TY  - JOUR
A1  - Hafner, Christian
A1  - Houben, Roland
A1  - Baeurle, Anne
A1  - Ritter, Cathrin
A1  - Schrama, David
A1  - Landthaler, Michael
A1  - Becker, Jürgen C.
T1  - Activation of the PI3K/AKT Pathway in Merkel Cell Carcinoma
JF  - PLoS One
N2  - Merkel cell carcinoma (MCC) is a highly aggressive skin cancer with an increasing incidence. The understanding of the molecular carcinogenesis of MCC is limited. Here, we scrutinized the PI3K/AKT pathway, one of the major pathways activated in human cancer, in MCC. Immunohistochemical analysis of 41 tumor tissues and 9 MCC cell lines revealed high levels of AKT phosphorylation at threonine 308 in 88% of samples. Notably, the AKT phosphorylation was not correlated with the presence or absence of the Merkel cell polyoma virus (MCV). Accordingly, knock-down of the large and small T antigen by shRNA in MCV positive MCC cells did not affect phosphorylation of AKT. We also analyzed 46 MCC samples for activating PIK3CA and AKT1 mutations. Oncogenic PIK3CA mutations were found in 2/46 (4%) MCCs whereas mutations in exon 4 of AKT1 were absent. MCC cell lines demonstrated a high sensitivity towards the PI3K inhibitor LY-294002. This finding together with our observation that the PI3K/AKT pathway is activated in the majority of human MCCs identifies PI3K/AKT as a potential new therapeutic target for MCC patients.
KW  - rare
KW  - T-antigen
KW  - PIK3CA mutations
KW  - squamous cell
KW  - melanoma
KW  - polymavirus
KW  - cancer
KW  - tumors
KW  - akt
KW  - expression
Y1  - 2012
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-131398
VL  - 7
IS  - 2
ER  - 
TY  - JOUR
A1  - Behr, Daniel S.
A1  - Peitsch, Wiebke K.
A1  - Hametner, Christian
A1  - Lasitschka, Felix
A1  - Houben, Roland
A1  - Schönhaar, Kathrin
A1  - Michel, Julia
A1  - Dollt, Claudia
A1  - Goebeler, Matthias
A1  - Marx, Alexander
A1  - Goerdt, Sergij
A1  - Schmieder, Astrid
T1  - Prognostic value of immune cell infiltration, tertiary lymphoid structures and PD-L1 expression in Merkel cell carcinomas
JF  - International Journal of Clinical and Experimental Pathology
N2  - Merkel cell carcinoma (MCC) is an aggressive, virus-associated, neuroendocrine tumor of the skin mainly affecting immunocompromised patients. Higher intratumoral infiltration with CD3 and CD8 positive T-cells is associated with a better prognosis, highlighting the relevance of the immune system for MCC development and progression. In this study 21 primary MCCs were stained with immune cell markers including CD3, CD4, CD8, CD68, CD20, and S100. Furthermore, tumor-infiltrating neutrophils, tertiary lymphoid structures and PD-L1 expression were analyzed and correlated with overall and recurrence free survival. All MCCs were Merkel Cell Polyomavirus positive. Overall and recurrence-free survival did not correlate with intra-and peritumoral CD3 and CD8 T-cell infiltration. In addition, no significant association regarding prognosis was found for tumor-associated neutrophils, tumor-associated macrophages or PD-L1 positivity in MCCs. Interestingly, the presence of tertiary lymphoid structures (TLS) in the tumor microenvironment significantly correlated with recurrence-free survival (P=0.025). In addition, TLS were significantly associated with a higher CD8/CD4 ratio in the tumor periphery (P=0.032), but not in the center of the tumor (P > 0.999). These results demonstrate for the first time that TLS, easily assessed in paraffin-embedded tissue in the tumor periphery of MCCs, may be a valuable prognostic factor indicating prolonged recurrence free survival.
KW  - CD8(+)
KW  - PD-L1
KW  - tertiary lymphoid structures
KW  - immune cell infiltration
KW  - polymavirus
KW  - survival
KW  - lymphocytes
KW  - responses
KW  - lung cancer
KW  - B-cells
KW  - breast cancer
KW  - antitumor immunity
KW  - T-antigens
KW  - Merkel cell carcinoma
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-117720
SN  - 1936-2625
VL  - 7
IS  - 11
ER  -