TY  - JOUR
A1  - Chopra, Martin
A1  - Lang, Isabell
A1  - Salzmann, Steffen
A1  - Pachel, Christina
A1  - Kraus, Sabrina
A1  - Bäuerlein, Carina A.
A1  - Brede, Christian
A1  - Jordán Garrote, Ana-Laura
A1  - Mattenheimer, Katharina
A1  - Ritz, Miriam
A1  - Schwinn, Stefanie
A1  - Graf, Carolin
A1  - Schäfer, Viktoria
A1  - Frantz, Stefan
A1  - Einsele, Hermann
A1  - Wajant, Harald
A1  - Beilhack, Andreas
T1  - Tumor Necrosis Factor Induces Tumor Promoting and Anti-Tumoral Effects on Pancreatic Cancer via TNFR1
JF  - PLoS ONE
N2  - Multiple activities are ascribed to the cytokine tumor necrosis factor (TNF) in health and disease. In particular, TNF was shown to affect carcinogenesis in multiple ways. This cytokine acts via the activation of two cell surface receptors, TNFR1, which is associated with inflammation, and TNFR2, which was shown to cause anti-inflammatory signaling. We assessed the effects of TNF and its two receptors on the progression of pancreatic cancer by in vivo bioluminescence imaging in a syngeneic orthotopic tumor mouse model with Panc02 cells. Mice deficient for TNFR1 were unable to spontaneously reject Panc02 tumors and furthermore displayed enhanced tumor progression. In contrast, a fraction of wild type (37.5%), TNF deficient (12.5%), and TNFR2 deficient mice (22.2%) were able to fully reject the tumor within two weeks. Pancreatic tumors in TNFR1 deficient mice displayed increased vascular density, enhanced infiltration of CD4+ T cells and CD4+ forkhead box P3 (FoxP3)+ regulatory T cells (Treg) but reduced numbers of CD8+ T cells. These alterations were further accompanied by transcriptional upregulation of IL4. Thus, TNF and TNFR1 are required in pancreatic ductal carcinoma to ensure optimal CD8+ T cell-mediated immunosurveillance and tumor rejection. Exogenous systemic administration of human TNF, however, which only interacts with murine TNFR1, accelerated tumor progression. This suggests that TNFR1 has basically the capability in the Panc02 model to trigger pro-and anti-tumoral effects but the spatiotemporal availability of TNF seems to determine finally the overall outcome.
KW  - Bioluminescence
KW  - cancer treatment
KW  - cell staining
KW  - cytokines
KW  - immune cells
KW  - metastasis
KW  - regulatory T cells
KW  - T cells
Y1  - 2013
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-97246
ER  - 
TY  - JOUR
A1  - Ronchi, Cristina L.
A1  - Sbiera, Silviu
A1  - Volante, Marco
A1  - Steinhauer, Sonja
A1  - Scott-Wild, Vanessa
A1  - Altieri, Barbara
A1  - Kroiss, Matthias
A1  - Bala, Margarita
A1  - Papotti, Mauro
A1  - Deutschbein, Timo
A1  - Terzolo, Massimo
A1  - Fassnacht, Martin
A1  - Allolio, Bruno
T1  - CYP2W1 Is Highly Expressed in Adrenal Glands and Is Positively Associated with the Response to Mitotane in Adrenocortical Carcinoma
N2  - Background

Adrenocortical tumors comprise frequent adenomas (ACA) and rare carcinomas (ACC). Human cytochrome P450 2W1 (CYP2W1) is highly expressed in some cancers holding the potential to activate certain drugs into tumor cytotoxins.

Objective

To investigate the CYP2W1 expression in adrenal samples and its relationship with clinical outcome in ACC.

Material and Methods

CYP2W1 expression was investigated by qRT-PCR in 13 normal adrenal glands, 32 ACA, 25 ACC, and 9 different non-adrenal normal tissue samples and by immunohistochemistry in 352 specimens (23 normal adrenal glands, 33 ACA, 239 ACC, 67 non-adrenal normal or neoplastic samples).

Results

CYP2W1 mRNA expression was absent/low in normal non-adrenal tissues, but high in normal and neoplastic adrenal glands (all P<0.01 vs non-adrenal normal tissues). Accordingly, CYP2W1 immunoreactivity was absent/low (H-score 0–1) in 72% of non-adrenal normal tissues, but high (H-score 2–3) in 44% of non-adrenal cancers, in 65% of normal adrenal glands, in 62% of ACAs and in 50% of ACCs (all P<0.001 vs non-adrenal normal tissues), being significantly increased in steroid-secreting compared to non-secreting tumors. In ACC patients treated with mitotane only, high CYP2W1 immunoreactivity adjusted for ENSAT stage was associated with longer overall survival and time to progression (P<0.05 and P<0.01, respectively), and with a better response to therapy both as palliative (response/stable disease in 42% vs 6%, P<0.01) or adjuvant option (absence of disease recurrence in 69% vs 45%, P<0.01).

Conclusion

CYP2W1 is highly expressed in both normal and neoplastic adrenal glands making it a promising tool for targeted therapy in ACC. Furthermore, CYP2W1 may represent a new predictive marker for the response to mitotane treatment.
KW  - CYP2W1
KW  - cancer treatment
KW  - adrenal glands
KW  - carcinomas
KW  - drug therapy
KW  - hormones
KW  - immune response
KW  - immunohistochemistry techniques
KW  - surgical oncology
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-113096
ER  -