Neuropeptide Y in cancer-biological functions and potential clinical implications

Abstract

Neuropeptide Y (NPY) is a sympathetic neurotransmitter widely distributed in the peripheral and central nervous system, affecting many physiological functions. Consequently, dysregulation of the NPY system contributes to numerous pathological disorders, including stress, obesity, and cancer. The pleiotropic functions of NPY in humans are mediated by G protein-coupled receptors (Y1R, Y2R, Y5R), which activate several signaling pathways and thereby regulate cell growth, differentiation, apoptosis, proliferation, angiogenesis, and metabolism. These activities of NPY are highly relevant to tumor biology and known hallmarks of cancer, including sustained proliferative potential, resisting cell death, angiogenesis, invasion, and metastases. In this comprehensive review, we describe the cellular functions of NPY and discuss its role in cancer pathobiology, as well as provide the current state of knowledge pertaining to NPY and its receptors in various cancer types. Moreover, we focus on potential clinical applications targeting the NPY system, such as its role as a prognostic and predictive factor, as well as its utility in cancer diagnostics, imaging, and treatment. Altogether, growing evidence supports the significant role of the NPY system in tumor pathobiology and implicates its potential therapeutic and diagnostic value in modern oncology.

Keywords: Biomarker; Cancer; Metastasis; Neuropeptide Y; Therapy.

Fig. 1

Physiological functions of NPY. A As one of the most abundant peptides in the brain, NPY is involved in central regulation of processes involved in stress response, appetite stimulation, circadian rhythm, immunity and bone homeostasis. B In the periphery, NPY is co-released with norepinephrine from sympathetic neurons, affecting metabolism, cardiovascular system, bone health and immune responses (figure created using Biorender)

Fig. 2

The biosynthesis and processing of neuropeptide Y. NPY is synthesized as a 97-amino acid Pre-Pro-NPY, which undergoes proteolytic cleavage in endoplasmic reticulum and the secretory pathway leading to the secretion of the mature amidated 36 amino acid peptide. In the extracellular space, NPY may be further cleaved by aminopapetidase P and dipeptidyl peptidase IV to its truncated forms NPY_2–36 or NPY_3–36, respectively. ER, endoplasmic reticulum; CPON, carboxyl-terminal flanking peptide of NPY; LDCV, large dense-core vesicles (figure created using Biorender)

Fig. 3

The molecular mechanism of NPY actions relevant to cancer biology. In humans, NPY acts mainly via three GPCRs—Y1R, Y2R, and Y5R. Y1R requires the full length NPY_1–36 for the activation, while Y2R and Y5R can also bind to NPY_3–36. All NPY receptors signal through G_i/o proteins and inhibit cAMP synthesis by adenylyl cyclase, which blocks the inhibitory effects of PKA on the downstream pathways. The second mechanism of NPY signaling, specific for Y1R and Y2R, involves Ca.²⁺ mobilization and subsequent calcium-dependent activation of PKC and CaMKII. Concomitantly, these signaling pathways lead to the activation of ERK1/2. Moreover, all NPY receptors are capable of activating the PI3K/Akt pathway. The specific feature of Y5R is the ability to activate RhoA and thereby regulate cytoskeleton remodeling (figure created using Biorender)

Fig. 4

The pleiotropic functions of neuropeptide Y in cancer biology. A Cancer types known to express NPY and/or its receptors. B Potential direct effects of NPY on cancer cells. C Processes regulated by NPY in the cancer microenvironment. D Systemic effects of NPY that can affect cancer development and progression (figure created using Biorender)

Fig. 5

NPY receptors in pediatric tumors. A Neuroblastoma—poorly differentiated, chemonaive tumor with strong and diffuse expression of Y2R. Y5R expression within the neoplastic cells is generally low, while high Y5R levels are seen in the endothelial cells and neuroblasts accumulated around blood vessels (200 ×). B Post-treatment chemoresistant neuroblastoma showing strong Y5R expression (200 ×). C Chemonaive Ewing sarcoma with strong Y5R expression (400 ×)

Fig. 6

NPY system in breast cancer. A Ductal carcinoma in situ of the breast—NPY with low and intermediate cytoplasmic expression, and intermediate Y5R expression in the preinvasive cells (400 × , 200 ×). B Invasive ductal carcinoma of the breast showing intermediate NPY and Y5R immunoreactivity in the cancer cells (400 ×). C Breast cancer metastasis to the bone with intense Y1R immunostaining (400 ×)

Fig. 7

NPY system in prostate cancer. A NPY staining is low and mostly membranous in the normal prostatic glands, while cancer cells exhibit strong and cytoplasmic immunoreactivity (200 ×). B NPY expression with gradient increasing toward the tumor invasive front and perineural invasion of the prostate cancer (100 ×). C Cancer cells infiltrating ganglion present with NPY staining comparable or higher than that observed in neuronal cells (400 ×). D–F NPY receptors within the prostate cancer in localized (Y1R, Y2R), and metastatic (Y5R) stages (100 × , 400 × , 400 × , respectively)

Fig. 8

NPY-positive cells in stomach cancer. Poorly-cohesive gastric cancer with heterogeneous NPY expression in the subsets of the infiltrating neoplastic cells (200 × , 400 ×)