Matei D, Emerson R E, Lai Y-C, Baldridge L A, Rao J, Yiannoutsos C, Donner D D
Indiana University Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Oncogene. 2006 Mar 30;25(14):2060-9. doi: 10.1038/sj.onc.1209232.
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.
通过微阵列杂交在卵巢癌细胞和肿瘤中发现了血小板衍生生长因子受体（PDGFR）α的表达。这促使我们测试卵巢癌是否也产生该受体的配体，因为这将证明此类恶性肿瘤通过自分泌激活来支持自身的生长和扩散。我们使用逆转录聚合酶链反应（RT-PCR）、免疫组织化学（IHC）和酶联免疫吸附测定（ELISA）检测了卵巢肿瘤、细胞系和腹水中PDGFR配体的表达。我们在大多数卵巢肿瘤中检测到了PDGFRα配体的强烈mRNA表达。免疫组织化学还分别在47例卵巢肿瘤中的34例和32例中检测到了受体和配体的表达（PDGFRα和PDGF AB）。PDGFRα和PDGF AB的染色呈强相关性（P值=0.014），表明自分泌环在卵巢癌中发挥作用。通过ELISA对腹水中的PDGF AA和BB进行定量。两种配体在卵巢癌腹水标本（n = 54）中的分泌水平均高于非恶性疾病患者的腹水（n = 8）。在卵巢癌细胞条件培养基中检测到了PDGF。这种条件培养基可诱导PDGFR、Akt和丝裂原活化蛋白激酶（MAPK）的激活，并刺激细胞增殖。一种中和性PDGF抗体可阻断这些作用。通过小干扰RNA（siRNA）或受体中和抗体对PDGFR进行特异性抑制，可抑制PDGF刺激的受体激活和细胞增殖，这表明靶向受体在卵巢癌治疗中具有作用。
