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Expression and Activation of the Nerve Growth Factor Receptor TrkA in Serous Ovarian Carcinoma

Departments of Pathology [B. D., J. M. N., M. S., B. R., V. A. F.] and Gynecologic Oncology [C. G. T.], The Norwegian Radium Hospital, Montebello N-0310 Oslo, Norway, and Department of Pharmacology and Experimental Therapeutics, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 91120, Israel [R. R., P. L.]

Purpose: 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.

Experimental Design: 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.

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