Autocrine activation of PDGFRα promotes the progression of ovarian cancer

Abstract

Platelet-derived growth factor receptor (PDGFR)a 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 PDGFRa ligands in most ovarian tumors. Receptor and ligand expressions (PDGFRa and PDGF AB) were also detected by IHC in, respectively, 34 and 32 of 47 ovarian tumors. The stainings for PDGFRa and PDGF AB were strongly correlated (P-value ¼ 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 ¼ 54) than in fluid from nonmalignant disorders (n ¼ 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.

Expression of platelet-derived growth factors and their receptors in ovarian clear-cell carcinoma and its putative precursors

“…Experiments in vivo have shown that PDGFRs activated by PDGFs modulate Akt and MAPK phosphorylation and significantly influence ovarian cancer cell proliferation and tumor expansion. 16 These observations suggest that the PDGF-PDGFR system may play a functional role in the progression of ovarian cancers through autocrine or paracrine activation within the tumor tissues.…”

“…Although such mutations and gene amplification have not been described previously in ovarian cancers, recent studies have demonstrated that PDGFR-a, PDGFR-b, and PDGF-AB are commonly expressed in ovarian cancers at frequencies as high as 87, 81, and 67%, respectively. [13][14][15][16] Moreover, Henriksen et al 17 have reported that PDGFRs or PDGFs were not detected in any of the benign ovarian tumors or normal ovarian epithelium they examined. Experiments in vivo have shown that PDGFRs activated by PDGFs modulate Akt and MAPK phosphorylation and significantly influence ovarian cancer cell proliferation and tumor expansion.…”

Rationale for the development of IMC‐3G3, a fully human immunoglobulin G subclass 1 monoclonal antibody targeting the platelet‐derived growth factor receptor α

“…2). [44][45][46][47][48][49][50][51][52][53][54][55][56][57][58][59][60] Several types of cancers, particularly those derived from the ovary, prostate, breast, lung, brain, skin, and bone, express PDGFRa on the malignant cells themselves (Table 1). 22 In 1 experiment in which a human tumor array was probed with a cross-reactive polyclonal rabbit antibody to PDGFRa, PDGFRa expression was noted in approximately 95% of osteosarcomas and chondrosarcomas, in 77% of prostate cancers, in 52% of ovarian cancers, in 65% of breast cancers, and in 51% of lung cancers (N. Loizos, ImClone Systems, unpublished results).…”

“…A separate investigation demonstrated strong immunohistochemical staining (2 to 3þ) in 89% of the clear cell histologic subtype of ovarian cancers. 50 Gene amplifications of PDGFRa have been identified in a subset of malignant gliomas, 62 and activating mutations of PDGFRa have been discovered in a proportion of gastrointestinal stromal tumors. 63 Tumor PDGFRa expression has been associated with disease progression in renal cell cancer, 64 diminished survival in ovarian cancer, 56 lymph node metastasis in breast cancer, 58 and bone metastases in prostate cancer.…”

“…59 Investigations in multiple cancer types have highlighted the relevance of both PDGF-activated tumor and supporting stromal cells in facilitating cancer growth and metastasis. [44][45][46][47][48][49][50][51]55,57,60 In some cases, specific autocrine or paracrine mechanisms that contribute to malignant progression have been suggested. In 1 experiment, NIH 3T3 cells were transformed when PDGF-A or PDGF-B gene expression was induced using a transfected promoter.…”