Pigment epithelium-derived factor targets endothelial and epithelial cells in Wilms\u27 tumor.

PURPOSE: Loss of pigment epithelium-derived factor (PEDF), a potent inhibitor of angiogenesis, has been linked to progression of angiogenesis-dependent diseases. We postulated that decreased levels of endogenous PEDF in the kidney creates a tumor permissive environment for Wilms\u27 tumor. METHODS: Fresh and frozen Wilms\u27 tumor (n = 28), adjacent (n = 3), and normal kidney (n = 8) were immunostained and graded. The Wilms\u27 tumor cells (SK-NEP-1), renal epithelial cells (NRK-52), and fresh tumor samples were grown in culture. Condition media were collected and analyzed by an in vitro angiogenesis assay and Western blot. The SK-NEP-1 cells were treated with PEDF and cell viability assessed. RESULTS: Wilms\u27 tumors expressed less PEDF than normal and adjacent kidney. Pigment epithelium-derived factor protein secretion was abundant in NRK-52 cells but significantly decreased in Wilms\u27 tumor. Pigment epithelium-derived factor acted as blockade to angiogenesis and it had a dose-dependent cytotoxic effect on Wilms\u27 tumor epithelial cells. CONCLUSION: Renal tubular epithelial cells are a rich source of PEDF in the normal kidney. Reduced levels of PEDF in Wilms\u27 tumor remove a critical endogenous renal barrier to angiogenesis and tumor cell survival. Therapeutic replacement of PEDF may prove to be an effective strategy to combat Wilms\u27 tumor progression

WNT7B mediates autocrine Wnt/β-catenin signaling and anchorage-independent growth in pancreatic adenocarcinoma.

Developmental and cancer models show Wnt/β-catenin-dependent signaling mediates diverse phenotypic outcomes in the pancreas that are dictated by context, duration and strength of activation. While generally assumed to be pro-tumorigenic, it is unclear to what extent dysregulation of Wnt/β-catenin signaling impacts tumor progression in pancreatic adenocarcinoma (PDAC). In the present study, Wnt/β-catenin activity was characterized across a spectrum of PDAC cell lines and primary tumors. Reporter and gene expression-based assays revealed wide heterogeneity in Wnt/β-catenin transcriptional activity across PDAC cell lines and patient tumors, as well as variable responsiveness to exogenous Wnt ligand stimulation. An experimentally generated, pancreas-specific gene expression signature of Wnt/β-catenin transcriptional activation was used to stratify pathway activation across a cohort of resected, early-stage PDAC tumors (N=41). In this cohort, higher Wnt/β-catenin activation was found to significantly correlate with lymphvascular invasion and worse disease-specific survival (median survival time 20.3 versus 43.9 months, log-rank P=0.03). Supporting the importance of Wnt ligand in mediating autocrine Wnt signaling, Wnt/β-catenin activity was significantly inhibited in PDAC cell lines by WLS gene silencing and the small-molecule inhibitor IWP-2, both of which functionally block Wnt ligand processing and secretion. Transcriptional profiling revealed elevated expression of WNT7B occurred in PDAC cell lines with high levels of cell autonomous Wnt/β-catenin activity. Gene-knockdown studies in AsPC-1 and HPAF-2 cell lines confirmed WNT7B-mediated cell autonomous Wnt/β-catenin activation, as well as an anchorage-independent growth phenotype. Our findings indicate WNT7B can serve as a primary determinant of differential Wnt/β-catenin activation in PDAC. Disrupting the interaction between Wnt ligands and their receptors may be a particularly suitable approach for therapeutic modulation of Wnt/β-catenin signaling in PDAC and other cancer contexts where Wnt activation is mediated by ligand expression rather than mutations in canonical pathway members