ReviewNeuropeptide Y (NPY) in neuroblastoma: Effect on growth and vascularization
Introduction
Neuroblastoma cells are commonly used in neuropeptide Y (NPY) research to study the regulation of peptide expression, its receptor signaling and trafficking [37], [60]. The best known neuroblastoma cell lines include SK-N-BE, SHSY5Y, SMS-KAN, SK-N-AS. In contrast, the SK-N-MC cell line, which has been initially described as a neuroblastoma and widely used to characterize NPY-Y1 receptors, in fact belongs to the Ewing's sarcoma family of tumors [7], [8], [38], [59], [64]. Due to this, SK-N-MC cells have a different biology and, consequently, a different NPY receptor pattern than neuroblastoma cells.
The purpose of this review is to show that neuroblastoma cells are not just models to study NPY and its receptors. They are derived from real patients, who often died despite intense treatment, and represent a real disease, which lacks an adequate treatment. Moreover, the review summarizes the evidence that NPY is not only a marker of neuronal differentiation in neuroblastomas, but in fact the NPY system serves as an important autocrine pathway, which sustains tumor growth and, consequently, may be a potential target for new therapies for these pediatric tumors.
Section snippets
Biology of neuroblastoma
Neuroblastoma, together with rhabdosarcoma and Ewing's sarcoma, belongs to a family of aggressive, small blue round cell tumors of childhood. Neuroblastoma is the most common malignant disease of infancy and is responsible for approximately 15% of all childhood cancer deaths [5], [10], [40]. It is one of the most diverse and enigmatic diseases among all known malignancies. The low grade neuroblastoma (stages 1 and 2) is a localized disease, has a good prognosis and does not require intensive
NPY in neuroblastoma
As tumors derived from sympathetic precursors, neuroblastomas synthesize and release various neuronal proteins, such as NPY, which is considered a marker of their neuronal differentiation. Due to this, neuroblastoma is often associated with elevated plasma levels of the peptide, which normalize after treatment [8], [26], [50], [51]. However, the first attempts to use NPY as a general diagnostic marker for neuroblastoma failed due to the high variability of the peptide concentrations. Further
NPY as a growth factor for neuroblastoma cells
The fact that neuroblastoma cells express both NPY and its receptors suggests that the peptide can act here as an autocrine growth factor. Indeed, exogenous NPY stimulates the proliferation of SK-N-BE(2) neuroblastoma cells, which is associated with transient activation of p44/42 MAPK (Fig. 2B) [26]. This effect is mimicked by both Y2 and Y5 agonists and blocked by Y2 and Y5 antagonists, suggesting that both receptors are involved in this process. Interestingly, the NPY receptor antagonists not
Role of NPY in tumor vascularization
Another aspect of NPYs role in neuroblastomas is associated with its angiogenic effect. The angiogenic properties of NPY have been established using variety of models. In vitro, the peptide stimulates endothelial cell proliferation and migration [68]. In vivo, it is involved in the revascularization of ischemic tissues, wound healing and retinopathy [20], [22], [32], [35], [66]. The angiogenic activities of the peptide are severely impaired in Y2−/− mice, indicating that Y2 is the main receptor
NPY in the neuroblastoma microenvironment
Taken together, studies on in vitro and in vivo models indicate that NPY may be an important growth factor for neuroblastoma, which stimulates their growth by two distinct inter-dependent mechanisms: an autocrine effect on neuroblastoma cell proliferation and paracrine angiogenic effect (Fig. 3) [26]. However, to understand the role of NPY in neuroblastoma, it is essential to study its function in the context of the entire tumor microenvironment and establish interactions of the NPY system with
NPY and its receptors as potential targets in neuroblastoma therapy
As described above, NPY is not just a marker of neuronal differentiation in neuroblastoma, but also a stimulator of their growth [26]. The fact that both NPY-induced neuroblastoma cell proliferation and angiogenesis seem to be Y2/Y5 receptor mediated (Fig. 3) suggests that blocking this pathway can be a bi-directional therapy for neuroblastoma, targeting both the growth of tumor cells and the formation of new blood vessels. Neuroblastomas are very well vascularized, angiogenesis-dependent
Future directions
Although the study summarized in this review provided a significant insight into understanding the role of NPY in neuroblastoma, several important questions remain unanswered. For example, is NPY involved in neuroblastoma metastases? In advanced neuroblastomas, elevated NPY plasma levels have been associated with poor outcome of the disease, which correlates with metastases and high tumor vascularization [14], [15], [17], [19], [21], [43]. Moreover, the concentration of NPY is significantly
Summary
In summary, NPY is a growth factor for neuroblastomas, stimulating their growth via a direct effect on tumor cell proliferation and indirectly, via its angiogenic activity. However, further studies are required to fully elucidate the functions of the peptide in a neuroblastoma microenvironment and, based on this, design potential treatment strategies for these children's tumors.
Acknowledgements
The author would like to thank Lydia Kuo for critical reading of the manuscript. This work was supported by the grant from Children's Cancer Foundation (Baltimore, MD) and American Cancer Society Institutional Research Grant IRG-97-152-13 to Joanna Kitlinska.
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