Nerve growth factor and its high-affinity receptor trkA participate in the control of vascular endothelial growth factor expression in epithelial ovarian cancer.
OBJECTIVE
To compare the expression of nerve growth factor (NGF) and its high-affinity receptor trkA in normal ovaries and in epithelial ovarian carcinomas. Given NGF acts as an angiogenic factor through a vascular endothelial growth factor (VEGF)-mediated mechanism in several types of tissues, we examined whether NGF regulates the expression of VEGF isoforms in epithelial ovarian cancer (EOC).


METHODS
The expression and localization of NGF and tyrosine kinase receptor A (trkA) in normal ovarian samples and in ovarian cancer samples were analyzed by RT-PCR and immunohistochemistry. NGF regulates the expression of three VEGF isoforms (VEGF(121), VEGF(165) and VEGF(189)); these were examined using RT-PCR in explants of EOC and ELISA in culture media.


RESULTS
TrkA mRNA levels were over-expressed in ovarian cancer compared to normal ovarian samples, whereas NGF mRNA levels remained unchanged. NGF and trkA proteins were absent or found in very low levels in normal ovarian surface epithelium (OSE), whereas they were highly expressed in epithelial cells of EOC. Additionally, NGF stimulated the expression of VEGF isoforms in cancer explants. The effect was dose-dependent and inhibited by a NGF antibody and by K(252a), a trk receptor inhibitor.


CONCLUSIONS
The abundance of NGF and trkA receptors in epithelial cells of EOC, together with the ability of NGF to increase VEGF expression strongly suggests an autocrine role of NGF in EOC. These findings suggest that blocking neurotrophin action could be a therapeutic target in treating ovarian cancer.
Campos
Ximena
X
Laboratorio de Endocrinología y Biología Reproductiva, Hospital Clinico Universidad de Chile, Chile.
Muñoz
Yenny
Y
Selman
Alberto
A
Yazigi
Roberto
R
Moyano
Leonor
L
Weinstein-Oppenheimer
Caroline
C
Lara
Hernán E
HE
Romero
Carmen
C
D000328:Adult; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D020932:Nerve Growth Factor / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D010053:Ovary / Q000201:enzymology / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020917:Receptor, trkA / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis* / Q000235:genetics
D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D020932:Nerve Growth Factor; D020917:Receptor, trkA