Neuropeptide Y (NPY) in tumor growth and progression: Lessons learned from pediatric oncology

Abstract

Neuropeptide Y (NPY) is a sympathetic neurotransmitter with pleiotropic actions, many of which are highly relevant to tumor biology. Consequently, the peptide has been implicated as a factor regulating the growth of a variety of tumors. Among them, two pediatric malignancies with high endogenous NPY synthesis and release – neuroblastoma and Ewing sarcoma – became excellent models to investigate the role of NPY in tumor growth and progression. The stimulatory effect on tumor cell proliferation, survival and migration, as well as angiogenesis in these tumors is mediated by two NPY receptors, Y2R and Y5R, which are expressed in either a constitutive or inducible manner. Of particular importance are interactions of the NPY system with the tumor microenvironment, as hypoxic conditions commonly occurring in solid tumors strongly activate the NPY/Y2R/Y5R axis. This activation is triggered by hypoxia-induced up-regulation of Y2R/Y5R expression and stimulation of dipeptidyl peptidase IV (DPPIV), which converts NPY to a selective Y2R/Y5R agonist, NPY3-36. While previous studies focused mainly on the effects of NPY on tumor growth and vascularization, they also provided insight into the potential role of the peptide in tumor progression into a metastatic and chemoresistant phenotype. This review summarizes our current knowledge of the role of NPY in neuroblastoma and Ewing sarcoma and its interactions with the tumor microenvironment in the context of findings in other malignancies, as well as discusses future directions and potential clinical implications of these discoveries.

Complexity of Neural Component of Tumor Microenvironment in Prostate Cancer

“…NPY is widely expressed in the central and peripheral nervous system, influencing via its Y receptors many physiological processes, such as cortical excitability, stress and immune response, food intake, circadian rhythms, cardiovascular function, glucose metabolism. NPY is also involved in biology of some tumors, controlling angiogenesis, tumor growth, metastasis and cancer cell metabolism [84]. An in vitro study revealed that Y1 and Y2 receptors are present in the androgen-independent human PC-3 cell line and that their activation by NPY stimulates cancer cell proliferation, which suggests its impact on castration-resistant regulation of PC [83,85].…”

Tumor progression: the neuronal input

“…As such it modulates many physiological functions ranging from stress responses, food intake, reproduction, circadian rhythms, anxiety and depression and pain processing (64). It exerts its principal activities through neuropeptide receptors 1, 2 and 5 and in the context of cancer (65), much information has been learned from two pediatric diseases with high endogenous NPY production-neuroblastoma and Ewing sarcoma-that have become models to investigate the role of NPY in tumor growth and progression (66). However, NPY and its receptor have been found to be expressed in cells and vasculatures from a variety of tumors (65) where they exert complex effects.…”

“…However, NPY and its receptor have been found to be expressed in cells and vasculatures from a variety of tumors (65) where they exert complex effects. It is generally accepted that NPY is an angiogenic factor, which strongly induces the endothelial cell proliferation, differentiation and migration, and promotes vascularization (66). Aside from being synthesized in tumor cells, NPY is also released systemically from sympathetic neurons (67).…”

“…While there are no significant reported side effects associated with the administration of NPY receptor antagonists in animals and people (34), the potential anorexigenic effects of NPY receptor blockage in cancer patients would have to be carefully monitored. Moreover, the use of a brainimpenetrable receptor antagonist could prevent such adverse central effects, while preserving peripheral activities on tumor growth and metastasis (66).…”

Recent advances in the understanding of how neuropeptide Y andα-melanocyte stimulating hormone function in adipose physiology

“…While well regarded as an orexigenic peptide in the brain, NPY functions in many other aspects of physiology, such as learning and memory, 102 tumor growth and progression, 103 and other processes related to adipose tissue. The effects of NPY that are related to adipose tissue and energy balance are summarized in Table 2 and Figure 1.…”