Opposing roles for calcineurin and ATF3 in squamous skin cancer.

Calcineurin inhibitors such as cyclosporin A (CsA) are the mainstay of immunosuppressive treatment for organ transplant recipients. Squamous cell carcinoma (SCC) of the skin is a major complication of treatment with these drugs, with a 65 to 100-fold higher risk than in the normal population. By contrast, the incidence of basal cell carcinoma (BCC), the other major keratinocyte-derived tumour of the skin, of melanoma and of internal malignancies increases to a significantly lesser extent. Here we report that genetic and pharmacological suppression of calcineurin/nuclear factor of activated T cells (NFAT) function promotes tumour formation in mouse skin and in xenografts, in immune compromised mice, of H-ras(V12) (also known as Hras1)-expressing primary human keratinocytes or keratinocyte-derived SCC cells. Calcineurin/NFAT inhibition counteracts p53 (also known as TRP53)-dependent cancer cell senescence, thereby increasing tumorigenic potential. ATF3, a member of the 'enlarged' AP-1 family, is selectively induced by calcineurin/NFAT inhibition, both under experimental conditions and in clinically occurring tumours, and increased ATF3 expression accounts for suppression of p53-dependent senescence and enhanced tumorigenic potential. Thus, intact calcineurin/NFAT signalling is critically required for p53 and senescence-associated mechanisms that protect against skin squamous cancer development.

Sentinel lymph node biopsy in nonmelanoma skin cancer patients.

The management of lymph nodes in nonmelanoma skin cancer patients is currently still debated. Merkel cell carcinoma (MCC), squamous cell carcinoma (SCC), pigmented epithelioid melanocytoma (PEM), and other rare skin neoplasms have a well-known risk to spread to regional lymph nodes. The use of sentinel lymph node biopsy (SLNB) could be a promising procedure to assess this risk in clinically N0 patients. Metastatic SNs have been observed in 4.5-28% SCC (according to risk factors), in 9-42% MCC, and in 14-57% PEM. We observed overall 30.8% positive SNs in 13 consecutive patients operated for high-risk nonmelanoma skin cancer between 2002 and 2011 in our institution. These high rates support recommendation to implement SLNB for nonmelanoma skin cancer especially for SCC patients. Completion lymph node dissection following positive SNs is also a matter of discussion especially in PEM. It must be remembered that a definitive survival benefit of SLNB in melanoma patients has not been proven yet. However, because of its low morbidity when compared to empiric elective lymph node dissection or radiation therapy of lymphatic basins, SLNB has allowed sparing a lot of morbidity and could therefore be used in nonmelanoma skin cancer patients, even though a significant impact on survival has not been demonstrated.

Selective inhibition of JNK with a peptide inhibitor attenuates pain hypersensitivity and tumor growth in a mouse skin cancer pain model.

Cancer pain significantly affects the quality of cancer patients, and current treatments for this pain are limited. C-Jun N-terminal kinase (JNK) has been implicated in tumor growth and neuropathic pain sensitization. We investigated the role of JNK in cancer pain and tumor growth in a skin cancer pain model. Injection of luciferase-transfected B16-Fluc melanoma cells into a hindpaw of mouse induced robust tumor growth, as indicated by increase in paw volume and fluorescence intensity. Pain hypersensitivity in this model developed rapidly (<5 days) and reached a peak in 2 weeks, and was characterized by mechanical allodynia and heat hyperalgesia. Tumor growth was associated with JNK activation in tumor mass, dorsal root ganglion (DRG), and spinal cord and a peripheral neuropathy, such as loss of nerve fibers in the hindpaw skin and induction of ATF-3 expression in DRG neurons. Repeated systemic injections of D-JNKI-1 (6 mg/kg, i.p.), a selective and cell-permeable peptide inhibitor of JNK, produced an accumulative inhibition of mechanical allodynia and heat hyperalgesia. A bolus spinal injection of D-JNKI-1 also inhibited mechanical allodynia. Further, JNK inhibition suppressed tumor growth in vivo and melanoma cell proliferation in vitro. In contrast, repeated injections of morphine (5 mg/kg), a commonly used analgesic for terminal cancer, produced analgesic tolerance after 1 day and did not inhibit tumor growth. Our data reveal a marked peripheral neuropathy in this skin cancer model and important roles of the JNK pathway in cancer pain development and tumor growth. JNK inhibitors such as D-JNKI-1 may be used to treat cancer pain.

Estimating the contribution of occupational solar ultraviolet exposure to skin cancer

BACKGROUND: Exposure to solar ultraviolet (UV) light is the main causative factor for skin cancer. Outdoor workers are at particular risk because they spend long working hours outside, may have little shade available and be bound to take their lunch at their workplace. Despite epidemiological evidence of a doubling in risk of squamous cell carcinoma in outdoor workers, the recognition of skin cancer as an occupational disease remains scarce. OBJECTIVE: To assess occupational solar UV doses and its contribution to skin cancer risk. METHODS: A numerical model (SimUVEx) was used to assess occupational and lunch break exposures, characterize exposure patterns and anatomical distribution. Risk of squamous cell carcinoma (SCC) was estimated from an existing epidemiological model. RESULTS: Horizontal body locations received 2.0-2.5 times more UV than vertical locations. Dose associated to lunch outdoor every day was similar to outdoor work one day per week but only half of a seasonal worker. Outdoor workers are associated with an increased risk of SCC but also of frequent acute episodes. CONCLUSION: Occupational solar exposure contributes largely to the overall lifetime UV dose, resulting in an excess risk of SCC. The magnitude of the estimated excess in risk supports the recognition of SCC as an occupational disease.

A general model to predict individual exposure to solar UV by using ambient irradiance data

Excessive exposure to solar ultraviolet (UV) is the main cause of skin cancer. Specific prevention should be further developed to target overexposed or highly vulnerable populations. A better characterisation of anatomical UV exposure patterns is however needed for specific prevention. To develop a regression model for predicting the UV exposure ratio (ER, ratio between the anatomical dose and the corresponding ground level dose) for each body site without requiring individual measurements. A 3D numeric model (SimUVEx) was used to compute ER for various body sites and postures. A multiple fractional polynomial regression analysis was performed to identify predictors of ER. The regression model used simulation data and its performance was tested on an independent data set. Two input variables were sufficient to explain ER: the cosine of the maximal daily solar zenith angle and the fraction of the sky visible from the body site. The regression model was in good agreement with the simulated data ER (R(2)=0.988). Relative errors up to +20% and -10% were found in daily doses predictions, whereas an average relative error of only 2.4% (-0.03% to 5.4%) was found in yearly dose predictions. The regression model predicts accurately ER and UV doses on the basis of readily available data such as global UV erythemal irradiance measured at ground surface stations or inferred from satellite information. It renders the development of exposure data on a wide temporal and geographical scale possible and opens broad perspectives for epidemiological studies and skin cancer prevention.

A numeric model to simulate solar individual ultraviolet exposure.

Exposure to solar ultraviolet (UV) light is the main causative factor for skin cancer. UV exposure depends on environmental and individual factors. Individual exposure data remain scarce and development of alternative assessment methods is greatly needed. We developed a model simulating human exposure to solar UV. The model predicts the dose and distribution of UV exposure received on the basis of ground irradiation and morphological data. Standard 3D computer graphics techniques were adapted to develop a rendering engine that estimates the solar exposure of a virtual manikin depicted as a triangle mesh surface. The amount of solar energy received by each triangle was calculated, taking into account reflected, direct and diffuse radiation, and shading from other body parts. Dosimetric measurements (n = 54) were conducted in field conditions using a foam manikin as surrogate for an exposed individual. Dosimetric results were compared to the model predictions. The model predicted exposure to solar UV adequately. The symmetric mean absolute percentage error was 13%. Half of the predictions were within 17% range of the measurements. This model provides a tool to assess outdoor occupational and recreational UV exposures, without necessitating time-consuming individual dosimetry, with numerous potential uses in skin cancer prevention and research.

Inferring ultraviolet anatomical exposure patterns while distinguishing the relative contribution of radiation components

Exposure to solar ultraviolet (UV) radiation is the main causative factor for skin cancer. UV exposure depends on environmental and individual factors, but individual exposure data remain scarce. UV irradiance is monitored via different techniques including ground measurements and satellite observations. However it is difficult to translate such observations into human UV exposure or dose because of confounding factors (shape of the exposed surface, shading, behavior, etc.) A collaboration between public health institutions, a meteorological office and an institute specialized in computing techniques developed a model predicting the dose and distribution of UV exposure on the basis of ground irradiation and morphological data. Standard 3D computer graphics techniques were adapted to develop this tool, which estimates solar exposure of a virtual manikin depicted as a triangle mesh surface. The amount of solar energy received by various body locations is computed for direct, diffuse and reflected radiation separately. The radiation components are deduced from corresponding measurements of UV irradiance, and the related UV dose received by each triangle of the virtual manikin is computed accounting for shading by other body parts and eventual protection measures. The model was verified with dosimetric measurements (n=54) in field conditions using a foam manikin as surrogate for an exposed individual. Dosimetric results were compared to the model predictions. The model predicted exposure to solar UV adequately. The symmetric mean absolute percentage error was 13%. Half of the predictions were within 17% range of the measurements. This model allows assessing outdoor occupational and recreational UV exposures, without necessitating time-consuming individual dosimetry, with numerous potential uses in skin cancer prevention and research. Using this tool, we investigated solar UV exposure patterns with respect to the relative contribution of the direct, diffuse and reflected radiation. We assessed exposure doses for various body parts and exposure scenarios of a standing individual (static and dynamic postures). As input, the model used erythemally-weighted ground irradiance data measured in 2009 at Payerne, Switzerland. A year-round daily exposure (8 am to 5 pm) without protection was assumed. For most anatomical sites, mean daily doses were high (typically 6.2-14.6 SED) and exceeded recommended exposure values. Direct exposure was important during specific periods (e.g. midday during summer), but contributed moderately to the annual dose, ranging from 15 to 24% for vertical and horizontal body parts, respectively. Diffuse irradiation explained about 80% of the cumulative annual exposure dose. Acute diffuse exposures were also obtained for cloudy summer days. The importance of diffuse UV radiation should not be underestimated when advocating preventive measures. Messages focused on avoiding acute direct exposures may be of limited efficiency to prevent skin cancers associated with chronic exposure (e.g., squamous cell carcinomas).

Prévention primaire et dépistage chez l'adulte: mise à jour 2010. [Prevention and screening in adults: trends in 2010].

This article proposes an update on the recommendations for the check-up and the primary and secondary prevention of cancers and cardio-vascular diseases. Indeed, new clinical data led the adaptation and clarification of some of them. The novelties for cancer screening concern mainly colorectal, breast and prostate cancers. Screening for low ankle brachial index is not recommended.

Dual role of the antioxidant enzyme peroxiredoxin 6 in skin carcinogenesis.

The antioxidant enzyme peroxiredoxin 6 (Prdx6) is a key regulator of the cellular redox balance, particularly under stress conditions. We identified Prdx6 as an important player in different phases of skin carcinogenesis. Loss of Prdx6 in mice enhanced the susceptibility to skin tumorigenesis, whereas overexpression of Prdx6 in keratinocytes of transgenic mice had the opposite effect. The tumor-preventive effect of Prdx6, which was observed in a human papilloma virus 8-induced and a chemically induced tumor model, was not due to alterations in keratinocyte proliferation, apoptosis, or in the inflammatory response. Rather, endogenous and overexpressed Prdx6 reduced oxidative stress as reflected by the lower levels of oxidized phospholipids in the protumorigenic skin of Prdx6 transgenic mice and the higher levels in Prdx6-knockout mice than in control animals. In contrast to its beneficial effect in tumor prevention, overexpression of Prdx6 led to an acceleration of malignant progression of existing tumors, revealing a dual function of this enzyme in the pathogenesis of skin cancer. Finally, we found strong expression of PRDX6 in keratinocytes of normal human skin and in the tumor cells of squamous cell carcinomas, indicating a role of Prdx6 in human skin carcinogenesis. Taken together, our data point to the potential usefulness of Prdx6 activators or inhibitors for controlling different stages of skin carcinogenesis.

Epidémiologie des cancers épithéliaux de la peau [Epidemiology of epithelial skin cancers]

With no less than 15,000 estimated new cases diagnosed per year, non melanomatous carcinomas are the commonest cutaneous cancers in the Swiss population. About 1 in 3 new cancer case is a basal (BCC) or a squamous cell carcinoma (SCC). Incidence rates are steadily increasing, faster for BCC than SCC. Rates are higher for men than women and increase exponentially with age. Systematic population-based registration of non melanomatous skin cancers faces many challenges that few cancer registries can meet. Rates of these cancers in Switzerland are among the highest in Europe. Primary and secondary nationwide prevention campaigns have been carried out for nearly 20 years with a focus on the deadliest cutaneous cancer: melanoma. However, detection of non melanomatous skin cancers benefits from these campaigns since prevention messages and means of early detection are similar for melanomas and other skin cancers.

Second primary cancers in the Vaud and Neuchâtel Cancer Registries

An increasing proportion of new cancers is registered in patients who have received a previous cancer diagnosis. As data are inconsistent across studies, we provided information for populations long covered by valid cancer registration. Data were derived from the Swiss cancer Registries of Vaud and Neuchâtel (885 000 inhabitants). Patients diagnosed with a new malignancy (except skin basal and squamous cell carcinomas) during the period 2005-2010 were included. Over the period 2005-2010, 24 859 patients were registered with incident cancer. Of these, 3127 (13%) had multiple primary cancers and 578 (2.3%) were synchronous. Breast, prostate, colorectum, skin, melanomas, and squamous cell carcinomas of the head and neck (SHN) and bladder/ureter were the most common sites of first neoplasms, whereas breast, lung, colorectum, prostate, melanoma, and SHN were the most common sites of second neoplasms. The most common pairing was breast with breast (31% synchronous), followed by the bladder/ureter with the prostate (72% synchronous), prostate with the colorectum, SHN with SHN, and SHN with lung. Five-year crude survival of patients with synchronous cancers (34%) was not significantly lower than that of patients with single neoplasms (39%).

Prévention du métanome en Suisse: où en sommes-nous [Melanoma prevention in Switzerland: where do we stand?]

Over the last 50 years, skin cancer rates (particularly melanoma) have markedly increased in Caucasian populations. Switzerland, with some 1,600 cases of, and 220 deaths from, malignant melanoma per year has among the highest rates in Europe. This public health issue, affecting relatively young people, has led to primary and secondary nationwide prevention campaigns being carried out for nearly 20 years. Observed changes in sun protection knowledge and attitudes have yet to impact on incidence trend. Early detection has resulted in a large increase in rates of thin melanoma with little change in rates of thick melanoma. Mortality has levelled off and a recent decrease, especially in women, cannot be ruled out. The efficiency of prevention campaigns should soon become more blatant if current efforts persist.

The "Solmobile" prevention campaigns (2001-5): synthesis and prospects

The 5-year "Solmobile" skin prevention campaigns carried out between 2001 and 2005 by the Swiss League against Cancer met their objectives. About 21'000 visits were recorded throughout Switzerland and 10'000 clinical skin examinations performed. This report briefly summarises the main results of the epidemiological evaluation of these campaigns.

Nuclear receptor peroxisome proliferator activated receptor (PPAR) beta/delta in skin wound healing and cancer

We review the functions of peroxisome proliferator activated receptor (PPAR) beta/delta in skin wound healing and cancer. In particular, we highlight the roles of PPAR beta/delta in inhibiting keratinocyte apoptosis at wound edges via activation of the PI3K/PKB alpha/Akt1 pathway and its role during re-epithelialization in regulating keratinocyte adhesion and migration. In fibroblasts, PPAR beta/delta controls IL-1 signalling and thereby contributes to the homeostatic control of keratinocyte proliferation. We discuss its therapeutic potential for treating diabetic wounds and inflammatory skin diseases such as psoriasis and acne vulgaris. PPAR beta/delta is classified as a tumour growth modifier; it is activated by chronic low-grade inflammation, which promotes the production of lipids that, in turn, enhance PPAR beta/delta transcription activity. Our earlier,work unveiled a cascade of events triggered by PPAR beta/delta that involve the oncogene Src, which promotes ultraviolet-induced skin cancer in mice via enhanced EGFR/Erk1/2 signalling and the expression of epithelial-to-mesenchymal transition (EMT) markers. Interestingly, PPAR beta/delta expression is correlated with the expression of SRC and EMT markers in human skin squamous cell carcinoma. Furthermore, there is a positive interaction between PPAR beta/delta, SRC, and TGF beta 1 at the transcriptional level in various human epithelial cancers. Taken together, these observations suggest the need for evaluating PPAR beta/delta modulators that attenuate or increase its activity, depending on the therapeutic target.

Nrf2 Activation Promotes Keratinocyte Survival during Early Skin Carcinogenesis via Metabolic Alterations.

Pharmacologic activation of the transcription factor NRF2 has been suggested to offer a strategy for cancer prevention. In this study, we present evidence from murine tumorigenesis experiments suggesting there may be limitations to this possibility, based on tumorigenic effects of Nrf2 in murine keratinocytes that have not been described previously. In this setting, Nrf2 expression conferred metabolic alterations in keratinocytes that were protumorigenic in nature, affecting enzymes involved in glutathione biosynthesis or in the oxidative pentose phosphate pathway and other NADPH-producing enzymes. Under stress conditions, coordinate increases in NADPH, purine, and glutathione levels promoted the survival of keratinocytes harboring oncogenic mutations, thereby promoting tumor development. The protumorigenic activity of Nrf2 in keratinocytes was particularly significant in a mouse model of skin tumorigenesis that did not rely upon chemical carcinogenesis. In exploring the clinical relevance of our findings, we confirm that NRF2 and protumorigenic NRF2 target genes were activated in some actinic keratoses, the major precancerous lesion in human skin. Overall, our results reveal an unexpected tumor-promoting activity of activated NRF2 during early phases of skin tumorigenesis. Cancer Res; 75(22); 4817-29. ©2015 AACR.