Long-term health risk to the skin of ultraviolet radiation

The major well-proven long-term health risks of excessive exposure to ultraviolet (UV) radiation relate to the skin. Premalignant skin lesions are seen very much earlier in white skinned populations exposed to excessive sunlight, and over time these same individuals develop larger numbers of all of the three major skin cancers than individuals who do not experience excessive UV exposure. These three skin cancers are squamous cell carcinoma (SCC), basal cell carcinoma (BCC), and malignant melanoma. In the case of SCC the major aetiological pattern is chronic long-term exposure, but for BCCs the pattern appears to be slightly different with short-term burning episodes being more important. In the case of melanomas, there is evidence that for the 4 main types of melanomas, the pattern of excess UV exposure which is most injurious varies.     

Growth and progression of melanoma and non-melanoma skin cancers regulated by ubiquitination

Basal cell carcinomas (BCC), squamous cell carcinoma (SCC), and melanomas are the major types of skin tumors. Despite being skin cancers, the characteristics of each cancer are widely varied. BCCs often do not proliferate rapidly, and rarely metastasize. Squamous cell carcinomas are more malignant and a certain subtype of SCC is highly metastatic. Melanomas are highly proliferative and invasive, and are most frequently metastatic. Ubiquitin and ubiquitin-related proteins post-translationally modify proteins and thereby alter the functions of their target proteins. The ubiquitination process is involved in various physiological responses, including cell growth, cell death, and DNA damage repair. Accumulating evidence suggests that ubiquitin pathways are involved in different types of cancers, including skin cancers. This review describes the major ubiquitin pathways in BCC, SCC, and melanoma. The ubiquitin pathways that are activated among the skin cancers are highly diverse, which might reflect the various characteristics of these three cancer types. Meanwhile, there are also common pathways between BCC, SCC, and melanoma. Therefore, examining the ubiquitin pathways will reveal the mechanisms of these three major skin cancer types and will suggest treatment options.     

YAP and TAZ are essential for basal and squamous cell carcinoma initiation

YAP and TAZ are key downstream regulators of the Hippo pathway, regulating cell proliferation and differentiation. YAP and TAZ activation has been reported in different cancer types. However, it remains unclear whether they are required for the initiation of major skin malignancies like basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). Here, we analyze the expression of YAP and TAZ in these skin cancers and evaluate cancer initiation in knockout mouse models. We show that YAP and TAZ are nuclear and highly expressed in different BCC types in both human and mice. Further, we find that cells with nuclear YAP and TAZ localize to the invasive front in well‐differentiated SCC, whereas nuclear YAP is homogeneously expressed in spindle cell carcinoma undergoing EMT. We also show that mouse BCC and SCC are enriched for YAP gene signatures. Finally, we find that the conditional deletion of YAP and TAZ in mouse models of BCC and SCC prevents tumor formation. Thus, YAP and TAZ are key determinants of skin cancer initiation, suggesting that targeting the YAP and TAZ signaling pathway might be beneficial for the treatment of skin cancers.     

Rapid,quantitative prediction of tumor invasiveness in non-melanoma skin cancers using mechanobiology-based assay

Biomechanics and Modeling in Mechanobiology - Non-melanoma skin cancers, including basal and squamous cell carcinomas (BCC and SCC), are the most common malignancies worldwide. BCC/SCC cancers are...     

Trends in incidence and survival analysis in non-melanoma skin cancer from 1994 to 2012 in Girona,Spain: A population-based study

IntroductionWe present an epidemiological study focused on Non-melanoma skin cancers (NMSC), including squamous cell carcinoma (SCC), basal cell carcinoma (BCC), Merkel cell carcinoma (MCC), dermatofibrosarcoma protuberans (DFS) and adnexal and skin appendages neoplasm (ASAN), a neoplasm understudied in cancer registries.Material and methodsWe analyze trends of incidence and survival of NMSC registered with the Cancer Registry of Girona, Spain.ResultsWe found 14389 cases of NMSC, accounting 3,474 SCC, 10729 BCC, 33 MCC, 61 DFSP and 71 ASAN. Incidence increased significantly in SCC and BCC with annual percentage of change of 1.6 and 1.5, respectively, but not in MCC, DFS or ASAN. Five-year relative survival for both sexes was 90.1% in SCC, 99.8% in BCC, 44.2% in MCC, 93.7% in DFS and 84% in ASAN.ConclusionsOur study confirms the increasing incidence and good survival of SCC and BCC and enhances knowledge on the epidemiology of the less incidental NMSC.     

Increased expression of Dsg2 in malignant skin carcinomas: A tissue-microarray based study

Desmoglein 2 (Dsg2), a transmembrane cadherin of the desmosomal cell-cell adhesion structure, is downregulated with epithelial differentiation. We recently demonstrated that overexpression of Dsg2 in epidermal keratinocytes deregulates multiple signaling pathways associated with increased growth rate, anchorage-independent cell survival, and the development of skin tumors. While changes in Dsg2 expression have been observed in neoplastic lesions, the correlation of expression levels and localization of Dsg2 and the state of tumor development has not been fully established. Here we generated a highly sensitive Dsg2 antibody (Ab10) and characterized that antibody along with a previously developed Dsg2 specific antibody 10D2. Using these antibodies in immunostaining of tissue microarrays, we show a dramatic upregulation of Dsg2 expression in certain human epithelial malignancies including basal cell carcinomas (BCC; n = 12), squamous cell carcinomas (SCC; n = 57), carcinomas of sebaceous and sweat glands (n = 12), and adenocarcinomas (n = 3). Dsg2 expression was completely absent in malignant fibrosarcomas (n = 16) and melanomas (n = 15). While Dsg2 expression was consistently strong in BCC, it varied in SCC with a minor correlation between a decrease of Dsg2 expression and tumor differentiation. In summary, we have identified Dsg2 as a potential novel marker for epithelial-derived malignancies.Key words: carcinogenesis, desmoglein, desmosome, skin     

Actinic keratosis associated with squamous and basal cell carcinomas: an evaluation of neoplastic progression by a standardized AgNOR analysis

In an attempt to investigate the neoplastic progression in different stages of actinic keratosis (AK), a standardized AgNOR analysis was performed in 94 cases of AK, 35 of which were associated with squamous cell carcinoma (SCC) or basal cell carcinoma (BCC), and in 31 cases of SCC and 22 cases of BCC. The cases were subdivided into low- and high-AgNOR-expressing (AgNOR status) AK by using the mean area of AgNORs per cell (NORA) value (3.996 micro(2)) as the cut-off. In AK samples, a progressive increase of the mean NORA value from Stage I to Stage IV was encountered. In addition, a significantly higher mean NORA value was found in the AK cases associated with SCC, in comparison to those without SCC; by contrast, no significant differences in the mean NORA value were noted between AK cases with or without BCC. A highly significant association between a high AgNOR quantity and the coexistence of SCC was encountered in AK; no association was appreciable between the AgNOR quantity and the co-occurrence of BCC. Moreover, when the co-existence of SCC in AK was considered as the reference point, the AK cases associated with SCC mostly (95.5%) presented a high AgNOR quantity (high sensitivity), but only 57.6% of cases without SCC displayed a low AgNOR quantity (low specificity). Additionally, our data document that the standardised AgNOR analysis represents a strong negative predictor for the association between SCC and AK. Indeed, a low AgNOR quantity mostly is associated with AK cases without SCC.     

Physiological model using diffuse reflectance spectroscopy for nonmelanoma skin cancer diagnosis

Diffuse reflectance spectroscopy (DRS) is a noninvasive, fast, and low‐cost technology with potential to assist cancer diagnosis. The goal of this study was to test the capability of our physiological model, a computational Monte Carlo lookup table inverse model, for nonmelanoma skin cancer diagnosis. We applied this model on a clinical DRS dataset to extract scattering parameters, blood volume fraction, oxygen saturation and vessel radius. We found that the model was able to capture physiological information relevant to skin cancer. We used the extracted parameters to classify (basal cell carcinoma [BCC], squamous cell carcinoma [SCC]) vs actinic keratosis (AK) and (BCC, SCC, AK) vs normal. The area under the receiver operating characteristic curve achieved by the classifiers trained on the parameters extracted using the physiological model is comparable to that of classifiers trained on features extracted via Principal Component Analysis. Our findings suggest that DRS can reveal physiologic characteristics of skin and this physiologic model offers greater flexibility for diagnosing skin cancer than a pure statistical analysis. Physiological parameters extracted from diffuse reflectance spectra data for nonmelanoma skin cancer diagnosis.     

Distinct innate immune gene expression profiles in non-melanoma skin cancer of immunocompetent and immunosuppressed patients

Squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) are the most frequent skin cancers in humans. An intact immune system is critical for protection against SCC since organ transplant recipients (OTR) have a 60- to 100-fold higher risk for developing these tumors. The role of the innate immune system in tumor immunosurveillance is unclear. Our aim was to determine the expression of selected innate immune genes in BCC and SCC arising in immunocompetent and OTR patients. Lesional and peri-lesional skin from 28 SCC and 19 BCC were evaluated for mRNA expression of toll-like receptors (TLR) 1-9, downstream TLR signaling molecules, and antimicrobial peptides. 11 SCC occurring in OTR patients were included in the analysis. We found that SCC but not BCC showed significantly elevated expression of TLRs 1-3, 5-8, TRIF and TRAF1. TNF was increased in SCC compared to normal skin. BCC showed increased IFNγ. hBD1, hBD2 and psoriasin mRNA and protein expression were significantly higher in SCC than in normal skin and higher than in BCC. SCC from OTR showed only an increase in hBD2 but no increase in hBD1 or psoriasin. We conclude that innate immune gene expression in SCC is distinct from normal skin and BCC. BCC shows lesser induction of innate immune genes. SCC from OTR patients have depressed expression of hBD1 and psoriasin compared to SCC from immunocompetent patients.     

Cytological diagnosis of basal cell carcinoma and actinic keratosis, using Papanicolaou and May–Grünwald–Giemsa stained cutaneous tissue smear

Objective:  Cytology may become the diagnostic method of choice with the advent of new non-invasive treatments for non-melanoma skin cancer, as the sampling technique for cytology entails little tissue disfiguration. The aim of this study was to compare and evaluate the diagnostic performance of scrape cytology using two different cytological staining techniques, and to evaluate additional touch imprint cytology, with that of histopathology of basal cell carcinoma (BCC) and actinic keratosis (AK).
Methods:  We investigated 50 BCC and 28 AK histologically verified lesions, from 41 and 25 patients, respectively. Two separate skin scrape samples and one touch imprint sample were taken from each lesion. The smears were stained with Papanicolaou (Pap) or May–Grünwald–Giemsa (MGG) stains. All cytological specimens were examined in random order by pathologists without knowledge of the histology. Cytodiagnostic results were compared with the histopathological report.
Results:  Scrape cytodiagnosis agreed with histopathology in 48 (Pap) and 47 (MGG) of the 50 BCC cases, and in 26 of 28 (Pap) and 21 of 26 (MGG) AK cases, yielding sensitivities of 96%, 94%, 93% and 81%, respectively. No significant difference in sensitivity between the two staining methods was found but a trend towards higher Pap sensitivity for AK was noted ( P  =   0.10). Touch imprint cytology confirmed histopathology in 38 of the 77 cases of BCC and AK.
Conclusion:  Cytological diagnosis with either Pap or MGG stain for BCC and AK is reliable, and differentiates well between BCC and AK. Imprint cytology proved to be non-diagnostic in half of the examined cases.     

Evaluation of aneuploidy frequency for chromosomes 6 and 17 in eyelid tumours using the FISH technique

Although basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) are very common skin tumours, the incidence of chromosome aneuploidy with regard to the eyelid has not been investigated. We aimed to find the frequency of chromosome 6 and 17 aneuploidies in eyelid tumours' interphase nuclei with fluorescence in situ hybridization (I-FISH) with chromosome specific DNA probes. I-FISH with chromosome 6 and 17 centromere specific DNA probes was used in the eyelids of 10 patients with BCC or SCC and the peripheral blood cells of 10 healthy donors as controls. The frequency of chromosome 6 and 17 aneuploidies was significantly higher in 7 out of 10 patients and 5 out of 10 patients, respectively, than in controls, indicating a higher frequency of aneuploidy in BCC than in SCC of the eyelid. Distribution of hybridization signals for chromosome 6 and 17 was wide ranging, indicating heterogeneity of cell populations with aneuploidy between patients. These findings indicate that acquisition of chromosome aneuploidies in eyelid tumours may have an important pathogenic role in both BCC and SCC of the eyelid area.     

Socioeconomic status and non-melanoma skin cancer: A nationwide cohort study of incidence and survival in Denmark

Background: The two main types of non-melanoma skin cancer differ with the pattern of exposure to ultraviolet radiation (UVR): basal cell carcinoma (BCC) appears to be more closely related to intermittent solar exposure and sunburn, while the risk for squamous cell carcinoma (SCC) is a result of lifetime cumulated exposure to UVR. As these exposures may differ by social position, we investigated its role in the risk for and survival after BCC and SCC diagnosed in Denmark in 1994–2006 with follow-up through 2006. Methods: The analyses were based on 52,166 cases of BCC and 5033 cases of SCC in a cohort of 3.7 million people born between 1925 and 1976 and residing in Denmark in 1992–2006. Information on cancer cases and socioeconomic indicators were obtained from population-based registries. We used log-linear Poisson regression models to estimate incidence rate ratios and cumulative relative survival to estimate survival up to 10 years after the first incident cases of BCC and SCC. Results: High socioeconomic status, measured by both education and disposable income, was strongly associated with a higher risk for BCC, whereas there was no association between SCC and educational level and only a weak association with income. In general, relative survival after BCC was better than after SCC; the pattern of survival was not affected by socioeconomic indicators. Conclusions: The observed pattern of social status and risk for non-melanoma skin cancer differed substantially for the two cancer types, supporting the hypothesis that they may have different aetiologies.     

Quantitative analysis of viral load per haploid genome revealed the different biological features of Merkel cell polyomavirus infection in skin tumor

Merkel cell polyomavirus (MCPyV) has recently been identified in Merkel cell carcinoma (MCC), an aggressive cancer that occurs in sun-exposed skin. Conventional technologies, such as polymerase chain reaction (PCR) and immunohistochemistry, have produced conflicting results for MCPyV infections in non-MCC tumors. Therefore, we performed quantitative analyses of the MCPyV copy number in various skin tumor tissues, including MCC (n?=?9) and other sun exposure-related skin tumors (basal cell carcinoma [BCC, n?=?45], actinic keratosis [AK, n?=?52], Bowen's disease [n?=?34], seborrheic keratosis [n?=?5], primary cutaneous anaplastic large-cell lymphoma [n?=?5], malignant melanoma [n?=?5], and melanocytic nevus [n?=?6]). In a conventional PCR analysis, MCPyV DNA was detected in MCC (9 cases; 100%), BCC (1 case; 2%), and AK (3 cases; 6%). We then used digital PCR technology to estimate the absolute viral copy number per haploid human genome in these tissues. The viral copy number per haploid genome was estimated to be around 1 in most MCC tissues, and there were marked differences between the MCC (0.119-42.8) and AK (0.02-0.07) groups. PCR-positive BCC tissue showed a similar viral load as MCC tissue (0.662). Immunohistochemistry with a monoclonal antibody against the MCPyV T antigen (CM2B4) demonstrated positive nuclear localization in most of the high-viral-load tumor groups (8 of 9 MCC and 1 BCC), but not in the low-viral-load or PCR-negative tumor groups. These results demonstrated that MCPyV infection is possibly involved in a minority of sun-exposed skin tumors, including BCC and AK, and that these tumors display different modes of infection.     

Different expression of cyclooxygenase-2 (COX-2) in selected nonmelanocytic human cutaneous lesions

The aim of our study was to elucidate the possible involvement of COX-2 in the development and/or progression of nonmelanocytic skin lesions. To evaluate the usefulness of that enzyme as a potential molecular marker, we examined the intensity and spatial distribution of COX-2 expression in selected types of such tumors using the same immunohistochemical procedure as in our earlier studies of melanocytic cancers. We examined 20 benign epithelial lesions, 11 precancerous lesions, 21 basal cell carcinomas (BCC), 14 squamous cell carcinomas (SCC) and eight fibromas. The levels of COX-2 expression detected in benign lesions and in normal skin were comparable. Elevated expression of this protein may play a role in the development of SCC, as indicated by strong immunostaining both in SCCs and precancerous lesions. Significantly stronger staining in SCCs compared to BCCs may indicate a role of COX-2 in cancer malignancy and serve as an indicator useful for differential diagnostics of the two types of cancer. Strong staining in all skin layers of SCC may help in detecting cancer cells infiltrating surrounding skin layers.     

Karyometry of nuclei from actinic keratosis and squamous cell cancer of the skin

OBJECTIVE: To use karyometric analysis methods to compare actinic keratoses (AKs) to squamous cell carcinomas (SCCs) to determine if SCCs showed a logical progression beyond that seen in AKs and to explore variability within and between lesion types to better understand distinctions between the 2. STUDY DESIGN: Biopsies from 31 subjects with AKs were obtained from upper inner arm skin, forearm skin and AK lesions. Biopsies from 23 different subjects in a related subproject provided SCC biopsies for comparison. RESULTS: Karyometric measures of nuclear abnormality and sun damage were derived. Mean actinic damage levels progressed logically from inner arm to sun-exposed skin, to AK, to SCC. Considerable heterogeneity existed at the case level. Unsupervised learning methods revealed 2 distinct clusters of progressed lesions with different nuclear signatures, reflecting differing levels of actinic damage. Number of AKs and SCCs and invasiveness and differentiation of SCCs were distributed across both clusters in roughly equivalent proportions. CONCLUSION: Karyometric methods, shown previously to be capable of sensitively detecting subtle nuclear changes, revealed the possibility of 2 progression pathways, each containing AKs and SCCs. This finding may have prognostic implications.     

A miR‐34a‐SIRT6 axis in the squamous cell differentiation network

Squamous cell carcinomas (SCCs) are highly heterogeneous tumours, resulting from deranged expression of genes involved in squamous cell differentiation. Here we report that microRNA‐34a (miR‐34a) functions as a novel node in the squamous cell differentiation network, with SIRT6 as a critical target. miR‐34a expression increases with keratinocyte differentiation, while it is suppressed in skin and oral SCCs, SCC cell lines, and aberrantly differentiating primary human keratinocytes (HKCs). Expression of this miRNA is restored in SCC cells, in parallel with differentiation, by reversion of genomic DNA methylation or wild‐type p53 expression. In normal HKCs, the pro‐differentiation effects of increased p53 activity or UVB exposure are miR‐34a‐dependent, and increased miR‐34a levels are sufficient to induce differentiation of these cells both in vitro and in vivo. SIRT6, a sirtuin family member not previously connected with miR‐34a function, is a direct target of this miRNA in HKCs, and SIRT6 down‐modulation is sufficient to reproduce the miR‐34a pro‐differentiation effects. The findings are of likely biological significance, as SIRT6 is oppositely expressed to miR‐34a in normal keratinocytes and keratinocyte‐derived tumours.     

Polo-like kinase 1 (Plk1) in non-melanoma skin cancers

Polo-like kinase 1 (Plk1) is becoming an increasingly attractive target for cancer management. Plk1 has been shown to be over-expressed in a variety of cancers; however its role in skin cancers is not well-understood. We recently demonstrated that Plk1 is over-expressed in human melanoma and gene-knockdown as well as chemical-inhibition of Plk1 resulted in a significant decrease in melanoma cell viability and growth without affecting the growth of the normal human epidermal melanocytes (NHEMs). Further, the observed anti-proliferative response of Plk1 was found to be accompanied with a significant G2/M cell cycle arrest, mitotic catastrophe and induction of apoptosis in melanoma cells. In this study, we determined the expression profile of Plk1 in non-melanoma skin cancers viz. basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). Our data demonstrated that like melanoma, Plk1 is significantly over-expressed in BCC and SCC samples. Further, we also found that compared to normal human epidermal keratinocytes (NHEKs), Plk1 was over-expressed at both the protein and mRNA levels in squamous A253 and A431 cells. In addition, a similar protein expression pattern was found for the downstream targets of Plk1, viz. Cdk1, Cyclin B1 and Cdc25C. We believe that the expression pattern of Plk1 in the various skin cancers, the insusceptibility of normal keratinocytes, to Plk1 inhibition and the easy accessibility for topical applications lends the skin as an attractive tissue for Plk1 based cancer chemoprevention and chemotherapeutic applications.     

Indoor tanning and skin cancer in Canada: A meta-analysis and attributable burden estimation

BackgroundConsistent epidemiologic and experimental studies have demonstrated that UV-emitting tanning devices cause melanoma and non-melanoma skin cancer. The purpose of this study was to estimate the relative risk of skin cancer associated with the use of indoor tanning devices relevant to Canada, to estimate the proportion and number of skin cancers in Canada in 2015 that were attributable to indoor tanning, and to explore differences by age and sex.MethodsSkin cancer cases attributable to the use of an indoor tanning devices were estimated using Levin’s population attributable risk (PAR) formula. Relative risks for skin cancer subtypes that were relevant to Canada were estimated through meta-analyses and prevalence of indoor tanning was estimated from the 2006 National Sun Survey. Age- and sex-specific melanoma data for 2015 were obtained from the Canadian Cancer Registry, while estimated NMSC incidence data were obtained from the 2015 Canadian Cancer Statistics report.ResultsEver use of indoor tanning devices was associated with relative risks of 1.38 (95% CI 1.22–1.58) for melanoma, 1.39 (1.10–1.76) for basal cell carcinoma (BCC), and 1.49 (1.23–1.80) for squamous cell carcinoma (SCC). Overall, 7.0% of melanomas, 5.2% of BCCs, and 7.5% of SCCs in 2015 were attributable to ever of indoor tanning devices. PARs were higher for women and decreased with age.ConclusionIndoor tanning contributes to a considerable burden of skin cancer in Canada. Strategies aimed at reducing use should be increased and a total ban or restrictions on use and UV-intensity should be considered by health regulators.     

Significance of eIF4E expression in skin squamous cell carcinoma

Cutaneous squamous cell carcinoma (SCC) is a malignant tumour of keratinising epidermal cells. This type of skin cancer is the second leading cause of death after melanoma, and it is the second most common type of non-melanoma skin cancer after basal cell carcinoma. The cellular and molecular events involved in the progression of skin cancers are largely unknown. Increased protein synthesis is necessary for the transition of cells from quiescence to proliferation. Translational control is critical for the proper regulation of the cell cycle, tissue induction and growth. Eukaryotic initiation factor eIF4E, an important regulator of translation, plays critical roles in neo-plastic transformation and cancer progression. We investigated eIF4E expression in 49 skin samples (six normal tissues, eight Bowen diseases, seven stage I, 10 stage II, 13 stage III and five stage IV SCCs). Results obtained demonstrated that all SCC samples, evaluated by SDS-PAGE, Western blotting and cap-affinity chromatography using m7GTP-sepharose, presented eIF4E expression (13.6+/-1.2), whereas, starting from stage 0 (4.1+/-0.9) to stage I (7.4+/-1.4), stage II (12.1+/-2.4), stage III (18.1+/-3.0) and stage IV (26.2+/-3.8) SCCs, a constant and significant increase of protein over expression (P<0.001) was observed. A high expression of eIF4E is correlated with advanced stages. The results presented in this study demonstrate a possible role of eIF4E in SCC.     

Immunohistochemical localization of heparin-binding epidermal growth factor-like growth factor in normal skin and skin cancers

Summary Heparin-binding epidermal growth factor (EGF)-like growth factor is a 22-kDa glycoprotein that was originally identified as a secreted product of cultured human macrophages. Although the growth factor mRNA has been identified in various cells and tissues, the tissue distribution of the protein itself has rarely been demonstrated. In this study, the EGF-like growth factor was detected immunohistochemically in a variety of human skin samples by indirect immunofluorescence using a polyclonal rabbit antiserum raised against residues 26–41 of mature heparin-binding EGF. The keratinocytes of a variety of epithelium-derived structures demonstrated reproducible, specific staining for the EGF. In normal tissues, this staining was prominent in the basal cells of the epidermis and in the epithelial cells lining epidermal appendages such as hair follicles, sebaceous sweat glands and eccrine sweat glands. In addition, specific staining was detected in skin cancers derived from the basal epithelial cell layer, including basal and squamous cell carcinomas of the skin, with no staining detected in melanoma specimens. Immunoreactive heparin-binding EGF was characteristically associated with the surface of cells. With minor exceptions, the immunoreactive sites are identical to the known EGF receptor distribution in the skin, and suggest that keratinocyte-derived heparin-binding EGF may act in concert with other EGF family members in processes such as skin morphogenesis and wound repair, as well as in the development of skin cancers This revised version was published online in November 2006 with corrections to the Cover Date.