Abstract
Neogenin-1 (NEO1) is a transmembrane receptor involved in axonal guidance, angiogenesis, neuronal cell migration and cell death, during both embryonic development and adult homeostasis. It has been described as a dependence receptor, because it promotes cell death in the absence of its ligands (Netrin and Repulsive Guidance Molecule (RGM) families) and cell survival when they are present. Although NEO1 and its ligands are involved in tumor progression, their precise role in tumor cell survival and migration remain unclear. Public databases contain extensive information regarding the expression of NEO1 and its ligands Netrin-1 (NTN1) and Netrin-4 (NTN4) in primary neuroblastoma (NB) tumors. Analysis of this data revealed that patients with high expression levels of both NEO1 and NTN4 have a poor survival rate. Accordingly, our analyses in NB cell lines with different genetic backgrounds revealed that knocking-down NEO1 reduces cell migration, whereas silencing of endogenous NTN4 induced cell death. Conversely, overexpression of NEO1 resulted in higher cell migration in the presence of NTN4, and increased apoptosis in the absence of ligand. Increased apoptosis was prevented when utilizing physiological concentrations of exogenous Netrin-4. Likewise, cell death induced after NTN4 knock-down was rescued when NEO1 was transiently silenced, thus revealing an important role for NEO1 in NB cell survival. In vivo analysis, using the chicken embryo chorioallantoic membrane (CAM) model, showed that NEO1 and endogenous NTN4 are involved in tumor extravasation and metastasis. Our data collectively demonstrate that endogenous NTN4/NEO1 maintain NB growth via both pro-survival and pro-migratory molecular signaling.
Highlights
Cancer is a complex chronic disease, characterized by the uncontrolled growth and dissemination of tumor cells
In order to determine the expression of NEO1 and its ligands, NTN1 and NTN4, in primary NB tumors, and to further correlate the patient prognosis with patient survival, we reviewed public available data from R2: Genomics Analysis and Visualization Platform
Tumor metastasis is orchestrated by several cellular processes, such as proliferation, cell survival, apoptosis, and cell migration [28]
Summary
Cancer is a complex chronic disease, characterized by the uncontrolled growth and dissemination of tumor cells. Within the several varieties of cancer, pediatric solid tumors represent about 30% of pediatric cancers, including brain tumors, rhabdomyosarcoma, Wilms' tumor, osteosarcoma, and neuroblastoma (NB) [1]. These tumors arise as a result of the imbalance between proliferation/apoptosis and cell differentiation during development [2]. Little is known about the specific genes and signaling pathways that are involved in the development and spread of this aggressive and highly metastatic disease www.impactjournals.com/oncotarget [3]. It is important to understand its etiology and the molecular mechanisms involved in tumor onset and progression control
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