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Placental growth factor supports neuroendocrine tumor growth and predicts disease prognosis in patients

Item Type:Article
Title:Placental growth factor supports neuroendocrine tumor growth and predicts disease prognosis in patients
Creators Name:Hilfenhaus, G. and Goehrig, A. and Pape, U.F. and Neumann, T. and Jann, H. and Zdunek, D. and Hess, G. and Stassen, J.M. and Wiedenmann, B. and Detjen, K. and Pavel, M. and Fischer, C.
Abstract:Placental growth factor (PlGF), a VEGF-homolog implicated in tumor angiogenesis and adaptation to antiangiogenic therapy, is emerging as candidate target in malignancies. Here, we addressed the expression, function and prognostic value of PlGF in neuroendocrine tumors (NETs). PlGF was determined in sera of NET patients collected retrospectively (n=88) and prospectively (n=87) using Roche-Elecsys and correlated with clinicopathological data. Tumoral PlGF was evaluated by immunohistochemistry, effects of PlGF on proliferation and migration in vitro were assessed using different NET cell lines and effects on tumor growth in vivo in orthotopic xenografts. Circulating and tumoral PlGF were elevated in patients with pancreatic NETs (pNETs) as compared to control sera and respective healthy tissue. De novo PlGF expression occurred primarily in the tumor stroma, suggesting paracrine stimulatory circuits. Indeed, PlGF enhanced NET proliferation and migration in vitro and, conversely, neutralizing antibodies to PlGF reduced tumor growth in vivo. Elevated circulating PlGF levels in NET patients correlated with advanced tumor grading and were associated with reduced tumor-related survival in pNETs. Subsequent determinations confirmed and extended our observation of elevated PlGF levels in a prospective cohort of grade 1 and grade 2 pNETs (n=30) and intestinal NETs (n=57). In low-grade pNETs, normal circulating PlGF levels were associated with better survival. In intestinal NETs, circulating PlGF above median emerged as an independent prognostic factor for shorter time-to-progression in multivariate analyses. These data assign to PlGF a novel function in the pathobiology of NETs and propose PlGF as prognostic parameter and therapeutic target.
Keywords:Neuroendocrine Tumor, NET, Placental Growth Factor, PIGF, Prognostic Biomarker
Source:Endocrine-Related Cancer
Publisher:Society for Endocrinology
Page Range:305-319
Date:20 May 2013
Official Publication:https://doi.org/10.1530/ERC-12-0223
PubMed:View item in PubMed

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