Expression and activation of the nerve growth factor receptor TrkA in serous ovarian carcinoma.
OBJECTIVE
The purpose is to analyze the possible correlation between expression and activation of the high-affinity nerve growth factor (NGF) receptor TrkA, cell cycle protein expression, and disease outcome in serous ovarian carcinoma. In addition, we wished to study the possible link between expression of NGF, a novel angiogenic factor and its receptor TrkA, and the expression of factors involved in angiogenesis in effusions and solid tumors.


METHODS
Sections from 80 malignant effusions and 65 corresponding solid tumors were evaluated for protein expression of NGF, TrkA, and phospho-TrkA (p-TrkA). Effusions were additionally studied for expression of p53, p21(WAF1/CIP1), Ki-67, and the M(r) 85,000-cleaved fragment of poly(ADP-ribose) polymerase (p85-PARP) using immunohistochemistry (IHC). Thirty-two effusions were studied for TrkA, p-TrkA, p53, and p21(WAF1/CIP1) expression using immunoblotting. mRNA expression of basic fibroblast growth factor (bFGF), interleukin 8, and vascular endothelial growth factor (VEGF) was studied in 63 effusions and all solid tumors using in situ hybridization. Protein expression of bFGF, interleukin 8, and VEGF was additionally studied in 30 effusions using IHC.


RESULTS
NGF, TrkA, and p-TrkA were expressed in carcinoma cells in effusions in 60 of 80 (75%), 64 of 80 (80%), and 15 of 80 (19%) specimens, respectively. In solid tumors, p-TrkA expression was more frequent (52 of 65 tumors; 80%) and was accompanied by p-TrkA expression in endothelial cells. NGF colocalized with bFGF protein (P = 0.016) and mRNA (P = 0.032) in effusions, and with VEGF (P < 0.001) and bFGF (P = 0.008) in solid tumors. In survival analysis, expression of p85-PARP (P = 0.017) and cytoplasmic TrkA (P < 0.001) in effusions predicted better outcome, whereas membrane expression of p-TrkA in solid tumors correlated with poor survival (P = 0.004). Diffuse expression of p53 and Ki-67 was often seen using IHC, whereas p21(WAF1/CIP1) and p85-PARP expression was infrequent and focal. None of these correlated with NGF or TrkA expression or activity.


CONCLUSIONS
Coexpression of NGF with molecules involved in angiogenesis and p-TrkA expression in endothelial cells suggest that the proangiogenic role attributed to NGF in vitro and in vivo may be relevant in clinical cancer. Expression of p85-PARP as a marker of apoptosis and cytoplasmic expression of TrkA (probably representing nonglycosylated receptor) predict better outcome, whereas p-TrkA activation correlates with poor outcome in advanced stage serous ovarian carcinoma.
Davidson
Ben
B
Department of Pathology, The Norwegian Radium Hospital, Montebello N-0310 Oslo, Norway. bend@ulrik.uio.no
Reich
Reuven
R
Lazarovici
Philip
P
Nesland
Jahn M
JM
Skrede
Martina
M
Risberg
Björn
B
Tropé
Claes G
CG
Flørenes
Vivi Ann
VA
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000032:analysis; D018284:Cystadenocarcinoma, Serous / Q000737:chemistry* / Q000401:mortality; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000235:genetics; D006801:Humans; D008875:Middle Aged; D020932:Nerve Growth Factor / Q000032:analysis; D010051:Ovarian Neoplasms / Q000737:chemistry* / Q000401:mortality; D010446:Peptide Fragments / Q000032:analysis; D011065:Poly(ADP-ribose) Polymerases / Q000032:analysis; D012333:RNA, Messenger / Q000032:analysis; D020917:Receptor, trkA / Q000032:analysis* / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000032:analysis; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D010446:Peptide Fragments; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; D020932:Nerve Growth Factor; D011065:Poly(ADP-ribose) Polymerases; D020917:Receptor, trkA