Lisa P. Abramson

Pigment epithelium-derived factor regulates the vasculature and mass of the prostate and pancreas

Angiogenesis sustains tumor growth and metastasis, and recent studies indicate that the vascular endothelium regulates tissue mass. In the prostate, androgens drive angiogenic inducers to stimulate growth, whereas androgen withdrawal leads to decreased vascular endothelial growth factor, vascular regression and epithelial cell apoptosis. Here, we identify the angiogenesis inhibitor pigment epithelium–derived factor (PEDF) as a key inhibitor of stromal vasculature and epithelial tissue growth in mouse prostate and pancreas. In PEDF-deficient mice, stromal vessels were increased and associated with epithelial cell hyperplasia. Androgens inhibited prostatic PEDF expression in cultured cells. In vivo, androgen ablation increased PEDF in normal rat prostates and in human cancer biopsies. Exogenous PEDF induced tumor epithelial apoptosis in vitro and limited in vivo tumor xenograft growth, triggering endothelial apoptosis. Thus, PEDF regulates normal pancreas and prostate mass. Its androgen sensitivity makes PEDF a likely contributor to the anticancer effects of androgen ablation.

Serum vascular endothelial growth factor as a surveillance marker for cellular rejection in pediatric cardiac transplantation.

BACKGROUND Early detection and treatment of acute rejection in cardiac transplant recipients significantly improves long-term survival. Endomyocardial biopsy is used routinely for diagnosing allograft rejection; however, in young children, this procedure carries some risk. We evaluated serum vascular endothelial growth factor (VEGF) as a potential surveillance marker of acute cellular rejection. METHODS Blood samples (n=62) were analyzed from 23 patients and compared with controls (n=18) using an ELISA for VEGF. Results were correlated with endomyocardial biopsy rejection grades. RESULTS Mean baseline VEGF levels of the transplant population were consistently higher than controls. Serum VEGF levels were significantly higher during acute cellular rejection when compared with the non-rejecting transplant group (700.7+/-154 pg/ml vs. 190.5+/-29 pg/ml). VEGF decreased two- to eightfold after immunosuppressive therapy in 9 of 11 rejection episodes. CONCLUSIONS These data suggest that VEGF may play a role in the pathogenesis of acute allograft rejection and it may serve as a reliable serologic surveillance marker.

Gene Transfer of Pigment Epithelium-Derived Factor Suppresses Tumor Growth and Angiogenesis in a Hepatoblastoma Xenograft Model

Normal hepatocytes express pigment epithelium-derived factor (PEDF), an endogenous antiangiogenic factor. We hypothesized that decreased PEDF expression may be one mechanism driving hepatoblastoma growth, and in vivo gene transfer of PEDF could suppress neovascularization and limit tumor growth. PEDF functional activity was determined in vitro using endothelial cell migration assays and in vivo using a subcutaneous tumor model. HUH-6 human hepatoblastoma tumors were treated with hybrid adenoviral/adeno-associated viral expression vectors for PEDF (Hyb-PEDF, n = 4) or β-galactosidase (Hyb-βgal, n = 4) daily for 4 d. Mitotic figures, microvascular density (MVD), PEDF, and VEGF expression were assessed. Hyb-PEDF treatment inhibited in vivo tumor growth (p < 0.008) and decreased MVD (p < 0.001), the number of mitotic figures (p < 0.001), and VEGF expression when compared with Hyb-βgal-treated tumors. HUH-6 expression of PEDF was dramatically reduced when cultured under hypoxic conditions and also when grown in vivo, and the addition of neutralizing anti-PEDF antibody increased the already high baseline angiogenic activity of the HUH-6 cell secretions in vitro (p < 0.04). PEDF is an important endogenous regulator of the liver vasculature. Augmenting intra-tumoral PEDF levels inhibits tumor growth by reducing angiogenesis and VEGF expression. Potent inhibitors of angiogenesis, such as PEDF, may be an effective alternative treatment for children with hepatoblastoma.

Presentation and management of late-onset duodenomegaly in a teenager with chronic obstruction from malrotation

Anomalies of intestinal rotation typically present in infancy and early childhood. The diagnosis in older children and adults may be vague and delayed. We discuss a case and management of a patient with late-onset duodenomegaly with chronic obstruction from malrotation.