Abstract
BackgroundNeuroblastoma (NB) represents the most frequent and aggressive form of extracranial solid tumor of infants. Nucleolin (NCL) is a protein overexpressed and partially localized on the cell surface of tumor cells of adult cancers. Little is known about NCL and pediatric tumors and nothing is reported about cell surface NCL and NB.MethodsNB cell lines, Schwannian stroma-poor NB tumors and bone marrow (BM)-infiltrating NB cells were evaluated for the expression of cell surface NCL by Flow Cytometry, Imaging Flow Cytometry and Immunohistochemistry analyses. The cytotoxic activity of doxorubicin (DXR)-loaded nanocarriers decorated with the NCL-recognizing F3 peptide (T-DXR) was evaluated in terms of inhibition of NB cell proliferation and induction of cell death in vitro, whereas metastatic and orthotopic animal models of NB were used to examine their in vivo anti-tumor potential.ResultsNB cell lines, NB tumor cells (including patient-derived and Patient-Derived Xenografts-PDX) and 70% of BM-infiltrating NB cells show cell surface NCL expression. NCL staining was evident on both tumor and endothelial tumor cells in NB xenografts. F3 peptide-targeted nanoparticles, co-localizing with cell surface NCL, strongly associates with NB cells showing selective tumor cell internalization. T-DXR result significantly more effective, in terms of inhibition of cell proliferation and reduction of cell viability in vitro, and in terms of delay of tumor growth in all NB animal model tested, when compared to both control mice and those treated with the untargeted formulation.ConclusionsOur findings demonstrate that NCL could represent an innovative therapeutic cellular target for NB.
Highlights
Neuroblastoma (NB) represents the most frequent and aggressive form of extracranial solid tumor of infants
Enhanced NCL membrane expression has recently been reported on activated lymphocytes, angiogenic endothelial cells and several types of cancer cells, acting as a binding partner of different molecules implicated in cell differentiation, adhesion, leukocyte trafficking, inflammation, angiogenesis, lymphangiogenesis and tumorigenesis [6, 7]
Of importance is the fact that the expression of cell surface NCL was demonstrated on NB cells derived from patients suffering with metastatic bone marrow tumor infiltration, both at recurrence and at onset, and on NB primary tumors masses, supporting NCL as a new marker and an useful cellular target molecule in the clinical setting
Summary
Neuroblastoma (NB) represents the most frequent and aggressive form of extracranial solid tumor of infants. Neuroblastoma (NB) represents the most frequent and aggressive form of extra-cranial solid tumor of infants, responsible for 15% of childhood cancer deaths [1]. Enhanced NCL membrane expression has recently been reported on activated lymphocytes, angiogenic endothelial cells and several types of cancer cells, acting as a binding partner of different molecules implicated in cell differentiation, adhesion, leukocyte trafficking, inflammation, angiogenesis, lymphangiogenesis and tumorigenesis [6, 7]. For all these reasons, NCL might represent a potential biomarker for cancer diagnosis and a target for cancer treatment
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