Expression and mutational analysis of tyrosine kinase receptors c-kit, PDGFRalpha, and PDGFRbeta in ovarian cancers.
Most women with epithelial ovarian cancer are diagnosed with advanced disease. Despite surgery and initial tumor reduction by standard chemotherapy, the tumors frequently recur and the patients eventually die of their disease. New drugs that inhibit tyrosine kinase receptors (TKRs) are being investigated for treatment and this study was undertaken to determine the expression and mutational state for 3 TKRs (c-kit, platelet-derived growth factor receptor [PDGFR] alpha, and PDGFR beta) in ovarian cancer. Tissue arrays containing 84 epithelial ovarian tumors were studied by immunohistochemistry with antibodies specific for c-kit, PDGFR alpha, and PDGFR beta. Immunoreactivity was detected in 78% of the tumor to at least one TKR. PDGFR alpha was expressed in the largest percentage of ovarian tumors (58%) whereas 29% expressed PDGFR beta. Two commercial antibodies against c-kit were studied and 33% of the tumors stained with one but only 6% were interpreted as positive with the second antibody. Activation of TKRs may occur through mutations but, by sequence analysis, no mutations were detected in 6 ovarian tumors with elevated immunoreactivity for each of the TKRs (c-kit, PDGFR alpha, and PDGFR beta). Tyrosine kinase receptors could also be activated through autocrine or paracrine stimulation of receptor by its ligand. Of 43 (35%) tumors tested for both c-kit receptor and its ligand (stem cell factor), 15 expressed both proteins indicating the possibility that this autocrine stimulation feedback loop is a factor in the growth of some ovarian cancers. This study demonstrates that PDGFR alpha, PDGFR beta, and c-kit are expressed in a high percentage of epithelial ovarian cancers suggesting that tyrosine kinase inhibitors may be useful in the treatment of these tumors.
Wilczynski
Sharon P
SP
Department of Pathology, City of Hope National Medical Center, Duarte, CA 91010, USA. swilczynski@coh.org
Chen
Yuan-Yuan
YY
Chen
Wengang
W
Howell
Stephen B
SB
Shively
John E
JE
Alberts
David S
DS
D000230:Adenocarcinoma / Q000737:chemistry / Q000235:genetics; D000236:Adenoma / Q000737:chemistry / Q000235:genetics; D002294:Carcinoma, Squamous Cell; D004252:DNA Mutational Analysis; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005260:Female; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D010051:Ovarian Neoplasms / Q000737:chemistry / Q000235:genetics*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D019009:Proto-Oncogene Proteins c-kit / Q000032:analysis / Q000235:genetics*; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000032:analysis / Q000235:genetics*; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000032:analysis / Q000235:genetics*; D017422:Sequence Analysis, DNA; D019089:Stem Cell Factor / Q000032:analysis
D004791:Enzyme Inhibitors; D019089:Stem Cell Factor; D011505:Protein-Tyrosine Kinases; D019009:Proto-Oncogene Proteins c-kit; D020796:Receptor, Platelet-Derived Growth Factor alpha; D020797:Receptor, Platelet-Derived Growth Factor beta