Expression, regulation and function of FGF18 in melanoma

FGF18 ist einer von 22 Fibroblasten Wachstumsfaktor. Deregulierung der zugehörigen Rezeptor Tyrosinkinasen (FGFR1-4) ist in diversen Krebsarten in der Tumorigenese involviert. Melanome sind bösartige Tumore. Jüngste Untersuchungen zeigten erhöhte Expressionsmengen an FGF18 in Melanom Zelllinien. Eines der Ziele dieser Diplomarbeit war es die Expressionsanalyse auf weitere Zelllinien auszudehnen. Weiters wurde die Expression von FGF18 als Protein in Gewebeproben von Nävi und malignen Läsionen in einem „tissue microarray“ verglichen. Zwei Melanom Zelllinien wurden herangezogen, um mittels „knock-down“ und Überexpression genauere Funktion von FGF18, bezüglich Viabilität, Migration und Invasion zu analysieren. Weiters wurde der Zusammenhang zwischen FGF18 Expression und der Wnt-Signaltransduktionsaktivität in Melanom Zelllinien überprüft. Um festzustellen inwiefern FGF18 die Neoangiogenese in Melanomen beeinflusst, wurde einerseits festgestellt, ob in Melanom Zelllinien FGF18 die VEGF Expression induziert und andererseits wurden Lymph- und Blutendothelzellen auf ihre Expression von FGF18 und FGF-Rezeptoren getestet, um ihre potenzielle Signalverarbeitung von FGF18 zu überprüfen. Die Expressionsanalyse zeigte hohe Werte von FGF18 in einem Großteil der Melanom Zelllinien. Ebenso wurde im „tissue microarray“ signifikante Erhöhung von FGF18 in malignen Läsionen gefunden. Die Analyse etwaiger autokriner Effekte von FGF18 hat gezeigt, dass diese vermutlich von der Menge an endogen exprimiertem FGF18 in der jeweiligen Zelllinie abhängen. Eine direkte Korrelation zwischen Wnt-Signalaktivität und FGF18 Expression in Melanom Zelllinien wurde nicht entdeckt. Ebenso scheint die VEGF-A Expression im Melanom nicht von FGF18 induziert zu werden. In Lymph- und Blutendothelzellen wurde eine niedrige Expressionsrate an FGF18 gefunden, andererseits aber adäquate Expression an FGFR4, was die Signalverarbeitung von FGF18 generell möglich macht.FGF18 is one of 22 fibroblast growth factors. Associated receptor tyrosin kinases (FGFR1-4) are involved in tumorgenesis in several cancer types. Melanoma is a malignancy derived from melanocytes. Recent studies unravelled high levels of FGF18 in melanoma cell lines. A panel of melanoma cell models was analysed for FGF18 expression. Furthermore a tissue array was evaluated for expression data on protein level. Two melanoma cell lines were chosen for knock-down and overexpression, in order to analyse effects of FGF18 on growth, viability, migration and invasion. Since FGF18 was found to be controlled by the Wnt-pathway in colorectal cancer, the correlation between β-catenin activation and FGF18 expression was investigated. To unravel the contribution of FGF18 to neoangiogenesis in melanoma, two approaches were performed. VEGF-A expression was analysed in melanoma cell lines and correlation to FGF18 expression was determined. Furthermore, immortalised lymph and blood endothelial cells were analysed for their expression of FGFRs and FGF18. The FGF18 expression data showed high expression in many of the melanoma cells. Tissue array data revealed significant increase of FGF18 in malignant lesions. Analysis of autocrine effects suggest, that this may depend on endogenous FGF18 expression levels in the respective cell line. Unlike in colorectal cancer, FGF18 expression is at least not directly regulated by Wnt-pathway. Neither does FGF18 induce VEGF-A expression. Analysis of lymph and blood endothelial cells unravelled the possibility of paracrine angiogenic effects of FGF18. Expression data showed low levels of FGF18, but sufficient levels of FGFR4 to enable signal reception

Tobacco products in the European Union Common Entry Gate (EU-CEG): A tool for monitoring the EU tobacco products directive.

INTRODUCTION: Under the European Union (EU) Tobacco Products Directive (2014/40/EU) (TPD), manufacturers and importers of tobacco products are required to report information to the European Commission (EC) and Member States (MS) on products intended to be placed on the market. We describe the distribution of notifications to the EU Common Entry Gate (EU-CEG) and identify key fields for improvement on reporting cigarettes or roll-your-own (RYO) tobacco. METHODS: A cross-sectional analysis of secondary data reported in the EU-CEG was conducted for tobacco products notified within EU-CEG between June 2016 and October 2019 for 12 EU MS. Analysis of compliance to specific regulations for priority additives that refer to cigarettes and RYO was conducted for 10 EU countries. RESULTS: Overall, 39170 tobacco products were notified. This included 16762 (42.8%) notifications of cigars, followed by cigarettes 11242 (28.7 %), waterpipes 3291 (8.4%), cigarillos (n=1783), pipe (n=1715), RYO (n=1635), chewing tobacco (n=1021), novel tobacco products (n=839), herbal products for smoking (n=535), other (n=258), nasal (n=74) and oral tobacco (n=15). In cigarettes and RYO tobacco products, the proportion of ingredients notified in all countries that contained an unknown Chemical Abstract Services (CAS) number was 3.8% and 2.1%, respectively. The proportion of underreporting flagging of priority additives ranged from 15.9% in Malta to 41.3% in Lithuania, the mean proportion of underreporting of the variable ‘priority additive’ for the 10 countries together was 24.7%. CONCLUSIONS: In the EU-CEG data base, for the period of analysis, a significant number of product notifications took place while large variations in the number of types of tobacco products notified across EU countries was noted. The timely monitoring of these data is needed so that products non-compliant within the EU-CEG system are assessed