Oncotarget

Research Papers:

Tumor necrosis is an important hallmark of aggressive endometrial cancer and associates with hypoxia, angiogenesis and inflammation responses

Geir Bredholt _, Monica Mannelqvist, Ingunn M. Stefansson, Even Birkeland, Trond Hellem Bø, Anne M. Øyan, Jone Trovik, Karl-Henning Kalland, Inge Jonassen, Helga B. Salvesen, Elisabeth Wik and Lars A. Akslen

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Oncotarget. 2015; 6:39676-39691. https://doi.org/10.18632/oncotarget.5344

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Abstract

Geir Bredholt1,*, Monica Mannelqvist1,*, Ingunn M. Stefansson1,2, Even Birkeland1, Trond Hellem Bø1,3, Anne M. Øyan4,5, Jone Trovik5,6, Karl-Henning Kalland4,5, Inge Jonassen3, Helga B. Salvesen5,6, Elisabeth Wik1,2, Lars A. Akslen1,2

1Centre for Cancer Biomarkers CCBIO, Department of Clinical Medicine, Section for Pathology, University of Bergen, Bergen, Norway

2Department of Pathology, Haukeland University Hospital, Bergen, Norway

3CCBIO, Department of Informatics, University of Bergen, Bergen, Norway

4Department of Microbiology, Haukeland University Hospital, Bergen, Norway

5Center for Cancer Biomarkers CCBIO, Department of Clinical Science, University of Bergen, Norway

6Department of Gynecology and Obstetrics, Haukeland University Hospital, Bergen, Norway

*These authors have contributed equally to this work

Correspondence to:

Lars A. Akslen, e-mail: [email protected]

Keywords: necrosis, hypoxia, angiogenesis, inflammation, gene signatures

Received: June 11, 2015     Accepted: August 26, 2015     Published: October 14, 2015

ABSTRACT

Aims: Tumor necrosis is associated with aggressive features of endometrial cancer and poor prognosis. Here, we investigated gene expression patterns and potential treatment targets related to presence of tumor necrosis in primary endometrial cancer lesions.

Methods and Results: By DNA microarray analysis, expression of genes related to tumor necrosis reflected multiple tumor-microenvironment interactions like tissue hypoxia, angiogenesis and inflammation pathways. A tumor necrosis signature of 38 genes and a related patient cluster (Cluster I, 67% of the cases) were associated with features of aggressive tumors such as type II cancers, estrogen receptor negative tumors and vascular invasion. Further, the tumor necrosis signature was increased in tumor cells grown in hypoxic conditions in vitro. Multiple genes with increased expression are known to be activated by HIF1A and NF-kB.

Conclusions: Our findings indicate that the presence of tumor necrosis within primary tumors is associated with hypoxia, angiogenesis and inflammation responses. HIF1A, NF-kB and PI3K/mTOR might be potential treatment targets in aggressive endometrial cancers with presence of tumor necrosis.


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