Inhibition of the Proprotein Convertases Represses the Invasiveness of Human Primary Melanoma Cells with Altered p53, CDKN2A and N-Ras Genes

Altered tumor suppressor p53 and/or CDKN2A as well as Ras genes are frequently found in primary and metastatic melanomas. These alterations were found to be responsible for acquisition of invasive and metastatic potential through their defective regulatory control of metalloproteinases and urokinase genes.Using primary human melanoma M10 cells with altered p53, CDKN2A and N-Ras genes, we found that inhibition of the proprotein convertases (PCs), enzymes involved in the proteolytic activation of various cancer-related protein precursors resulted in significantly reduced invasiveness. Analysis of M10 cells and their gastric and lymph node derived metastatic cells revealed the presence of all the PCs found in the secretory pathway. Expression of the general PCs inhibitor alpha1-PDX in these cells in a stable manner (M10/PDX) had no effect on the mRNA expression levels of these PCs. Whereas, in vitro digestion assays and cell transfection experiments, revealed that M10/PDX cells display reduced PCs activity and are unable to process the PCs substrates proIGF-1R and proPDGF-A. These cells showed reduced migration and invasion that paralleled decreased gelatinase MMP-2 activity and increased expression and secretion of tissue inhibitor of metalloproteinase-1 (TIMP-1) and TIMP-2. Furthermore, these cells showed decreased levels of urokinase-type plasminogen activator receptor (uPAR) and increased levels of plasminogen activator inhibitor-1 (PAI-1).Taken together, these data suggest that inhibition of PCs activity results in decreased invasiveness of primary human melanoma cells despite their altered p53, CDKN2A and N-Ras genes, suggesting that PCs may serve as novel therapeutic targets in melanoma

A Reliable Method for the Selection of Exploitable Melanoma Archival Paraffin Embedded Tissues for Transcript Biomarker Profiling

The source tissue for biomarkers mRNA expression profiling of tumors has traditionally been fresh-frozen tissue. The adaptation of formalin-fixed, paraffin-embedded (FFPE) tissues for routine mRNA profiling would however be invaluable in view of their abundance and the clinical information related to them. However, their use in the clinic remains a challenge due to the poor quality of RNA extracted from such tissues. Here, we developed a method for the selection of melanoma archival paraffin-embedded tissues that can be reliably used for transcript biomarker profiling. For that, we used qRT-PCR to conduct a comparative study in matched pairs of frozen and FFPE melanoma tissues of the expression of 25 genes involved in angiogenesis/tumor invasion and 15 housekeeping genes. A classification method was developed that can select the samples with a good frozen/FFPE correlation and identify those that should be discarded on the basis of paraffin data for four reference genes only. We propose therefore a simple and inexpensive assay which improves reliability of mRNA profiling in FFPE samples by allowing the identification and analysis of “good” samples only. This assay which can be extended to other genes would however need validation at the clinical level and on independent tumor series

Structured Expert Consensus on Actinic Keratosis:Treatment Algorithm Focusing on Daylight PDT

BACKGROUND: A practical and up-to-date consensus among experts is paramount to further improve patient care in actinic keratosis (AK). OBJECTIVES: To develop a structured consensus statement on the diagnosis, classification, and practical management of AK based on up-to-date information. METHODS: A systematic review of AK clinical guidelines was conducted. This informed the preparation of a 3-round Delphi procedure followed by a consensus meeting, which combined the opinions of 16 clinical experts from 13 countries, to construct a structured consensus statement and a treatment algorithm positioning daylight photodynamic therapy (dl-PDT) among other AK treatment options. RESULTS: The systematic review found deficiencies in current guidelines with respect to new AK treatments such as ingenol mebutate and dl-PDT. The Delphi panel established consensus statements across definition, diagnosis, classification, and management of AK. While the diagnosis of AK essentially rests on the nature of lesions, treatment decisions are based on several clinical and nonclinical patient factors and diverse environmental attributes. Participants agreed on ranked treatment preferences for the management of AK and on classifying AK in 3 clinical situations: isolated AK lesions requiring lesion-directed treatment, multiple lesions within a small field, and multiple lesions within a large field, both requiring specific treatment approaches. Different AK treatment options were discussed for each clinical situation. CONCLUSIONS: The results provide practical recommendations for the treatment of AK, which are readily transferable to clinical practice, and incorporate the physician's clinical judgement. The structured consensus statement positioned dl-PDT as a valuable option for patients with multiple AKs in small or large fields

Correction to: Long-term safety and efficacy of vismodegib in patients with advanced basal cell carcinoma: final update of the pivotal ERIVANCE BCC study

Following publication of the original article [1], it was reported that the legend for Fig. 1 was incomplete. The complete figure legend is:https://deepblue.lib.umich.edu/bitstream/2027.42/148648/1/12885_2019_Article_5568.pd

Recent Advanced in the Treatment of Advanced SCC Tumors

Squamous cell carcinoma (SCC) is the second most frequent form of skin cancer after basal cell carcinoma. While most SCC can be treated by surgery or radiotherapy, some progress into an advanced form and are no longer suitable for these treatments. Guidelines and staging systems have help to define these advanced SCC (aSCC), for which prognosis was very poor until recently. Platin-based chemotherapy was traditionally used, but few prospective trials and no treatment regimen was recommended. Furthermore, toxicity in elderly patients limited its use. The development of immunotherapy has improved the prognosis of these difficult-to-treat aSCC. In this review, we define high risk and aSCC and explored current treatment strategies for these tumors

Facteurs de risques et gènes impliqués dans la carcinogenèse cutanée épithéliale

PARIS7-Bibliothèque centrale (751132105) / SudocSudocFranceF

Recherche des facteurs pronostiques du mélanome nodulaire épais (étude sur 37 patients)

LYON1-BU Santé (693882101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Réponse des cellules cutanées aux UV (rôle du gène p16INK4A et des systèmes de réparation de l'ADN)

PARIS7-Bibliothèque centrale (751132105) / SudocSudocFranceF

Voie Patched/Sonic Hedgehog et carcinomes basocellulaires

La découverte récente de la voie Patched/Sonic Hedgehog et de son rôle dans la prédisposition génétique et dans l’oncogenèse du carcinome basocellulaire ont permis des avancées majeures dans la compréhension de la genèse de cette tumeur. Pour la première fois, des modèles murins de carcinome basocellulaire ont été développés, qui devraient permettre, d’une part, de mieux comprendre les autres mécanismes moléculaires impliqués et, d’autre part, de tester de nouvelles stratégies thérapeutiques préventives ou curatives, pour tenter de maîtriser les formes multiples de carcinome basocellulaire, souvent invalidantes.The recent discovery of the role of the Patched Sonic Hedgehog pathway in the physiopathogeny of BCC (basocellular carcinoma) and Gorlin’s syndrome has greatly improved our knowledge on the mechanism of development of these tumors. For the first time, murine models have been developed allowing to further understand other molecular events implicated in such tumors as well as providing in vivo models to search for new curative or preventive therapeutical strategies which would be helpful to control CBC multiple forms, that are often disabling

Recent Advanced in the Treatment of Advanced SCC Tumors

Squamous cell carcinoma (SCC) is the second most frequent form of skin cancer after basal cell carcinoma. While most SCC can be treated by surgery or radiotherapy, some progress into an advanced form and are no longer suitable for these treatments. Guidelines and staging systems have help to define these advanced SCC (aSCC), for which prognosis was very poor until recently. Platin-based chemotherapy was traditionally used, but few prospective trials and no treatment regimen was recommended. Furthermore, toxicity in elderly patients limited its use. The development of immunotherapy has improved the prognosis of these difficult-to-treat aSCC. In this review, we define high risk and aSCC and explored current treatment strategies for these tumors