Glucose metabolism and angiogenesis in granulosa cell tumors of the ovary: activation of Akt, expression of M2PK, TKTL1 and VEGF.
OBJECTIVE
Very little is known about the biology of granulosa cell tumors of the ovary. A hallmark of granulosa cell tumors of the ovary is extensive growth, distant metastases however, are rarely found. We hypothesise that granulosa cell tumors of the ovary on the one hand need to stimulate vascularisation; on the other hand glucose metabolism has to be altered to ensure the supply of nutrients and metabolites. Increased glycolysis, the main source of energy supply, is considered to be important during malignant transformation. Thus, we focussed on a selection of key factors in angiogenesis and tumor glycolysis to study metabolic characteristics of granulosa cell tumors of the ovary.


METHODS
We analysed 32 tumor specimens for immunohistochemical expression of vascular endothelial growth factor, phosphorylated Akt, M2 pyruvate kinase isoenzyme, and transketolase-like enzyme 1. As controls, we stained 10 samples of normal ovaries.


RESULTS
We found expression of vascular endothelial growth factor in 94%, transketolase-like enzyme 1 in 81%, and phosphorylated Akt as well as M2 pyruvate kinase isoenzyme in 53% of the specimens. There were no significant differences between the expression levels in primary and those in recurrent tumors. Temporal analysis of marker expression in primary tumors and recurrences in the same patients revealed no increase or decrease of marker expression overtime. In contrast to granulosa cell tumors, normal ovaries showed no expression of the markers analysed in granulosa cells.


CONCLUSIONS
Our results show that granulosa cell tumors of the ovary express vascular endothelial growth factor as an important stimulator of tumor angiogenesis as well as several molecular markers for glycolysis. The dependence of granulosa cell tumors of the ovary on the glycolytic pathway may provide a biochemical basis for therapeutic strategies involving glycolytic inhibitors.
Schmidt
Melanie
M
Department of Gynaecology and Obstetrics, University of Wurzburg, Josef-Schneider-Strasse 4, 97080 Wurzburg, Germany. melanie_weigand@hotmail.de
Kammerer
Ulrike
U
Segerer
Sabine
S
Cramer
Andreas
A
Kohrenhagen
Nico
N
Dietl
Johannes
J
Voelker
Hans-Ullrich
HU
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D005260:Female; D006019:Glycolysis / Q000502:physiology*; D006106:Granulosa Cell Tumor / Q000378:metabolism*; D006801:Humans; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011770:Pyruvate Kinase / Q000378:metabolism; D014174:Transketolase / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C505431:TKTL1 protein, human; D014174:Transketolase; D011770:Pyruvate Kinase; D051057:Proto-Oncogene Proteins c-akt