Synaptic Vesicle Protein 2 and Vesicular Monoamine Transporter 1 and 2 Are Expressed in Neuroblastoma

Abstract

Neuroblastoma (NB), the most common extracranial cancer in childhood, exhibits neuroendocrine (NE) differentiation. Two well-established NE markers, chromogranin A (CgA) and synaptophysin (syn), are used in the histopathological diagnostics. Our aims were to explore if the NE markers synaptic vesicle protein 2 (SV2) and vesicular monoamine transporter 1 (VMAT1) and 2 (VMAT2) also are expressed in human NB and if so, evaluate their usefulness in NB histopathological diagnostics. Tumor specimens from 21 NB patients, before and/or after chemotherapy, were immunostained for CgA, syn, SV2, VMAT1, and VMAT2. Clinical data was extracted from patients' records. SV2 was highly expressed in NB, as was CgA while syn was less frequently expressed compared to the other two. Both VMATs were expressed in several NB, VMAT2 in more cases than VMAT1 and its expression was similar to syn. Chemotherapy did not affect the immunoreactivity in an obvious way. SV2 was highly expressed in NB and can thus be useful marker in NB diagnostics. VMAT1 and VMAT2 were also expressed in NB but similar to syn less reliable as tumor markers.

Validation of SV2A-Targeted PET Imaging for Noninvasive Assessment of Neuroendocrine Differentiation in Prostate Cancer

“…Given the significantly elevated SV2A expression in NEPC cells and xenografts, we performed a pilot small animal PET/CT imaging evaluation with 18 F-SynVesT-1 in NOD-SCID mice bearing NCI-H660 xenografts. We acknowledge that although 18 F-SynVesT-1 has entered clinical trials [ 41 , 51 ], it is a neuroimaging agent that targets SV2A in the brain for synaptic density assessment but not in NEPC for oncological imaging. Despite the undesired high hepatic accumulation due to its lipophilic nature, 18 F-SynVesT-1 was able to clearly visualize the SV2A + NCI-H660 tumor within 1 h p.i.…”

“…To provide a proof of concept, we performed an imaging evaluation of SV2A using 18 F-SynVesT-1 in NEPC xenograft mouse models established by NCI-H660 and DU145. Even with the neuroimaging agent that targets SV2A in the brain for synaptic density assessment but not SV2A in NEPC for oncological imaging [ 41 , 51 ], we were able to clearly visualize the SV2A + tumors and confirm the desired SV2A-imaging specificity ( Figure 4 ) for noninvasive assessment of NED in NEPC or other innervated cancer types. Clinically, NEPC features reduced expressions of PSMA, while the expressions of SSTRs (1–5) in NEPC remain inconclusive.…”

“…An upregulated expression of SYP reflects an activated synaptic machinery that may cause or enhance tumor innervation and growth [ 11 , 35 , 36 , 37 ]. It has been reported that SV2A can be used for pathological assessment of NED in NETs [ 38 , 39 , 40 , 41 ], interestingly, with a greater similarity to SYP than to CgA [ 38 ]. In addition, SV2A has been identified as the key membrane receptor for botulinum neurotoxin, which might be of therapeutic potential for treatment of tumors featuring NE phenotypes, including CRPC [ 11 , 35 , 36 ].…”

Bombesin Receptor Family Activation and CNS/Neural Tumors: Review of Evidence Supporting Possible Role for Novel Targeted Therapy

“…Neuroblastomas are frequently classified as neuroendocrine tumors (NET) because they can show neuroendocrine differentiation with immunocytochemical staining for NET markers (chromogranin, synaptophysin, etc.) (181,182). In addition, similar to NETs, neuroblastomas can demonstrate amine precursor uptake and decarboxylation, as well as secrete numerous biologically active peptides/amine including vasoactive intestinal peptide, gastrin, catecholamines, serotonin, and GRP (181,(183)(184)(185).…”

“…(181,182). In addition, similar to NETs, neuroblastomas can demonstrate amine precursor uptake and decarboxylation, as well as secrete numerous biologically active peptides/amine including vasoactive intestinal peptide, gastrin, catecholamines, serotonin, and GRP (181,(183)(184)(185).…”