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Merkel Cell Carcinoma (MCC) is an aggressive neuroendocrine skin cancer that is highly immunogenic. Approximately 80% of MCC tumors are virus positive (VP-MCC) and express Merkel cell polyomavirus (MCPyV) T antigens that drive oncogenesis. As VP-MCC have a low mutation burden with few predicted neoantigens, viral oncogenes are thought to be the primary target for anti-cancer immunity. Immune checkpoint inhibitors improve MCC survival, yet <50% of patients have durable benefit. Patients who fail checkpoint inhibition or who have immune dysfunction may benefit from adoptive cellular therapy using virus reactive T cells from HLA-matched donors.
Gap junctional intercellular communication is crucial for epidermal cellular homeostasis. Inability to establish melanocyte-keratinocytes contacts and loss of intercellular junction’s integrity may contribute to melanoma development. Connexins, laminins and desmocollins have been implicated in the control of melanoma growth where their reduced expression has been reported in metastatic lesions. We have investigated Connexin 31.1 (GJB5) expression and looked for any association with BRAF mutational status, patient prognosis and MAPK inhibitors (MAPKi) treatment.
The most lethal complication of recessive dystrophic epidermolysis bullosa (RDEB) is the development of aggressive cutaneous squamous cell carcinoma (cSCCs), which lead the high mortality rates in these patients. Elevated levels of phospho-STAT3 have been found in two RDEB-derived cSCC cell lines, demonstrating that constitutive activation and dysregulation of the JAK/STAT pathway may play a role in RDEB-cSCC pathogenesis. Ruxolitininb is an FDA approved JAK1/2 inhibitor that has efficacy in myelofibroblast, human head, and neck squamous cell carcinomas, as well as lung and breast carcinomas.
The majority of the heredity of melanoma remains unexplained, however inherited copy number changes have not yet been systematically studied. The genetic environment is highly relevant to treatment stratification, and new gene discovery is therefore desirable. Using an unbiased whole genome screening approach for copy number we identify here a novel melanoma predisposing factor, familial duplications of gene PPP2R3B, encoding a regulatory unit of critical phosphatase PP2A. Significant correlation between expression of PPP2R3B in tumour tissue and survival in a large melanoma cohort was confirmed, and associated with a non-immunological expression profile.
Cutaneous Squamous Cell Carcinoma (cSCC) is a malignant neoplasm of the skin resulting from the accumulation of somatic mutations due to solar radiation. It is one of the fastest increasing malignancies that represents a particular problem among immunosuppressed individuals. MicroRNAs (miRNAs) are short non-coding RNAs that regulate the expression of protein-coding genes at the posttranscriptional level. Global analysis of miRNA expression in human cSCC identified miR-130a as one of the miRNAs that downregulated in cSCC and in this study we investigated its function in the disease in in vitro and in vivo disease models.
Basosquamous carcinoma (BSC) is an aggressive skin neoplasm with features of both basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). While genetic and molecular drivers of BCC and SCC development have been extensively characterized, BSC pathogenesis remains unclear, in particular regarding the reprogramming of tumor keratinocytes towards basaloid or squamatized phenotypes. Here, by analogy to pathway switching previously observed in BCC escaping Hedgehog (Hh) inhibition, we demonstrate loss of Hh signaling and MAPK pathway activation associated with squamatization of BSC.
Angiosarcoma is a rare malignant tumor derived from endothelial cells and its prognosis is poor because advanced angiosarcoma is resistant to standard chemotherapy, and new therapies are urgently needed. Endoglin (CD105) is a membrane glycoprotein that acts as a coreceptor for transforming growth factor-β (TGF-β) signaling. Endoglin is overexpressed in the tumor-associated endothelial cells, and it enhances angiogenesis. Numerous clinical trials are testing the effectiveness of anti-endoglin antibody in various types of malignancies.
Non-melanoma skin cancers (NMSC) arise from keratinocytes, the main epidermal cell type, and are considered one of the most frequent malignancies worldwide. Among them, cutaneous squamous cell carcinoma (cSCC) represents the clinically most important tumor type due to its substantial risk of metastasis. Chronic exposure to ultraviolet radiation (UVR) is the main cause of cSCC, which typically arises in highly exposed regions like the head or the neck from precursor and in situ lesions, such as actinic keratosis (AK) or Bowen’s disease, respectively.
Human skin contains multiple memory T cell subtypes which are crucial in protective cutaneous immunity and in mediating inflammatory dermatoses, but their roles in cutaneous squamous cell carcinoma (cSCC) are unclear. In this study, phenotypic and functional characterisation of memory T cells in human cSCCs and patient-matched normal skin and peripheral blood was performed. Flow cytometry of lymphocytes from cSCCs (n=53) showed 77.2% of tumoral T cells were CCR7-CD45RA- effector memory T cells, with fewer CCR7+CD45RA- central memory, CCR7-CD45RA+ effector memory RA, CCR7+CD45RA+ naive and CCR7+L-selectin- migratory memory T cells.
We have established an immune cell therapy with immortalized induced pluripotent stem-cell-derived myeloid lines (iPS-ML). The benefits of using iPS-ML is the infinite proliferative capacity and ease of genetical modification. 4-1BB is an inducible receptor of the TNF superfamily expressed on activated T cells. The interaction between the receptor 4-1BB and its ligand 4-1BBL provides co-stimulatory signals for T-cell activation. In this study, we introduced 4-1BBL gene to iPS-ML (iPS-ML-41BBL). The analysis of the cell-surface molecules showed that the expressions of CD80 and CD86 were upregulated in iPS-ML-41BBL compared to control iPS-ML.
Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer and actinic keratosis (AK) is one of the superficial variant of cSCC. Since there are not enough treatments established for advanced cSCC, it is necessary to control the development. Most AK cases are restricted to the epidermis for a long time through the suppression of epithelial-to-mesenchymal transition (EMT). OVO-like (OVOL) 1 and OVOL2 are known as important factors against EMT, but their function is not wholly understood in skin tumors.
Advanced-stage cutaneous T-cell lymphomas (CTCL) are associated with a global decrease in normal T cell numbers and diversity, leading to a profound immunodeficiency and recurrent severe infections. The mechanisms of this normal T-cell depletion remain unclear, although several mechanisms may be suggested. Here we observed that CTCL cell lines and tumor cells from patients with Sezary syndrome expressed Fas ligand mRNA. Fas ligand was not expressed at the cell surface of CTCL cells but was present in the cytoplasm and localized in secretory microvesicles.
Antibodies against PD1, such as nivolumab and pembrolizumab, are widely used for treating various cancers, including advanced melanoma. PD1 antibody-based immunotherapy, co-administration of nivolumab and ipilimumab, is one of the optimal immunotherapies, especially in advanced melanoma with a high tumor mutation burden. Since this combined therapy leads to a high frequency of serious immune-related adverse events (irAEs) in patients with advanced melanoma, biomarkers are needed to evaluate the nivolumab efficacy to avoid serious irAEs caused by ipilimumab.
Hypoxia inducible factor (HIF) 1 is a heterodimeric transcription factor consisting of α and β subunits. The β subunit is constitutively expressed, while the expression of the α subunit is regulated by the relative concentration of oxygen. When stabilized, HIF-1α play a pivotal role in many biological processes by affecting the expression of hundreds of genes involved in angiogenesis, cell growth and apoptosis, cell adhesion and migration, the energy metabolism and DNA repair. Others and we showed that HIF-1α is constitutively expressed in mouse and human epidermis and that HIF-1α plays an important role in the skin, especially in local and systemic adaptation to environmental stresses including ultraviolet (UV) radiation.
Non-melanoma skin cancers (NMSC), including cutaneous basal and squamous cell carcinomas (cBCC and cSCC), are the most frequent malignancies worldwide, with substantial associated morbidity and cost. A better understanding of the molecular changes (such as genomic and energy metabolic alterations) involved in skin cancer progression from precancerous lesions to localized tumors and then to metastasis will aid in early detection, development of biomarkers and future targeted treatment strategies.
We aimed to:1) Analyse telomerase reverse transcriptase (TERT) mutations in cutaneous basal cell carcinoma (CBC) tumours and describe its relationship with intra-tumour enzyme activity and telomere length (TL). 2) Compare TERT activity between tumour and clinically healthy peritumoral skin. 3) Compare TL between CBC and peripheral blood. A cohort of 45 patients with 50 CBC were included. All tumours were located in the neck, face or scalp. Usual clinicopathological variables were recorded for each patient and tumour.
To investigate the molecular mechanisms contributing to senescence-escape in nevus-associated melanoma (NAM). To characterize the associated inflammatory profile of senescence-escaped cells in early melanoma development. Immunohistochemistry for select targets was performed in NAM and de-novo melanoma (DNM) patient samples. Images were evaluated by computer-aided cell-by-cell analysis. A p16-dependent cell line model of naïve, senescent and senescence-escaped cells was established to measure cell-intrinsic mRNA levels of different cell-states.
DNA methylation is an important component of epigenetic modification. Global genome hypomethylation in cancer cells can lead to chromosomal instability and activate endogenous elements including long interspersed nuclear elements-1(LINE-1). LINE-1 is recognized as a useful surrogate marker of whole genome methylation levels, encoding two proteins: open reading frame (ORF)1 and ORF2. Various types of internal organ cancers have been reported to show immunoreactivity to LINE-1 ORF1 protein. However, the expression of LINE-1 protein in skin tumors has not yet been investigated.
Dermoscopy is a convenient tool to diagnose melanocytic lesions, especially nevus and melanoma. Various pigmented structures, including pigment network, dots and globules, and streaks, are observed in dermoscopy. Usually, 2D vertical images are used to explain the correlation of dermoscopy and histopathology. However, since the image of dermoscopy is horizontal, it is difficult for beginners to understand the horizontal view of dermoscopy by the vertical view of histopathology. Our objectives were to provide the better understanding for dermoscopy-pathology correlation in the pigmented skin tumors.