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The aging-associated increase of cancer risk is linked with stromal fibroblast senescence and concomitant cancer- associated fibroblast (CAF) activation. Surprisingly little is known about the role of androgen receptor (AR) signaling in this context.We have found downmodulated AR expression in dermal fibroblasts underlying premalignant skin cancer lesions (actinic keratoses and dysplastic nevi) as well as in CAFs from the 3 major skin cancer types, squamous cell carcinomas (SCCs), basal cell carcinomas, and melanomas. Functionally, decreased AR expression in primary human dermal fibroblasts (HDFs) from multiple individuals induced early steps of CAF activation, and in an orthotopic skin cancer model, AR loss in HDFs enhanced tumorigenicity of SCC and melanoma cells. Forming a complex, AR converged with CSL/RBP-J[kappa] in transcriptional repression of key CAF effector genes. AR and CSL were positive determinants of each other's expression, with BET inhibitors, which counteract the effects of decreased CSL, restoring AR expression and activity in CAFs. Increased AR expression in these cells overcame the consequences of CSL loss and was by itself sufficient to block the growth and tumor-enhancing effects of CAFs on neighboring cancer cells. As such, the findings establish AR as a target for stroma-focused cancer chemoprevention and treatment., IntroductionThe aging-associated increase of many cancer types has been linked with stromal fibroblast senescence and concomitant production of diffusible growth factors, cytokines, and extracellular matrix/ remodeling proteins (1) that are [...]

Seborrheic keratoses (SKs) are common, benign epithelial tumors of the skin that do not, or very rarely, progress into malignancy, for reasons that are not understood. We investigated this by gene expression profiling of human SKs and cutaneous squamous cell carcinomas (SCCs) and found that several genes previously connected with keratinocyte tumor development were similarly modulated in SKs and SCCs, whereas the expression of others differed by only a few fold. In contrast, the tyrosine kinase receptor FGF receptor-3 (FGFR3) and the transcription factor forkhead box Nl (FOXN1) were highly expressed in SKs, and close to undetectable in SCCs. We also showed that increased FGFR3 activity was sufficient to induce FOXN1 expression, counteract the inhibitory effect of EGFR signaling on FOXN1 expression and differentiation, and induce differentiation in a FOXNl-dependent manner. Knockdown of FOXN1 expression in primary human keratinocytes cooperated with oncogenic RAS in the induction of SCC-like tumors, whereas increased FOXN1 expression triggered the SCC cells to shift to a benign SK-like tumor phenotype, which included increased FGFR3 expression. Thus, we have uncovered a positive regulatory loop between FGFR3 and FOXN1 that underlies a benign versus malignant skin tumor phenotype., Introduction In both clinical and experimental situations, the majority of benign tumors fail to progress into malignancy for reasons that are poorly understood. The skin provides an intensely studied model [...]

A study to show that Notch1 gene expression and activity are substantially down-modulated in keratinocyte cancer cell lines and tumors with its expression controlled by p53 was conducted. Results suggest that Notch1 gene is a p53 target in human keratinocytes with a role in tumor suppression of this cell type through negative regulation of the ROCK1/2 and MRCK[alpha] kinases.

Basal cell carcinoma (BCC) is the most common human malignancy, and its incidence increases yearly. In this contribution we investigate the feasibility of combining multimodal reflectance and fluorescence polarization imaging (RFPI) with spectroscopic analysis of the reflectance images for facilitating intraoperative delineation of BCCs. Twenty fresh thick BCC specimens were obtained within 1 h after Mohs micrographic surgeries. The samples were soaked for up to 2 min in an aqueous 0.2 mg/ml solution of methylene blue, briefly rinsed in saline solution, and imaged. Reflectance images were acquired in the range from 395 to 735 nm, with steps of 10 nm. Fluorescence polarization images were excited at 630 nm and registered in the range between 660 and 750 nm. The results yielded by RFPI were qualitatively compared to each other and to histopathology. From the copolarized reflectance images the spectral responses including the optical densities and their wavelength derivatives were calculated. The differences in the spectral responses of the benign and malignant stained skin structures were assessed. Statistical analysis, i.e., Student’s t-test, was employed to verify the significance of the discovered differences. Both reflectance and fluorescence polarization images correlated well with histopathology in all the cases. Reflectance polarization images provided more detailed information on skin morphology, with the appearance of skin structures resembling that of histopathology. Fluorescence polarization images exhibited higher contrast of cancerous tissue as compared to reflectance imaging. The analysis of the optical densities and their wavelength derivatives for tumor and normal tissues has confirmed statistical significance of the differences that can be used for intraoperative cancer delineation. The results of the study indicate that spectral analysis is a useful adjunct to RFPI for facilitating skin cancer delineation. [ABSTRACT FROM AUTHOR]