title: Placental growth factor supports neuroendocrine tumor growth and predicts disease prognosis in patients.
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 NET patients' sera 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 was elevated in patients with pancreatic NETs (pNETs) compared with 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 a prognostic parameter and therapeutic target.
authors: Charité Medical Faculty and the Max-Delbrück Center for Molecular Medicine, Lindenberger Weg 80, 13125 Berlin, Germany.
authors: Georg
authors: G
authors: Hilfenhaus
authors: Andreas
authors: A
authors: Göhrig
authors: Ulrich-Frank
authors: UF
authors: Pape
authors: Tabea
authors: T
authors: Neumann
authors: Henning
authors: H
authors: Jann
authors: Dietmar
authors: D
authors: Zdunek
authors: Georg
authors: G
authors: Hess
authors: Jean Marie
authors: JM
authors: Stassen
authors: Bertram
authors: B
authors: Wiedenmann
authors: Katharina
authors: K
authors: Detjen
authors: Marianne
authors: M
authors: Pavel
authors: Christian
authors: C
authors: Fischer
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000097:blood*; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000097:blood* / Q000175:diagnosis / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D018358:Neuroendocrine Tumors / Q000097:blood* / Q000175:diagnosis / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000097:blood* / Q000175:diagnosis / Q000473:pathology; D000072483:Placenta Growth Factor; D011257:Pregnancy Proteins / Q000097:blood*; D011379:Prognosis; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000097:blood; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; C000608036:PGF protein, human; D011257:Pregnancy Proteins; D000072483:Placenta Growth Factor; C501162:FLT1 protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1
keywords: NET; PlGF; neuroendocrine tumor; placental growth factor; prognostic biomarker