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1.
Anticancer Res ; 40(1): 501-509, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31892605

RESUMO

BACKGROUND: Intensive scientific debate is ongoing about whether moderate solarium use increases melanoma risk. The authors of some recent publications demand the debate be closed and propose "actions against solarium use for skin cancer prevention" because new studies have convincingly demonstrated causality. This minireview aims to investigate whether those demands are sufficiently supported by present scientific knowledge and comply with the principles of evidence-based medicine. MATERIALS AND METHODS: We performed a systematic literature search (through June 2019; PubMed, ISI Web of Science) to identify publications investigating how solarium use affects melanoma risk. RESULTS: We found no studies that demonstrate a causal relationship between moderate solarium use and melanoma risk. Results of cohort and case-control studies published to date, including recent investigations, do not prove causality, and randomized controlled trials providing unequivocal proof are still lacking. Moreover, the overall quality of observational studies is low as a result of severe limitations (including unobserved or unrecorded confounding), possibly leading to bias. We also disagree with recent claims that Hill's criteria for the epidemiological evidence of a causal relationship between a potential causal factor and an observed effect are fulfilled in regard to the conclusion that moderate solarium use per se would increase melanoma risk Conclusion: Current scientific knowledge does not demonstrate a causal relationship between moderate solarium use and melanoma risk. Therefore, the debate is not closed.


Assuntos
Melanoma/epidemiologia , Banho de Sol , Animais , Humanos , Fatores de Risco , Raios Ultravioleta
2.
Artigo em Inglês | MEDLINE | ID: mdl-30544646

RESUMO

There have been many public health recommendations for avoiding UV radiation exposures. This is primarily due to concerns about skin cancer and especially melanoma, the most serious type of skin cancer. However, UV radiation is also known as the primary source of vitamin D and other compounds needed for good health. This brief commentary lists several of the many important recent studies of adverse health effects associated with low sun exposure, including some specific cancers, multiple sclerosis, diabetes, cardiovascular disease, autism, Alzheimer's disease, and age-related macular degeneration. Our conclusion is that non-burning UV exposure is a health benefit and-in moderation-should be recommended as such.


Assuntos
Exposição Ambiental/efeitos adversos , Raios Ultravioleta/efeitos adversos , Humanos , Saúde Pública , Raios Ultravioleta/classificação
3.
Photochem Photobiol Sci ; 17(12): 1946-1955, 2018 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-30397693

RESUMO

Low serum 25-hydroxyvitamin D (25OHD) concentrations have been associated with increased cancer risk, but the relative importance of seasonality, i.e. high summer concentrations versus low winter concentrations, is unclear. We investigated this issue in a high risk group: kidney transplant recipients with known increased risk of cancer and low vitamin D statuses. We examined the relationship between registered concentrations of 25OHD binned by quarter and subsequent risk of internal malignancy or cutaneous squamous cell carcinoma in 1112 kidney transplant recipients. Hazard ratios for internal malignancies were significantly increased with lower pre-diagnostic 25OHD concentrations in the first quarter of the year (January-March); a 1.4 fold increase (95%CI 1.1;1.7) per 10 nmol L-1 decrease in 25OHD. Except for women in April-June (1.3 (1.01;1.7) per 10 nmol L-1 decrease) pre-diagnostic 25OHD concentrations in the other quarters were not statistically significantly associated with internal malignancies. Higher 25OHD concentrations tended to be associated with the development of cutaneous squamous cell carcinomas, independent of the time of the year. Our study indicates that low wintertime 25OHD concentrations are associated with an increased risk of internal malignancies and that transplant recipients may benefit from wintertime vitamin D supplementation. Our findings need further corroboration, but suggest that the lowest concentrations of vitamin D, which occur in winter, are important for the risk of internal malignancies.


Assuntos
Transplante de Rim , Neoplasias/diagnóstico , Vitamina D/análogos & derivados , Adolescente , Adulto , Idoso , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/etiologia , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/etiologia , Modelos de Riscos Proporcionais , Fatores de Risco , Estações do Ano , Transplantados , Vitamina D/sangue , Adulto Jovem
5.
Front Med (Lausanne) ; 5: 165, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29896477

RESUMO

UV radiation in sunlight has long been recognized as the main exogenous cause of skin carcinomas. We present a brief historical perspective on the progress in understanding the pathogenesis of skin carcinomas, and recent advances. Sun-exposed skin carries numerous UV-related mutations, and skin carcinomas rank among the tumors with the highest mutational loads. In this multitude of mutations only a few are crucial in driving the tumor. Some are known from hereditary (skin) cancer syndromes and other recurrent ones have been validated in transgenic mice. Considering the continuous renewal of the epidermis, the question arises whether the lifelong residing stem cells are the main targets in skin carcinogenesis, a multistep process that would require ample time to evolve. Therefore, classic quiescent stem cells have been studied as potential tumor-initiating cells, as well as more recently discovered actively dividing stem cells (either Lgr5+ or Lgr6+). Interesting differences have emerged between experimental UV and two-stage chemical carcinogenesis, e.g., the latter appears to originate from follicular stem cells, in contrast to the former.

6.
J Invest Dermatol ; 138(10): 2244-2252, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29730334

RESUMO

Public health guidance recommends limiting sun exposure to sub-sunburn levels, but it is unknown whether these can gain vitamin D (for musculoskeletal health) while avoiding epidermal DNA damage (initiates skin cancer). Well-characterized healthy humans of all skin types (I-VI, lightest to darkest skin) were exposed to a low-dose series of solar simulated UVR of 20%-80% their individual sunburn threshold dose (minimal erythema dose). Significant UVR dose responses were seen for serum 25-hydroxyvitamin D and whole epidermal cyclobutane pyrimidine dimers (CPDs), with as little as 0.2 minimal erythema dose concurrently producing 25-hydroxyvitamin D and CPD. Fractional MEDs generated equivalent levels of whole epidermal CPD and 25-hydroxyvitamin D across all skin types. Crucially, we showed an epidermal gradient of CPD formation strongly correlated with skin darkness (r = 0.74, P < 0.0001), which reflected melanin content and showed increasing protection across the skin types, ranging from darkest skin, where high CPD levels occurred superficially, with none in the germinative basal layer, to lightest skin, where CPD levels were induced evenly across the epidermal depth. People with darker skin can be encouraged to use sub-sunburn UVR-exposure to enhance their vitamin D. In people with lighter skin, basal cell damage occurs concurrent with vitamin D synthesis at exquisitely low UVR levels, providing an explanation for their high skin cancer incidence; greater caution is required.


Assuntos
Neoplasias Cutâneas/genética , Pigmentação da Pele/efeitos dos fármacos , Pele/efeitos dos fármacos , Raios Ultravioleta , Vitamina D/análogos & derivados , Vitamina D/farmacologia , Adulto , Dano ao DNA , Relação Dose-Resposta à Radiação , Feminino , Seguimentos , Humanos , Incidência , Masculino , Estudos Retrospectivos , Pele/efeitos da radiação , Neoplasias Cutâneas/epidemiologia , Neoplasias Cutâneas/metabolismo , Pigmentação da Pele/efeitos da radiação , Reino Unido/epidemiologia , Vitamina D/metabolismo , Vitamina D/efeitos da radiação , Vitaminas/farmacologia
7.
Anticancer Res ; 38(2): 1111-1120, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29374748

RESUMO

The European Commission's Scientific Committee on Health, Environmental and Emerging Risks and the World Health Organization recently published reports which concluded that a large proportion of melanoma and non-melanoma skin cancer is attributable to sunbed use, and that there is no need to use sunbeds as there are no health benefits and they are not needed to achieve an optimal vitamin D level. The overall conclusion from both bodies was that there is no safe limit for UV irradiance from sunbeds. We are, however, deeply concerned that these assessments appear to be based on an incomplete, unbalanced and non-critical evaluation of the literature. Therefore, we rebut these conclusions by addressing the incomplete analysis of the adverse health effects of UV and sunbed exposure (what is 'safe'?) and the censored representation of beneficial effects, not only but especially from vitamin D production. The stance taken by both agencies is not sufficiently supported by the data and in particular, current scientific knowledge does not support the conclusion sunbed use increases melanoma risk.


Assuntos
Meio Ambiente , Melanoma/etiologia , Neoplasias Induzidas por Radiação/etiologia , Neoplasias Cutâneas/etiologia , Banho de Sol , Raios Ultravioleta/efeitos adversos , Grupos Étnicos , Humanos , Organização Mundial da Saúde
8.
Exp Dermatol ; 27(10): 1172-1175, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-28987003

RESUMO

We studied Lgr6+ stem cells in experimental UV carcinogenesis in hairless mice. For further characterization through RNA-seq, these stem cells were isolated by FACS from transgenic hairless mice bearing an EGFP-Ires-CreERT2 reporter cassette inserted into exon 1 of the Lgr6 gene (purity confirmed by human ERT2 expression). Between Lgr6/EGFP+ and Lgr6/EGFP- basal cells (Tg/wt), 682 RNAs were differentially expressed, indicating stemness and expression of cancer-related pathways in Lgr6/EGFP+ cells. We discovered that suspected "Lgr6 null" mice (Tg/Tg) expressed RNA of an Lgr6 isoform (delta-Lgr6, lacking 74 N-terminal aa) which could be functional and explain the lack of a phenotype.


Assuntos
Receptores Acoplados a Proteínas-G/genética , Células-Tronco , Transcriptoma , Animais , Carcinogênese/genética , Carcinogênese/efeitos da radiação , Feminino , Proteínas de Fluorescência Verde/genética , Masculino , Camundongos , Camundongos Transgênicos , Isoformas de Proteínas , Análise de Sequência de RNA , Raios Ultravioleta
9.
Exp Dermatol ; 26(7): 557-562, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28266726

RESUMO

The skin is known to adapt to UV exposures, that is become less sensitive to sunburn. Reported decreases in sensitivity vary widely from well over 10-fold down to a negligible 10%. This appears to depend importantly on the UV irradiation spectrum to which the skin adapts and on the UV irradiation spectrum that is used to test the sensitivity. The sensitivity is conventionally and generally assessed by the reciprocal of the minimal erythema dose (MED): the UV dose causing a just perceptible reddening of the skin after 8-24 hours. However, MED is much too subtle for everyday life: people will not notice a minimal reddening and commonly consider themselves sunburnt at considerably higher UV doses causing an intense reddening. Levels of adaptation of a well-tanned skin may be substantially higher at these more intense levels of reddening than MED levels. This expectation is based on the fact that people with a constitutively coloured skin may show moderate differences in MED compared with fair-skinned people but far less steep increases in reddening with overexposures to solar-simulated radiation (SSR). UVA exposure is known to enhance pigmentation and may thus be important in protection against overexposure to SSR.


Assuntos
Pigmentação da Pele/efeitos da radiação , Queimadura Solar/prevenção & controle , Queimadura Solar/fisiopatologia , Raios Ultravioleta , Adaptação Fisiológica , Relação Dose-Resposta à Radiação , Eritema/etiologia , Humanos , Inflamação , Melaninas/biossíntese , Estações do Ano , Pele/efeitos da radiação , Queimadura Solar/diagnóstico , Luz Solar , Fatores de Tempo
10.
Lab Anim ; 51(1): 24-35, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26946120

RESUMO

Previous studies have established that 7,12-dimethylbenz(a)anthracene (DMBA) can initiate skin tumourigenesis in conventional furred mouse models by acting on hair follicle stem cells. However, further cancer progression depends on repeated applications of tumour promoter agents. This study evaluated the timeline involved in skin tumourigenesis and progression in immunocompetent hairless SKH1-hr mice with dysfunctional hair follicles using only DMBA with no additional tumour promoter agents. The results showed that topical application of 30 µg (117 nmol) of DMBA over the back and flank regions of the mouse once a week and 15 µg (58.5 nmol) twice a week produced skin tumours after 7-8 weeks. However, by week 14 a heavy benign tumour load required the mice to be euthanized. Lowering the DMBA dose to 15 µg (58.5 nmol) once a week produced tumours more slowly and allowed the mice to be studied for a longer period to week 23. This low-dose DMBA regimen yielded a high percentage of malignant tumours (58.8%) after 23 weekly applications. Additionally DMBA-treated skin showed an increase in mean epidermal thickness in comparison to untreated and acetone-treated skin. Despite the aberrant hair follicles in SKH1-hr mice, this chemically driven skin cancer model in hairless mice can serve as a suitable alternative to the ultraviolet-induced skin cancer models and can be reliably replicated as demonstrated by both the pilot and main experiments.


Assuntos
9,10-Dimetil-1,2-benzantraceno/farmacologia , Carcinogênese/induzido quimicamente , Progressão da Doença , Camundongos , Neoplasias Cutâneas/induzido quimicamente , 9,10-Dimetil-1,2-benzantraceno/administração & dosagem , Administração Tópica , Animais , Carcinógenos/administração & dosagem , Carcinógenos/farmacologia , Modelos Animais de Doenças , Feminino , Camundongos Pelados
11.
J Cutan Pathol ; 44(1): 28-33, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27717097

RESUMO

BACKGROUND: For selecting therapy, it is important to distinguish different types of keratinocytic neoplasia. It is sometimes difficult to make histopathologic diagnosis, especially in organ transplant recipients (OTR) who develop numerous lesions. METHODS: To investigate p16 immunostaining in different types of keratinocytic neoplasia in OTR, we studied 59 actinic keratoses (AK), 51 Bowen' s disease (BD), 63 squamous cell carcinomas (SCC), 16 benign keratotic lesions (BKL) from 31 OTR patients and 25 controls (eczema and psoriasis). Tissue sections were stained for H&E and p16. We scored intensity, proportion and distribution of p16 positive lesional cells. RESULTS: In 19% of AK, 92% of BD, 35% of SCC and 12% of BKL more than 15% of lesional cells were p16-positive. In 16% of AK, 80% of BD, 18% of SCC and 13% of BKL strong p16 staining was observed. BKL, AK and SCC showed focal and patchy staining, BD showed diffuse pattern with strong staining of all atypical cells. Sparing of the basal layer was predominantly seen in BD. No control specimen showed p16-overexpression. CONCLUSIONS: p16 immunostaining shows a characteristic pattern in BD, but not in AK, SCC and BKL. It appears useful in recognizing BD, but not in differentiating between other keratinocytic neoplasia.


Assuntos
Doença de Bowen/diagnóstico , Inibidor p16 de Quinase Dependente de Ciclina/análise , Neoplasias Cutâneas/diagnóstico , Biomarcadores Tumorais/análise , Carcinoma de Células Escamosas/diagnóstico , Humanos , Imuno-Histoquímica , Ceratose Actínica/diagnóstico , Transplantados
12.
Dermatoendocrinol ; 8(1): e1248325, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27942349

RESUMO

Public health authorities in the United States are recommending that men, women and children reduce their exposure to sunlight, based on concerns that this exposure will promote skin cancer. On the other hand, data show that increasing numbers of Americans suffer from vitamin D deficiencies and serious health problems caused by insufficient sun exposure. The body of science concerning the benefits of moderate sun exposure is growing rapidly, and is causing a different perception of sun/UV as it relates to human health. Melanoma and its relationship to sun exposure and sunburn is not adequately addressed in most of the scientific literature. Reports of favorable health outcomes related to adequate serum 25(OH)D concentration or vitamin D supplementation have been inappropriately merged, so that benefits of sun exposure other than production of vitamin D are not adequately described. This review of recent studies and their analyses consider the risks and benefits of sun exposure which indicate that insufficient sun exposure is an emerging public health problem. This review considers the studies that have shown a wide range health benefits from sun/UV exposure. These benefits include among others various types of cancer, cardiovascular disease, Alzheimer disease/dementia, myopia and macular degeneration, diabetes and multiple sclerosis. The message of sun avoidance must be changed to acceptance of non-burning sun exposure sufficient to achieve serum 25(OH)D concentration of 30 ng/mL or higher in the sunny season and the general benefits of UV exposure beyond those of vitamin D.

13.
Oncotarget ; 7(52): 86740-86754, 2016 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-27880932

RESUMO

Lgr6+ cells have been identified as a novel class of proliferating (Ki67+) stem cells in mouse epidermis. We investigated their response to UV exposure in Lgr6-EGFP-Ires-CreERT2/R26R-LacZ haired and hairless mice and whether they become initiating cells of UV- or chemically induced skin tumors. UV overexposure erased Lgr6+ cells (EGFP+) from the interfollicular epidermis (IFE), but - as after wounding - they apparently repopulated the IFE from the hair follicles. Under sub-sunburn chronic UV exposure, Lgr6+ cells and their progeny (LacZ+ after pulse of tamoxifen) diminished strongly in the IFE. Although the inter-tumoral IFE clearly showed Lgr6 progeny, none of the UV- or chemically induced tumors (n = 22 and 41, respectively) appeared to be clonal expansions of Lgr6+ stem cells; i.e. no Lgr6+ cells or progeny in the proliferating tumor bulk. In checking for promoter methylation we found it to occur stochastically for the EGFP-Cre cassette. Lgr6 mRNA measured by qPCR was found to be diminished in skin tumors (also in UV tumors from wt type mice). The ratio of Lgr6/Ki67 was significantly reduced, pointing at a loss of Lgr6+ cells from the proliferative pool. Our data show that Lgr6+ cells are not major tumor-initiating cells in skin carcinogenesis.


Assuntos
Epiderme/metabolismo , Receptores Acoplados a Proteínas-G/genética , Neoplasias Cutâneas/genética , Células-Tronco/metabolismo , Animais , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Proliferação de Células/efeitos da radiação , Transformação Celular Neoplásica/efeitos dos fármacos , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/efeitos da radiação , Metilação de DNA/efeitos dos fármacos , Metilação de DNA/efeitos da radiação , Epiderme/efeitos dos fármacos , Epiderme/efeitos da radiação , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Folículo Piloso/efeitos dos fármacos , Folículo Piloso/metabolismo , Folículo Piloso/efeitos da radiação , Camundongos Pelados , Camundongos Transgênicos , Regiões Promotoras Genéticas/genética , Receptores Acoplados a Proteínas-G/metabolismo , Pele/efeitos dos fármacos , Pele/metabolismo , Pele/efeitos da radiação , Neoplasias Cutâneas/metabolismo , Raios Ultravioleta
15.
Oncotarget ; 7(32): 52085-52094, 2016 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-27409834

RESUMO

Actively proliferating Lgr5+ skin stem cells are found deep in the hair follicle (HF). These cells renew the HF and drive its expansion in anagen phase. Their long residence and continuous mitotic activity make them prime candidates to transform into skin tumor-initiating cells. This was investigated by subjecting Lgr5-EGFP-Ires-CreERT2/R26R-LacZ mice (haired and hairless) to chemical and UV carcinogenic regimens. In the course of these regimens Lgr5+ cells (EGFP+) remained exclusively located in HFs, and in deep-seated cysts of hairless skin. In haired mice, progeny of Lgr5+ stem cells (LacZ+ after a pulse of tamoxifen) appeared in the interfollicular epidermis upon UV-induced sunburn and in TPA-induced hyperplasia. In hairless mice the progeny remained located in deep-seated cysts and in HF remnants. Progeny in hairless skin was only detected interfollicularly at a late stage, in between outgrowing tumors. Lgr5+ stem cells were absent in the ultimate tumor masses, and no tumor appeared to be a (clonal) expansion of Lgr5+ cells (52 tumors with tamoxifen at the start of carcinogenesis, 42 tumors with tamoxifen late during tumor outgrowth). In contrast to CD34/K15+ quiescent bulge stem cells, actively proliferating Lgr5+ stem cells do therefore not appear to be tumor drivers in experimental skin carcinogenesis.


Assuntos
Transformação Celular Neoplásica/patologia , Folículo Piloso/patologia , Receptores Acoplados a Proteínas-G/metabolismo , Neoplasias Cutâneas/patologia , Células-Tronco/patologia , Animais , Epiderme/patologia , Camundongos , Camundongos Pelados , Camundongos Transgênicos
16.
PLoS One ; 10(9): e0138002, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26368812

RESUMO

Uveal melanomas (UM) originate from melanocytes in the interior wall of the eye, namely from the iris, ciliary body and the choroid with marked differences in light exposure (from dark anterior to illuminated posterior). In contrast to UV radiation, focused or converging visible light readily reaches the retina and can damage DNA which possibly contributes to UM development. In this report choroidal, ciliochoroidal and iridociliary melanomas were analyzed for GNAQ and GNA11 mutations which were subsequently correlated to the location of tumor origin. Hotspot mutations in GNAQ and GNA11 can be divided in A>T and in A>C mutation signatures. The GNAQ A626C mutation (Q209P) was almost exclusively observed in choroidal melanomas from the illuminated posterior side. On the other hand, ciliochoroidal UM from the dark anterior side with mostly A>T mutations were clearly associated with light-colored eyes. Combined these data suggest a light and a pigment dependent etiology in UM development.


Assuntos
Subunidades alfa de Proteínas de Ligação ao GTP/genética , Melanoma/genética , Mutação de Sentido Incorreto , Proteínas de Neoplasias/genética , Raios Ultravioleta/efeitos adversos , Neoplasias Uveais/genética , Substituição de Aminoácidos , Feminino , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP , Humanos , Masculino , Melanoma/patologia , Neoplasias Uveais/patologia
19.
Int J Cancer ; 136(2): 271-7, 2015 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-24890436

RESUMO

Mortality from colorectal cancer increases with latitude and decreases with ambient UV radiation. We investigated whether moderate UV dosages could inhibit intestinal tumor development and whether this corresponded with UV-induced vitamin D. FabplCre;Apc(15lox/+) mice, which develop intestinal tumors, and their parents were put on a vitamin D-deficient diet. Next to a control group, one group was vitamin D supplemented and another one group was daily UV irradiated from 6 weeks of age. Vitamin D statuses after 6 weeks of treatment were markedly increased: mean ± SD from 7.7 ± 1.9 in controls to 75 ± 15 nmol/l with vitamin D supplementation (no gender difference), and to 31 ± 13 nmol/l in males and 85 ± 17 nmol/l in females upon UV irradiation. The tumor load (area covered by tumors) at 7.5 months of age was significantly reduced in both the vitamin D-supplemented group (130 ± 25 mm(2), p = 0.018) and the UV-exposed group (88 ± 9 mm(2), p < 0.0005; no gender differences) compared to the control group (202 ± 23 mm(2)). No reductions in tumor numbers were found. Only UV exposure appeared to reduce progression to malignancy (p = 0.014). Our experiments clearly demonstrate for the first time an inhibitory effect of moderate UV exposure on outgrowth and malignant progression of primary intestinal tumors, which at least in part can be attributed to vitamin D.


Assuntos
Genes APC/fisiologia , Neoplasias Intestinais/patologia , Neoplasias Intestinais/prevenção & controle , Raios Ultravioleta , Vitamina D/administração & dosagem , Vitaminas/administração & dosagem , Animais , Suplementos Nutricionais , Progressão da Doença , Feminino , Neoplasias Intestinais/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL
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