Neuropeptide Y as a Biomarker and Therapeutic Target for Neuroblastoma

Abstract

Neuroblastoma (NB) is a pediatric malignant neoplasm of sympathoadrenal origin. Challenges in its management include stratification of this heterogeneous disease and a lack of both adequate treatments for high-risk patients and noninvasive biomarkers of disease progression. Our previous studies have identified neuropeptide Y (NPY), a sympathetic neurotransmitter expressed in NB, as a potential therapeutic target for these tumors by virtue of its Y5 receptor (Y5R)-mediated chemoresistance and Y2 receptor (Y2R)-mediated proliferative and angiogenic activities. The goal of this study was to determine the clinical relevance and utility of these findings. Expression of NPY and its receptors was evaluated in corresponding samples of tumor RNA, tissues, and sera from 87 patients with neuroblastic tumors and in tumor tissues from the TH-MYCN NB mouse model. Elevated serum NPY levels correlated with an adverse clinical presentation, poor survival, metastasis, and relapse, whereas strong Y5R immunoreactivity was a marker of angioinvasive tumor cells. In NB tissues from TH-MYCN mice, high immunoreactivity of both NPY and Y5R marked angioinvasive NB cells. Y2R was uniformly expressed in undifferentiated tumor cells, which supports its previously reported role in NB cell proliferation. Our findings validate NPY as a therapeutic target for advanced NB and implicate the NPY/Y5R axis in disease dissemination. The correlation between elevated systemic NPY and NB progression identifies serum NPY as a novel NB biomarker.

Murine neuroblastoma cell lines developed by conditional reprogramming preserve heterogeneous phenotypes observed in vivo

“…As the mesenchymal NB cells have been implicated in NB migratory phenotype, these findings are consistent with potential role of NPY5R in the metastatic phenotype of NB mediated by cytoskeleton regulation. 12,40 Hence, this data further supports the notion that CR-NB primary cultures accurately preserve the tumor cell heterogeneity observed in vivo. Importantly, the NB cells isolated in this study retained their ability to grow under anchorage-independent conditions -the hallmark feature used to test tumorigenic potential of cells.…”

“…This association of high NPY5R levels with an angioinvasive phenotype of NB cells was previously described by us in human NB tissues. 40 In line with this, in CR-NB cultures, NPY5R was expressed in both cell populations, yet only in mesenchymal cells its subcellular distribution aligned with F-actin fibers. As the mesenchymal NB cells have been implicated in NB migratory phenotype, these findings are consistent with potential role of NPY5R in the metastatic phenotype of NB mediated by cytoskeleton regulation.…”

“…NPY concentration in the media was determined using Neuropeptide Y Enzyme Immunoassay Kit (Bachem Peninsula Laboratories, San Carlos, CA), as previously described. 39,40…”

Upregulation of MAPK10, TUBB2B and RASL11B may contribute to the development of neuroblastoma

“…A number of potential markers for early diagnosis and therapeutic targets of NB have been investigated. The neuropeptide Y (NPY), a sympathetic neurotransmitter expressed in the central nervous system, was significantly overexpressed in NB tumor tissues of a TH-MYCN mouse model and its increased expression level was associated with poor survival, tumor metastasis and relapse of NB (6). Astrocyte elevated gene-1, which encodes for metadherin, was upregulated in NB and promotes NB cell proliferation by activating the phosphatidylinositol-3-kinase/AKT serine/threonine kinase 1 signaling pathway (7).…”

Cytoprotective effect of neuropeptides on cancer stem cells: vasoactive intestinal peptide-induced antiapoptotic signaling

“… 19 , 20 , 21 In addition, some of these neuropeptides can increase the invasion and migration of cancer cells leading to metastasis. 22 , 23 , 24 Because of the extensive role in carcinogenesis, VIP has drawn a special focus. Specifically, an elevated expression of VIP receptors (VIPR) has been found in several cancers.…”