Tumor-associated macrophages (TAMs) and cyclooxygenase-2 (COX-2) are associated with invasion, angiogenesis, and poor prognosis in many human cancers. However, the role of TAMs in human basal cell carcinoma (BCC) remains elusive. We found that the number of TAMs infiltrating the tumor is correlated with the depth of invasion, microvessel density, and COX-2 expression in human BCC cells. TAMs also aggregate near COX-2 expressing BCC tumor nests. We hypothesize that TAMs might activate COX-2 in BCC cells and subsequently increase their invasion and angiogenesis. TAMs are a kind of M2 macrophage derived from macrophages exposed to Th2 cytokines. M2-polarized macrophages derived from peripheral blood monocytes were cocultured with BCC cells without direct contact. Coculture with the M2 macrophages induced COX-2-dependent invasion and angiogenesis of BCC cells. Human THP-1 cell line cells, after treated with phorbol myristate acetate (PMA), differentiated to macrophages with M2 functional profiles. Coculture with PMA-treated THP-1 macrophages induced COX-2-dependent release of matrix metalloproteinase-9 and subsequent increased invasion of BCC cells. Macrophages also induced COX-2-dependent secretion of basic fibroblast growth factor and vascular endothelial growth factor-A, and increased angiogenesis in BCC cells.

We performed multiphoton fluorescence (MF) and second-harmonic generation (SHG) imaging on human basal cell carcinoma samples. In the dermis, basal cell carcinomas can be identified by masses of autofluorescent cells with relatively large nuclei and marked peripheral palisading. In the normal dermis, SHG from dermal collagen contributes largely to the multiphoton signal. However, within the cancer stroma, SHG signals diminish and are replaced by autofluorescent signals, indicating that normal collagen structures responsible for SHG have been altered. To better delineate the cancer cells and cancer stroma from the normal dermis, a quantitative MF to SHG index is developed. We demonstrate that this index can be used to differentiate cancer cells and adjacent cancer stroma from the normal dermis. Our work shows that MF and SHG imaging can be an alternative for Mohs' surgery in the real-time guidance of the secure removal of basal cell carcinoma.

Background: Geriatric health care has become a worldwide concern, but relatively few statistical studies are available about geriatric skin diseases. Moreover, no information exists regarding skin disorders among the elderly population in Taiwan that has become a geriatric country. Objective: To determine the characteristic pattern and the prevalence of various skin disorders for the elderly who visited the National Taiwan University in the last 7 years. Methods: Using a database from the Dermatology Outpatient Clinic of the National Taiwan University Hospital, 1993–1999 file, we conducted a retrospective cross-sectional study by evaluating the age, proportion, and gender of each specific cutaneous disease category, χ² tests were used for analyzing statistical significance. The analysis supplied odds ratios and 95% confidence intervals. Results: A total of 16,924 patients aged 65 years and older, which constituted 11% of the total patients seen at the Clinic of Dermatology from 1993 through 1999, were studied. The male to female ratio was 1.3 to 1. The most common cutaneous disorder in the elderly was dermatitis (58.7%), followed by fungal infections (38.0%), pruritus (14.2%), benign tumors (12.8%), and viral infections (12.3%). Cutaneous malignant tumors were found in 2.1%. Basal cell carcinoma occurred in 29.8%, actinic keratosis in 22.4%, Bowen’s disease in 13.3% and squamous cell carcinoma 13.3%. Interestingly, our cases of extramammary Paget’s disease showed a male predominance. Most melanomas were acral lentiginous melanoma located on the soles. The prevalence of common diseases in elderly patients compared with those outpatients of less than 65 years showed a 3-fold increased risk for pruritus. Moreover, the pattern of geriatric skin diseases in Taiwan was significantly different from Western countries. Conclusion: The prevalence of skin diseases in elderly patients emphasizes the importance of health education in geriatric people in Taiwan concerning appropriate use of emollients, proper foot care, sun protection and early detection of skin cancers.

Chronological skin aging is associated with flattening of the dermal-epidermal junction (DEJ), but to date no quantitative analysis focusing on the aging changes in the dermal papillae (DP) has been performed. The aim of the study is to determine the architectural changes and the collagen density related to chronological aging in the dermal papilla zone (DPZ) by in vivo harmonic generation microscopy (HGM) with a sub-femtoliter spatial resolution. We recruited 48 Asian subjects and obtained in vivo images on the sun-protected volar forearm. Six parameters were defined to quantify 3D morphological changes of the DPZ, which we analyzed both manually and computationally to study their correlation with age. The depth of DPZ, the average height of isolated DP, and the 3D interdigitation index decreased with age, while DP number density, DP volume, and the collagen density in DP remained constant over time. In vivo high-resolution HGM technology has uncovered chronological aging-related variations in DP, and sheds light on real-time quantitative skin fragility assessment and disease diagnostics based on collagen density and morphology.

IGF II mRNA-binding protein 3 (IMP-3) has been reported to be a marker of melanoma progression. However, the mechanisms by which it impacts melanoma are incompletely understood. In this study, we investigate the clinical significance of IMP-3 in melanoma progression and also its underlying mechanisms. We found that IMP-3 expression was much higher in advanced-stage/metastatic melanomas and that it was associated with a poor prognosis (P=0.001). Univariate analysis showed that IMP-3 expression was associated with stage III/IV melanomas (odds ratio=5.40, P=0.031) and the acral lentiginous subtype (odds ratio=3.93, P=0.0034). MeWo cells with overexpression of IMP-3 showed enhanced proliferation and migration and significantly increased tumorigenesis and metastatic ability in nude mice. We further demonstrated that IMP-3 could bind and enhance the stability of the mRNA of high mobility group AT-hook 2 (HMGA2). It was also confirmed that IMP-3 had an important role in melanoma invasion and metastasis through regulating HMGA2 mRNA expression. IMP-3 expression was positively correlated with HMGA2 expression in melanoma cells and also in melanoma tissues. Our results show that IMP-3 expression is a strong prognostic factor for melanoma, especially acral lentiginous melanoma.

We have previously demonstrated a xenograft of interleukin-6 (IL-6) overexpressing basal cell carcinoma (BCC) cell line induced tumors with high vasculature in nude mice. Here we asked whether IL-6 could induce angiogenic activity in BCC cell line. Tenfold concentrated conditioned medium (CM) from IL-6 overexpressing BCC cells exhibited higher angiogenic activities in chorioallantoic membrane and Matrigel plug assays, when compared with CM from vector control or parental BCC cells. The level of basic fibroblast growth factor 2 (bFGF) mRNA and secreted bFGF increased in IL-6 overexpressing BCC cells as shown by RT-PCR and ELISA, respectively. Concordantly, recombinant IL-6 treatment caused the elevation of bFGF mRNA and protein levels in parental BCC cells in a time-dependent manner. Neutralizing bFGF function by anti-bFGF antibody significantly inhibited CM-induced human umbilical vein endothelial cells (HUVEC) tube formation and Matrigel plug formation. Meanwhile, cyclooxygenase 2 (COX-2)-specific siRNA markedly abolish HUVEC tube formation. These data indicated both bFGF and COX-2 play an essential role for IL-6-induced angiogenesis in BCC cell line. Treatment with AG490 (Janus tyrosine kinase [JAK] inhibitor) and LY294002 (PI3-Kinase inhibitor) inhibited IL-6-mediated upregulation of bFGF mRNA and protein secretion. Consistently, transfection with dominant negative mutants of signal transducer and activator of transcription 3 (STAT3) and acutely transforming retrovirus AKT8 in rodent T cell lymphoma (Akt) effectively abolished IL-6-mediated expression of bFGF mRNA and protein. Our data suggest that under in vitro experimental condition, bFGF and COX-2 are downstream effectors of IL-6-induced angiogenic activity in BCC cell. The IL-6-mediated bFGF upregulation is through activation of JAK/STAT3 and PI3-Kinase/Akt pathways.

Nevus sebaceus is frequently associated with the development of secondary neoplasms. Incidences of malignant transformation vary among different reports and few data is available regarding Asian populations. We aimed to determine the characteristics of secondary tumors developing from nevus sebaceus in a Taiwanese population and to review the published work. Patients with clinically and histologically confirmed nevus sebaceus were identified from 1992 to 2012 in a medical center. Among the 450 cases of nevus sebaceus, 38 secondary neoplasms were noted, accounting for 8.5% of all cases. Benign tumors represented more than 80% of all tumors. Syringocystadenoma papilliferum (2.7%) was the most common benign tumor, followed by trichoblastoma (1.6%) and trichilemmoma (1.6%) whereas basal cell carcinoma (0.9%) was the most frequent malignant tumor on nevus sebaceus and its clinical features were not typical. All the malignant tumors on nevus sebaceus were noted only in adulthood and the mean age of those with basal cell carcinoma was significantly older than that of trichoblastoma (P = 0.028). Our study concludes that malignant transformation is rare in nevus sebaceus and occurs uniquely in adulthood. On the basis of the findings, prophylactic excision of nevus sebaceus can be elective during childhood but is strongly advocated at puberty due to the increased risk of malignant transformation with time.

Skin aging is an important issue in geriatric and cosmetic dermatology. To quantitatively analyze changes in keratinocytes related to intrinsic aging, we exploited a 1230 nm-based in vivo harmonic generation microscopy, combining second- and third-harmonic generation modalities. 52 individuals (21 men and 31 women, age range 19–79) were examined on the sun-protected volar forearm. Through quantitative analysis by the standard algorithm provided, we found that the cellular and nuclear size of basal keratinocytes, but not that of granular cells, was significantly increased with advancing age. The cellular and nuclear areas, which have an increase of 0.51 μm2 and 0.15 μm2 per year, respectively, can serve as scoring indices for intrinsic skin aging.