Abstract
Neuroblastoma (NB) is the most common extracranial solid tumor of childhood and is a rapidly growing, highly-vascularized cancer. NBs frequently express angiogenic factors and high tumor angiogenesis has been associated with poor outcomes. Placental growth factor (PlGF) is an angiogenic protein belonging to the vascular endothelial growth factor (VEGF) family and is up-regulated mainly in pathologic conditions. Recently, PlGF was identified as a member of a gene expression signature characterizing highly malignant NB stem cells drawing attention as a potential therapeutic target in NB. In the present study, we sought to investigate the expression of PlGF in NB patients and the effect of PlGF inhibition on high-risk MYCN-non-amplified SK-N-AS NB xenografts. Human SK-N-AS cells, which are poorly differentiated and express PlGF and VEGF-A, were implanted subcutaneously in athymic nude mice. Treatment was done by intratumoral injection of replication-incompetent adenoviruses (Ad) expressing PlGF- or VEGF-specific short hairpin (sh)RNA, or soluble (s)VEGF receptor 2 (VEGFR2). The effect on tumor growth and angiogenesis was analyzed. High PlGF expression levels were observed in human advanced-stage NBs. Down-regulating PlGF significantly reduced NB growth in established NB xenografts by reducing cancer cell proliferation but did not suppress angiogenesis. In contrast, blocking VEGF by administration of Ad(sh)VEGF and Ad(s)VEGFR2 reduced tumor growth associated with decreased tumor vasculature. These findings suggest that PlGF and VEGF-A modulate MYCN-non-amplified NB tumors by different mechanisms and support a role for PlGF in NB biology.
Highlights
Neuroblastoma (NB) arises from primitive neuroepithelial cells of the neural crest and is the most frequently occurring solid tumor in children
Placental Growth Factor (PlGF) Expression Is up-Rregulated in Neuroblastoma
vascular endothelial growth factor (VEGF) blockade affected the tumor vasculature but did not affect tumor cell proliferation. These results suggest that both Placental growth factor (PlGF) and VEGF are critical to NB growth in established MYCN-non-amplified NB and that they act via different mechanisms
Summary
Neuroblastoma (NB) arises from primitive neuroepithelial cells of the neural crest and is the most frequently occurring solid tumor in children. NBs are heterogeneous in their biological characteristics and tumor stage, as well as patient age, are important prognostic factors that strongly correlate with survival and are used for treatment assignment [2]. Together with other prognostic factors, they have been used to categorize patients in four categories, very low risk, low risk, intermediate risk, and high risk [1,3]. Several reports on NB have shown the important dependency of NB on angiogenesis, demonstrating that high vascularity is characteristic for the progressed tumor stages and poor outcome in human NB [4,5]. High-risk NB patients have poor prognosis and a very unfavorable balance of the regulators with several pro-angiogenetic factors working together to achieve more effective angiogenesis and aggressive tumor growth [6]. Inhibition of angiogenesis has been considered as a strategy for therapy of NB [6]
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