant tumors compared to mice in the 10-week exposure model, which correlated with increases in total and mutant p53-positive epidermal cells. Only topical diclofenac decreased tumor number and burden in both sexes regardless of UVB exposure length. These data support the commonly assumed but not previously demonstrated fact that increased cumulative UVB exposure increases the risk of UVB-induced SCC development and can also affect therapeutic efficacies. Our study suggests that cessation of UVB exposure by at-risk patients may decrease tumor development and that topical NSAIDs such as diclofenac may be chemopreventive.
RESUMEN
Because of the ever-increasing incidence of ultraviolet light B (UVB)-induced skin cancer, considerable attention is being paid to prevention through the use of both sunscreens and after sun treatments, many of which contain antioxidants. Vitamin E is included as an antioxidant in many sunscreens and lotions currently on the market. Studies examining the efficacy of vitamin E as a topical preventative agent for UVB-induced skin cancer have yielded conflicting results. A likely contributor to differences in study outcome is the stability of vitamin E in the particular formulation being tested. In the current study we examined the effects of topical vitamin E alone as well as vitamin E combined with vitamin C and ferulic acid in a more stable topical formula (C E Ferulic®). Mice were exposed to UVB for 10 weeks in order to induce skin damage. Then, before the appearance of any cutaneous lesions, mice were treated for 15 weeks with a topical antioxidant, without any further UVB exposure. We found that topical C E Ferulic decreased tumor number and tumor burden and prevented the development of malignant skin tumors in female mice with chronically UVB-damaged skin. In contrast, female mice chronically exposed to UVB and treated topically with vitamin E alone showed a trend towards increased tumor growth rate and exhibited increased levels of overall DNA damage, cutaneous proliferation, and angiogenesis compared to vehicle-treated mice. Thus, we have demonstrated that topical 5% alpha tocopherol may actually promote carcinogenesis when applied on chronically UVB-damaged skin while treating with a more stable antioxidant compound may offer therapeutic benefits.
Asunto(s)
Carcinogénesis/efectos de los fármacos , Ácidos Cumáricos/química , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/patología , Rayos Ultravioleta/efectos adversos , Vitamina E/química , Vitamina E/farmacología , Administración Tópica , Animales , Antioxidantes/administración & dosificación , Antioxidantes/efectos adversos , Antioxidantes/química , Antioxidantes/farmacología , Vasos Sanguíneos/efectos de los fármacos , Vasos Sanguíneos/metabolismo , Vasos Sanguíneos/efectos de la radiación , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/etiología , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patología , Catalasa/metabolismo , Proliferación Celular/efectos de los fármacos , Proliferación Celular/efectos de la radiación , Química Farmacéutica , Femenino , Glutatión Peroxidasa/metabolismo , Ratones , Molécula-1 de Adhesión Celular Endotelial de Plaqueta/metabolismo , Neoplasias Cutáneas/etiología , Neoplasias Cutáneas/metabolismo , Carga Tumoral/efectos de los fármacos , Carga Tumoral/efectos de la radiación , Proteína p53 Supresora de Tumor/metabolismo , Vitamina E/administración & dosificación , Vitamina E/efectos adversosRESUMEN
Skin cancer incidence and mortality are higher in men compared with women, but the causes of this sex discrepancy remain largely unknown. UV light exposure induces cutaneous inflammation and neutralizes cutaneous antioxidants. Gr-1(+)CD11b(+) myeloid cells are heterogeneous bone marrow-derived cells that promote inflammation-associated carcinogenesis. Reduced activity of catalase, an antioxidant present in the skin, has been associated with skin carcinogenesis. We used the outbred, immune-competent Skh-1 hairless mouse model of UVB-induced inflammation and non-melanoma skin cancer to further define sex discrepancies in UVB-induced inflammation. Our results demonstrated that male skin had relatively lower baseline catalase activity, which was inhibited following acute UVB exposure in both sexes. Further analysis revealed that skin catalase activity inversely correlated with splenic Gr-1(+)CD11b(+) myeloid cell percentage. Acute UVB exposure induced Gr-1(+)CD11b(+) myeloid cell skin infiltration, which was inhibited to a greater extent in male mice by topical catalase treatment. In chronic UVB studies, we demonstrated that the percentage of splenic Gr-1(+)CD11b(+) myeloid cells was 55% higher in male tumor-bearing mice compared with their female counterparts. Together, our findings indicate that lower skin catalase activity in male mice may at least in part contribute to increased UVB-induced generation of Gr-1(+)CD11b(+) myeloid cells and subsequent skin carcinogenesis.
Asunto(s)
Catalasa/efectos de la radiación , Células Mieloides/patología , Células Mieloides/efectos de la radiación , Piel/enzimología , Piel/efectos de la radiación , Rayos Ultravioleta , Animales , Antígeno CD11b/metabolismo , Proliferación Celular , Femenino , Inflamación/etiología , Inflamación/metabolismo , Masculino , Ratones , Ratones Pelados , Células Mieloides/enzimología , Neoplasias Inducidas por Radiación/patología , Receptores de Quimiocina/metabolismo , Factores Sexuales , Piel/patología , Neoplasias Cutáneas/patologíaAsunto(s)
Queratinocitos/fisiología , Neoplasias Cutáneas/genética , Piel/patología , Factores de Transcripción/genética , Proteína p53 Supresora de Tumor/genética , Animales , Ratones , Ratones de la Cepa 129 , Ratones Noqueados , Piel/metabolismo , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/patología , Factores de Transcripción de la Familia Snail , Factores de Transcripción/metabolismoRESUMEN
Light in the UVB spectrum (280-320 nm) induces a number of changes in the epidermis and dermis of mice and humans, resulting in a robust inflammatory response. A standardized black raspberry extract (BRE) has been effective in reducing signaling pathways commonly initiated by inflammatory stimuli. In this study, we determined whether this extract could reduce cutaneous UVB-induced inflammation and carcinogenesis. In our carcinogenesis model, female SKH-1 hairless mice were exposed to one minimal erythemal dose of UVB thrice weekly on nonconsecutive days for 25 weeks. Immediately after each exposure, the mice were treated topically with either BRE dissolved in vehicle or with vehicle only. Beginning on week 19, mice treated with BRE had a significant reduction in tumor number and in average tumor size. This reduction correlated with a significant reduction in tumor-infiltrating CD3(+)foxp3(+) regulatory T-cells. In the acute model, mice were exposed to a single minimal erythemal dose of UVB and treated topically with BRE or with vehicle. At 48 hours post-UVB exposure, topical BRE treatment significantly reduced edema, p53 protein levels, oxidative DNA damage, and neutrophil activation. The ability of topical BRE to reduce acute UVB-induced inflammation and to decrease tumor development in a long-term model provides compelling evidence to explore the clinical efficacy of BRE in the prevention of human skin cancers.
Asunto(s)
Administración Tópica , Frutas , Inflamación , Neoplasias Inducidas por Radiación/prevención & control , Neoplasias/prevención & control , Linfocitos T Reguladores/inmunología , Animales , Complejo CD3/biosíntesis , Carcinógenos , Carcinoma de Células Escamosas , Daño del ADN , Femenino , Ratones , Neoplasias/etiología , Neutrófilos/metabolismo , Extractos Vegetales/farmacología , Proteína p53 Supresora de Tumor/metabolismo , Rayos UltravioletaRESUMEN
Prostaglandin E2 (PGE2) upregulation in response to UV light exposure is a significant factor in the development of non-melanoma skin cancer. It is known that PGE2 signals via the E prostanoid receptors, EP1-4, but the role that each receptor plays in skin carcinogenesis is unclear. Immunohistochemical analysis of EP receptor staining in unirradiated and UVB-exposed SKH-1 mouse skin demonstrated the localization of EP1 and EP2 to the plasma membrane of differentiated epidermal keratinocytes. In contrast, the EP3 receptor localized to the basal layer of the epidermis in unirradiated skin and throughout the epidermis in UVB-exposed skin. In unirradiated skin, cytoplasmic EP4 staining was seen throughout the epidermis, in dermal leukocytes, and in vascular endothelium. However, UVB exposure resulted in relocalization of the EP4 receptor to the plasma membrane of keratinocytes, with no change in the dermal staining pattern. In tumors isolated from UVB-exposed mice, EP1 and EP2 staining was detected in the more differentiated cells surrounding keratin pearls, whereas EP3 and EP4 were detectable throughout the tumors. Differential expression of the EP receptors suggests that each receptor may play a distinct role in skin tumor development.
Asunto(s)
Receptores de Prostaglandina E/análisis , Piel/efectos de la radiación , Rayos Ultravioleta , Animales , Femenino , Inmunohistoquímica , Ratones , Ratones Pelados , Neoplasias Inducidas por Radiación/química , Neoplasias Inducidas por Radiación/tratamiento farmacológico , ARN Mensajero/análisis , Receptores de Prostaglandina E/antagonistas & inhibidores , Receptores de Prostaglandina E/genética , Receptores de Prostaglandina E/fisiología , Subtipo EP1 de Receptores de Prostaglandina E , Subtipo EP2 de Receptores de Prostaglandina E , Subtipo EP3 de Receptores de Prostaglandina E , Subtipo EP4 de Receptores de Prostaglandina E , Piel/química , Neoplasias Cutáneas/química , Neoplasias Cutáneas/tratamiento farmacológicoRESUMEN
Exposure to UVB induces an inflammatory response in the skin that results in high levels of cyclooxygenase-2 (COX-2) and its enzymatic product, prostaglandin E2 (PGE(2)). PGE(2) signals via one of four E prostanoid (EP) receptors, EP1-4, but the roles of each of these receptors in UVB-mediated inflammation and skin carcinogenesis have not been fully defined. Topical application of ONO-8713, an EP1 antagonist, reduced the acute inflammatory effects of UVB irradiation. This compound also reduced UVB-induced tumor formation by approximately 50%, suggesting that signaling of PGE(2) via the EP1 receptor may play a role in UVB-mediated inflammation and carcinogenesis. Our laboratory has demonstrated that the EP1 receptor localized to the suprabasal layers of the epidermis and the EP3 receptor was found in the basal keratinocytes of unirradiated murine skin. While UVB exposure induced no change in the localization of the EP1 receptor, the EP3 receptor was detected in all layers of the epidermis in response to UVB. In mice that were topically treated with ONO-8713, UVB-induced changes in EP3 localization were prevented. This alteration in EP3 receptor localization was not seen following topical application of the anti-inflammatory drug celecoxib, indicating that the effects of ONO-8713 were not because of its anti-inflammatory properties. These results suggest a previously undescribed interaction between the EP1 and EP3 receptors in the epidermis.