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


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.
Centre for Cancer Biomarkers CCBIO, Department of Clinical Medicine, Section for Pathology, University of Bergen, Bergen, Norway.
Geir
G
Bredholt
Centre for Cancer Biomarkers CCBIO, Department of Clinical Medicine, Section for Pathology, University of Bergen, Bergen, Norway.
Monica
M
Mannelqvist
Centre for Cancer Biomarkers CCBIO, Department of Clinical Medicine, Section for Pathology, University of Bergen, Bergen, Norway.|Department of Pathology, Haukeland University Hospital, Bergen, Norway.
Ingunn M
IM
Stefansson
Centre for Cancer Biomarkers CCBIO, Department of Clinical Medicine, Section for Pathology, University of Bergen, Bergen, Norway.
Even
E
Birkeland
Centre for Cancer Biomarkers CCBIO, Department of Clinical Medicine, Section for Pathology, University of Bergen, Bergen, Norway.|CCBIO, Department of Informatics, University of Bergen, Bergen, Norway.
Trond Hellem
TH
Bø
Department of Microbiology, Haukeland University Hospital, Bergen, Norway.|Center for Cancer Biomarkers CCBIO, Department of Clinical Science, University of Bergen, Norway.
Anne M
AM
Øyan
Center for Cancer Biomarkers CCBIO, Department of Clinical Science, University of Bergen, Norway.|Department of Gynecology and Obstetrics, Haukeland University Hospital, Bergen, Norway.
Jone
J
Trovik
Department of Microbiology, Haukeland University Hospital, Bergen, Norway.|Center for Cancer Biomarkers CCBIO, Department of Clinical Science, University of Bergen, Norway.
Karl-Henning
KH
Kalland
CCBIO, Department of Informatics, University of Bergen, Bergen, Norway.
Inge
I
Jonassen
Center for Cancer Biomarkers CCBIO, Department of Clinical Science, University of Bergen, Norway.|Department of Gynecology and Obstetrics, Haukeland University Hospital, Bergen, Norway.
Helga B
HB
Salvesen
Centre for Cancer Biomarkers CCBIO, Department of Clinical Medicine, Section for Pathology, University of Bergen, Bergen, Norway.|Department of Pathology, Haukeland University Hospital, Bergen, Norway.
Elisabeth
E
Wik
Centre for Cancer Biomarkers CCBIO, Department of Clinical Medicine, Section for Pathology, University of Bergen, Bergen, Norway.|Department of Pathology, Haukeland University Hospital, Bergen, Norway.
Lars A
LA
Akslen
D016000:Cluster Analysis; D016889:Endometrial Neoplasms / Q000098:blood supply / Q000235:genetics* / Q000473:pathology; D004717:Endometrium / Q000378:metabolism* / Q000473:pathology; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods*; D015972:Gene Expression Regulation, Neoplastic; D063990:Gene Ontology; D006801:Humans; D000860:Hypoxia / Q000235:genetics; D007249:Inflammation / Q000235:genetics; D008875:Middle Aged; D009336:Necrosis / Q000235:genetics; D009389:Neovascularization, Pathologic / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D011446:Prospective Studies; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics
angiogenesis; gene signatures; hypoxia; inflammation; necrosis