Autocrine activation of PDGFRalpha promotes the progression of ovarian cancer.
Platelet-derived growth factor receptor (PDGFR)alpha expression was found in ovarian cancer cells and tumors by microarray hybridization. This led us to test whether ovarian cancers also produce ligands for this receptor, as this would demonstrate that such malignancies support their own growth and spread through autocrine activation. We assayed the expression of ligands for the PDGFR in ovarian tumors, cell lines and peritoneal fluid using RT-PCR, immunohistochemistry (IHC) and ELISA. We detected strong mRNA expression for the PDGFRalpha ligands in most ovarian tumors. Receptor and ligand expressions (PDGFRalpha and PDGF AB) were also detected by IHC in, respectively, 34 and 32 of 47 ovarian tumors. The stainings for PDGFRalpha and PDGF AB were strongly correlated (P-value=0.014), suggesting that an autocrine loop is functional in ovarian cancer. PDGF AA and BB were quantified in peritoneal fluid by ELISA. Both ligands are secreted at higher levels in ovarian cancer ascites specimens (n=54) than in fluid from nonmalignant disorders (n=8). PDGF was detected in media conditioned by ovarian cancer cells. Such conditioned media induced activation of the PDGFR, Akt and MAPK and stimulated cell proliferation. A neutralizing PDGF antibody blocked these effects. Specific PDGFR inhibition by siRNA or a neutralizing antibody to the receptor inhibited PDGF-stimulated receptor activation and cell proliferation, suggesting that receptor targeting has a role in ovarian cancer treatment.
Matei
D
D
Indiana University Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA. dmatei@iupui.edu
Emerson
R E
RE
Lai
Y-C
YC
Baldridge
L A
LA
Rao
J
J
Yiannoutsos
C
C
Donner
D D
DD
D001202:Ascitic Fluid / Q000378:metabolism; D001483:Base Sequence; D002455:Cell Division; D045744:Cell Line, Tumor; D017077:Culture Media, Conditioned; D017931:DNA Primers; D018450:Disease Progression; D004789:Enzyme Activation; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000378:metabolism* / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D017077:Culture Media, Conditioned; D017931:DNA Primers; D020796:Receptor, Platelet-Derived Growth Factor alpha; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases