Chemotherapy and radiotherapy are, unfortunately, unspecific antitumor treatments currently used in clinical practice. Both treatments lead to severe side effects (e.g., radiotherapy can damage healthy tissues); thus, new antitumor strategies are urgently needed. Peptidergic systems are involved in cancer progression and regulate crucial roles such as cell proliferation, migration, and angiogenesis ^[1][2][1,2]. In this sense, the knowledge of the roles played by the substance P/neurokinin-1 receptor system in cancer progression has been dramatically increased in recent years and, according to critical findings, the repurposing of aprepitant (a neurokinin-1 receptor antagonist currently used in clinical practice as an antiemetic) as an antitumor agent has been proposed ^[2][3][2,3]. One essential difference between normal and cancer cells is the expression of peptide receptors ^[2][4][2,4]. Compared with normal cells, these receptors are generally overexpressed in cancer cells, and this crucial observation opens the door to developing specific antitumor strategies alone (e.g., using peptide receptor antagonists) or combined with chemotherapy or radiotherapy ^[2][4][5][6][2,4,5,6]. Accordingly, peptide–drug conjugates can be used as a targeted antitumor therapy against cancer cells overexpressing peptide receptors [4]. This therapeutic strategy could avoid the administration of compounds showing no selectivity against tumor cells, as unfortunately occurs with chemotherapeutic agents.

On the contrary, due to the overexpression of peptide receptors and through targeted antitumor therapy (peptide–drug conjugates), selective drug delivery (e.g., cytotoxic molecules, radionuclides) can be achieved ^[4][6][4,6]. A tumor-to-normal peptide receptor expression ratio of 3/1 or higher is required to achieve selective drug delivery into tumors, whereas healthy tissues are spared [4]. The peptide–drug conjugate strategy is used for cancer diagnosis and treatment. For example, primary tumors and metastatic sites were observed in breast cancer patients treated with a technetium-99 m labeled [F7, P34]-NPY (neuropeptide Y) conjugate, but no peptide uptake was observed in healthy individuals [7]. This finding shows the high specificity of the peptide–drug conjugate strategy; hence, this research line must be potentiated and developed in the future.

Another crucial research line must be thoroughly investigated: using peptide receptor antagonists as antitumor drugs [2]. These antagonists are known to block tumor cell proliferation and migration, angiogenesis, and promote the death of tumor cells by apoptosis ^[2][8][9][2,8,9]. This is a more straightforward antitumor strategy than using peptide–drug conjugates because, to synthesize these conjugates, the cytotoxic agents must be linked to the peptides. In addition, the administration of NPY receptor antagonists showed no severe side effects in both experimental animals and humans [10]. 

The NPY family in mammals forms a system of three homologous peptides with diverse functions: NPY, expressed in the brain and gut, and PYY and PP, only present in the digestive system [11]. These hormones bind to and activate a group of YRs ^[12][13][12,13], building a complex gut–brain molecular network influencing numerous physiological events related to food intake, energy balance, glycemia homeostasis, pain, bone metabolism, cardiovascular function, stress, anxiety, and cell growth and proliferation ^{[14][15][16][17][18]}[14,15,16,17,18].

NPY is a neurotransmitter or modulator with a sequence of 36 amino acids determined approximately three decades ago [19]. Dipeptidyl peptidase-4 (DPP-4) hydrolyzes NPY to generate its N-terminal truncated NPY3-36 product, a selective Y2R agonist [20]. The polypeptide appearance extends through the brain–gut axis (enteric neurons, primary afferent neurons, and several brain areas and neuronal pathways) [21] and exerts biological activity by binding to all YRs in human cells.

The human gene hNPY on chromosome 7p15.3 encodes a pro-NPY polypeptide containing the 36 amino acid sequence corresponding to NPY. Posttranslational modification of pro-NPY consists of a hydrolytic cleavage to separate the N-terminal signal peptide and the C-flanking peptide and the amidation of the C-terminal tyrosine to liberate the mature sequence of NPY [22]. Among the gene variants described for the NPY gene, the substitution of leucine in position 7 of the signal peptide to proline (variant rs780799208) is associated with high alcohol consumption and cardiovascular pathologies ^[22][23][22,23].

Enteroendocrine nutrient-sensing L-cells in the ileum and colon secrete polypeptide PYY1-36 after meals ^[24][27]. It is also produced in the central nervous system ^[18][25][18,28]. The 36 amino acid sequence of PYY was first determined in PYY isolated from the porcine intestine [19]; following hydrolysis by dipeptidyl peptidase-4 (DPP-4), its product is the N-terminal truncated PYY3-36 ^[26][29]. Both peptides circulate in the bloodstream to participate in the gut–brain axis controlling many different physiological processes. The complete form of PYY has an affinity for all human Y1R, Y2R, Y4R, and Y5Rs, whereas PYY3-36 exhibits high specificity for Y2R ^[27][30]. Degradation products of PYY peptides after cleavage of C-terminal residues are under study to determine possible metabolic roles ^{[18][28][29][30]}[18,31,32,33].

The endocrine pancreas secretes pancreatic polypeptide (PP), a hormone involved in the gut–hypothalamic axis control of satiety and appetite ^[31][34]. It exhibits a selective affinity for Y4R [12]. PP is the first identified and characterized peptide of the NPY family ^[32][35]. Both peptidases DPP-4 and neprilysin (NEP) rapidly degrade the molecule, which has a short life once released into the bloodstream ^[33][36].

The human gene hPYY on chromosome 17 (17q21.1) encodes two functional peptides, PYY (36 amino acids) and the amino-truncated shorter form PYY3-36 (34 amino acids) ^[34][35][37,38], after proteolytic processing of the encoded 97 amino acid propeptide [22]. Both PYY peptides, NPY and PP, share high sequence identity and an identical pentapeptide with an amidated tyrosine at the C-terminal end.

On chromosome 17, around 10 kb apart from the hPYY gene, the hPPY, a tandem duplication of the hPYY gene, encodes the pancreatic polypeptide (PP) and pancreatic icosapeptide ^[11][36][37][11,39,40].

The NPY polypeptides and their receptors build a piece of complex molecular machinery. They all have a 36 amino acid sequence length and an amidated C-terminal tyrosine. A commonly denominated PP-fold (hairpin structure) tertiary structure consisting of an N-terminal extended polyproline-like helix and a C-terminal alpha helix in PPY and PP delineating a hydrophobic pocket determines their binding to specific Y receptors and their consequent bioactivity ^[38][39][40][43,44,45]. In contrast, the structure of NPY slightly differs from the other two members since its N-terminal domain appears disordered ^[38][43]. In humans, four functional Y receptor types, Y1R, Y2R, Y4R, and Y5R, broadly distributed in the central, peripheric nervous system and other tissues, process the signaling of this group of peptides. The affinities and potencies of the NPY family peptides are different for the four mentioned receptors [12]. This family of receptors controls food intake and obesity, stress, anxiety, and cancer development ^{[1][41][42][43]}[1,46,47,48]. Researchers next describe the principal features of the architecture, dynamics, and signaling of this family of human receptors belonging to the G-protein-coupled receptors (GPCR), type A.

The neuropeptide Y receptor 1 (Y1R) is a 384 amino acid membrane protein with affinity for the main NPY peptides in the following rank order: NPY > PYY > PYY3-36 > PP. Posttranslational modifications of the protein include glycosylation of Asn 2, 11, and 17, a disulfide bridge between Cys113 and Cys198, a lipidation site on Cys338, and a phosphorylated Ser368 (UniProt, P25929 ^[22][44][22,49]). Its sequence extends through the plasma membrane with seven transmembrane domains.

Structural analysis of Y1R bound to NPY and a G-protein (active conformation) by cryo-electron microscopy ^[45][46][50,51] and of Y1R antagonist UR-MK299 (inactive conformation) by X-ray diffraction [16] has provided detailed information on how the ligands interact with the receptor protein. Analysis of differences in the binding mode of natural agonists and antagonists contributes to better ascertaining the receptor’s molecular dynamics. The functional study of mutations and molecular dynamics simulations also add valuable information concerning the inactive state structure and how the natural agonists activate the receptor by recruiting a G-protein transducer. The C-terminal unstructured tail of NPY enters deeply into the protein and interacts with a pocket conformed by the transmembrane domains TM3, TM4, TM6, and TM7. The amphipathic helix wobble connects with the extracellular domains of Y1R. Given its disordered and flexible structure, the binding coordinates of the N-terminal region of NPY are more challenging to determine ^[45][50]. The conformational flexibility of NPY allows the binding to different YRs by adapting its structure to the receptors ^[46][51].

Upon binding, NPY forces an outward displacement of TM7, opens the binding site ^[45][50], and induces conformational changes consisting of rearrangements of some receptor residues that lead to recruiting a G-protein, triggering receptor activation.

The neuropeptide Y receptor 2 (Y2R) is a 381 amino acid membrane protein with affinity for the NPY peptides in the following rank order: PYY > NPY > PYY3-36 > PP. Posttranslational modifications of the protein include glycosylation of Asn 11, a disulfide bridge between Cys123 and Cys203, a lipidation site on Cys342, and a phosphorylated Ser at 251, 351, 369, and 374 positions (UniProt, P49146 ^[22][44][22,49]). Its sequence extends through the plasma membrane with seven transmembrane domains.

The structure of an engineered crystal of Y2R copurified with the specific antagonist JNJ-31020028 ^[46][51] provided conformational and functional data indicating that the binding of the antagonist forces inward and outward movements of transmembrane domains II and VI and suggests that the complex Y2R-JNJ-31020028 adopts an inactive state conformation similar to the idle state described for Y1R [16].

Y2R with two mutated positions, namely H1943.51Y and S2806.47C (superscripts depict Ballesteros–Weinstein numbers), was complexed to natural ligands NPY and PYY3-36 to analyze its structure by cryo-electron microscopy. Additional molecular dynamics calculations, functional studies, and bioluminescence resonance energy transfer (BRET) studies revealed important details concerning unique features of the binding of peptide PYY3-36, receptor activation states, and coupling mechanisms to transducers ^[47][53]. Peptide binding to Y2R disturbs a polar interaction between Q1303.32 and H3117.39, establishing hydrogen bonds with the ligand amidated Tyr36. These movements displace other amino acid residues and finally conform the ligand pocket within Y2R. Cryo-electron maps of NPY bound to Y2R coupled to heterotrimeric Gi protein show that the C-terminal pentapeptide inserts deep into the Y2R structure, forcing the α-helix to incline toward the N-terminal domain establishing contact with extracellular domains 2 and 3. The N-terminal region accommodates the outer part of receptor helix 5 ^[46][51]. Additionally, toggle residue W6.48 interacting with the ligand C-terminal residue Y36 seems to influence the Y2R-dependent activation of transducers Gi and β-arrestin ^[48][54]. These studies’ principal structural dynamics results are essential to ascertain the molecular basis of ligand–receptor interactions applied to decipher the pathophysiological role fully and to rational and successful drug design.

The neuropeptide Y receptor 4 (Y4R) is a 375 amino acid membrane protein with affinity for the NPY peptides in the following rank order: PP > PYY > NPY > PYY3-36. Posttranslational modifications of the protein include glycosylation of Asn 2, 19, 29, and 187, a disulfide bridge between Cys114 and Cys201, and a lipidation site on Cys340 (UniProt, P50391, ^[22][44][22,49]). Its amino acid sequence extends through the plasma membrane with seven transmembrane domains.

PP prefers Y4R over other YRs. Calculating binding energies from molecular dynamics simulation and docking analysis showed that PYY binds Y4R with a higher affinity than Y2R ^[49][57]. Based on the structure of PP, synthesized short peptides with modifications and amino acid substitutions have provided relevant information concerning the binding mode and activity. One fact is that the C-terminal amidated end is essential for binding and activity ^[50][58]. Short-cycled peptides with carbamoylated arginines or arginines substituted with N-acylated ornithine exhibit better affinities and selectivities for Y4R and serve as a reference for better defining binding sites and compounds with agonist, partial agonist, and antagonist properties ^[51][59].

Cryo-electron microscopy studies of the complex formed by Y4R-Gi heterotrimeric protein-PP report the extensive peptide site delimited by the extracellular loops and transmembrane domains 2 to 7. The carboxy end of PP (Y36-T32) penetrates deep within the packed receptor structure ^[52][55].

The stereoisomer (S)-VU0637120 is a synthetic antagonist that selectively inhibits Y4R activation by a negative allosteric mechanism ^[53][56]. The compound occupies a site within the receptor structure defined by specific principal interactions with amino acids in transmembrane domains 1, 2, 3, 4, and 7. Additionally, the extracellular loop 2 (ECL2) plays a vital role in the allosteric regulation performed by the antagonist. Both binding sites slightly overlap according to docking and mutagenesis studies ^[53][56]. The definition of orthostatic and allosteric sites within Y4R offers vital information for designing selective allosteric agonists and modulators, permitting fine-tuned regulation of altered Y4R activity.

The neuropeptide Y receptor 5 (Y5R) has 445 amino acids. The affinity of Y peptides for Y5R is higher for NPY, followed by PYY and PP (NPY > PYY > PP) ^[54][60]. Posttranslational modifications of the protein include glycosylation of Asn 10 and 17, a disulfide bridge between Cys114 and Cys198, and a lipidation site on Cys442 (UniProt, Q15761, ^[22][44][22,49]. Its sequence extends through the plasma membrane with seven transmembrane domains.

The AlphaFold method ^[55][61] allows the prediction of a protein structure with the serpentine arrangement disposed within the plasma membrane [22]. Additionally, a structural model of the interaction of NPY with Y5R based on computational and biochemical analysis places the peptide close to the ECL3, with the alpha-helical domain wrapping the ECL1. The peptide is secured through a hydrophobic grouping formed by L4.69, L5.24, L24, and I28 ^[56][62]. Mutagenesis studies provided fundamental ligand–receptor interactions with R25 and D2.68 and R33 with D6.59 ^[57][63]. Further structural determination of Y5R by X-ray diffraction, NMR, or cryo-electron microscopy will permit us to better define the binding site for agonists, antagonists, and allosteric modulators, as well as the molecular movements responsible for its activation or dormant states.

The functional diversity of this multi-receptor multiligand system comes from tissue localization and abundance, together with receptor structural features that adapt to the natural ligands in different ways and determine their signaling profile. It also depends on the Y receptors’ biased signaling mechanisms when triggered by the NPY family of peptides and the cross-talk with other receptor systems ^[47][58][59][53,64,65].

Peptide binding activates YRs, which, through differentiated transduction mechanisms, trigger biochemical events leading to metabolic changes, adaptations, and gene expression modulations, eventually contributing to functional cell metabolism homeostasis, cell growth, motility, and migration ^{[13][60][61][62][63]}[13,66,67,68,69].

Human YRs activate transducers, heterotrimeric G proteins, and β-arrestins, resulting in diversified intracellular signaling pathways. YRs 1, 2, and 5 preferentially turn on Gi/o alpha subunits and inhibit cyclic adenosine monophosphate (cAMP) formation. Gi/o may also regulate the activity of plasma membrane K⁺ and Ca²⁺ ion channels. Y2R and Y4R stimulate Gq/11 alpha subunit dissociation to increase intracellular calcium levels and protein kinase C (PKC) activation ^[54][60]. YR signaling routes may coexist and connect with other receptor-triggered pathways turning on downstream biochemical signaling changes and leading to adaptive changes controlling cell behavior ^{[64][65][66][67][68][69][70][71]}[70,71,72,73,74,75,76,77].

Determining and quantifying the conformational landscape of YR impacts activating defined signaling events is capital to designing new drugs that may interfere with excessive functional or non-functional receptor states and control their role in biochemical mechanisms leading to disease ^[72][78]. Additionally, analyzing the mechanisms underlying receptor activation and desensitization will aid the chemical design of effective drugs to control YR biochemical behavior ^[73][79].

3. Involvement of Neuropeptide Y, Peptide YY, and Pancreatic Polypeptide in Cancer

NPY has been negatively correlated with COL5A1, COL3A1, and COL4A1 collagen gene expressions in a pan-cancer study ^[74][80]. NPY promoted an antinociceptive effect that was inhibited with Y1R or Y2R antagonists (BIBO3304 and BIIEo246, respectively), and the peptide was upregulated in cancer-induced bone pain ^[75][81]. NPY induced inflammation-induced tumorigenesis by promoting epithelial cell proliferation (intestinal epithelial T84 cell line) ^[76][82], and the peptide, through the phosphatidyl-inositol-3-kinase (PI3K)-β-catenin signaling, was involved in this proliferation, decreased apoptosis and p21 expression, increased c-myc/cyclin D1 expressions and inhibited miR-375 expression (apoptosis regulating microRNA) ^[76][82]. NPY also favored, through the p38 mitogen-activated protein kinases (MAPK) and extracellular signal-regulated protein kinase (ERK), the migration of human monocyte-derived immature dendritic cells as well as their transendothelial migration ^[77][83]. Y1R mediated these actions. However, by upregulating interleukins 6 and 10, NPY promoted a T helper 2 polarizing profile to dendritic cells ^[77][83]. This fact means that NPY, via Y1R, can exert a pro-inflammatory action (immature dendritic cell recruitment) or an anti-inflammatory effect (favoring a T helper 2 polarization). NPY also linked longevity and dietary restriction in experimental animal models, and spontaneous tumors were attenuated in NPY-null animals ^[78][84]. Table 1 summarized the participation of NPY, PYY, and PP in the development of many cancer types.

Tumor	NPY-PYY-PP
Brain	Y1R high expression [79][86]. Y2R high expression: glioblastoma (grade IV) [80][88]. Medulloblastomas, meningiomas, and primitive neuroectodermal tumors: Y1R/Y2R expressions [80][88]. Astrocytomas (grades I to III): Y2R expression [80][88]. Higher NPY levels in differentiated tumors than in poorly differentiated neurological tumors [81][89]. Cerebellar hemangioblastoma: PYY expression [82][92].
Breast	Higher Y1R gene expression predicts a better relapse-free survival/overall survival in estrogen receptor-positive cancer patients [83][98].
	High Y1R level positively correlated with lymph node metastasis/clinical stage. Patients with Y1R expression: shorter cancer-specific survival [84][100]. High Y1R expression is associated with metastasis, advanced stages, poor Nottingham prognostic index, and perineural invasion [85][101]. Primary human breast tumors/breast cancer-derived metastases: Y1R overexpression [6]. Normal human breast tissues: Y2R expression [6]. Y5R mediates tumor cell growth and migration [10][86][10,94]. NPY favors proliferation/migration and angiogenesis [86][87][93,94]. NPY blocks cAMP accumulation and promotes ERK phosphorylation and tumor cell migration [88][97]. Y5R antagonists inhibit cell growth and migration and induce the death of tumor cells expressing Y5R [88][97]. Y5R agonists favor VEGF release from tumor cells, favoring angiogenesis [87][93]. PYY blocks tumor cell growth [89][90][91][110,111,112]. PYY/vitamin E co-administration: higher antitumor action [90][111]. PYY decreases the cAMP level [89][110].
Cholangiocarcinoma	Higher NPY levels in the center of tumors than in the invasion fronts [92][113]. NPY blocks tumor cell growth/invasion; both effects are counteracted with anti-NPY antibodies [92][113]. Y2R inhibitors, but not Y1R/Y5R inhibitors, inhibited tumor cell proliferation blockade mediated by NPY [92][113].
Colorectal	NPY gene methylation: a biomarker for metastatic progression [93][94][95][96][97][115,116,117,119,120]. Plasma NPY decrease: associated with tumor size/body weight loss [98][114]. NPY/Y2R overexpression. Y2R antagonists block tumor growth [99][121]. NPY favors angiogenesis [99][121]. Blood vessels considerably altered histologically [100][124]. Rectal tumors express PYY/PP [101][126]. A low PYY level indicates malignant potential [102][129]. PYY overexpression blocks proliferation, migration/invasion of tumor cells, favoring apoptosis [103][131]. Patients with colon cancer: higher PP level [104][134]. PP is released from tumor cells [105][136].
Esophageal	PYY3-36 promotes apoptosis and blocks tumor cell growth [106][137].
Ewing sarcoma	Plasma NPY level: high and higher in patients with tumors from a pelvic/bone origin [107][146]. Intratumoral blood vessels: Y1R expression [108][139]. NPY, Y1R, and Y5R expressions and NPY favor tumor cell death [10][108][109][110][10,138,139,140]. NPY3-36 favors tumor cell migration and angiogenesis [10][110][10,140]. Hypoxia: NPY acts as a tumor growth-promoting agent [10][110][10,140]. Hypoxia counteracts the growth-inhibitory pathway mediated by Y1R/Y5R [109][110][138,140]. Hypoxia: Y2R expression in intratumoral endothelial cells. Y2R antagonists decrease tumor vascularization [10].
	NPY/Y5R upregulated in distant metastasis. Y5R blockade counteracts bone metastasis and polyploidization [111][145]. Bone destruction degree: positively correlated with NPY release from tumors [112][144].
Gastric	Experimental model: high serum/tumor tissue PYY levels [113][147]. High plasma PP level [114][148].
Hemangioma	NPY in cells expressing Y1R [115][149].
Head and neck	NPY gene promoter methylation status: a biomarker for tumor prognosis/risk [116][150].
Kidney	Renal cell carcinoma: Y1R expression [117][151]. Nephroblastoma: Y1R/Y2R expressions [117][151]. Intratumoral blood vessels: high Y1R density [117][151]. Nerve fibers containing NPY are close to blood vessels/tumor cells [117][151]. Primary neuroendocrine carcinoma: PP in cancer cells [118][153].
Leukemia	Children with B-cell precursor leukemia: high plasma NPY level [119][154]. Children with high plasma NPY levels: better outcomes than those showing a normal level [119][154]. NPY, via Y1R, activates ERK [120][155]. NPY did not activate p38MAPK, jun N-terminal kinase, PKC, and phospholipase D [120][155]. NPY13-36 blocks intracellular Ca++ increase mediated by NPY [121][157].
Liver	NPY, via Y1R, blocks tumor cell growth [122][159]. Protein/mRNA Y1R level decrease [122][159]. Low Y1R expression: associated with poor prognosis [122][159]. Knockdown of Y1R: increase in tumor cell proliferation [122][159]. NPY/Y5R is involved in tumor cell proliferation, migration/invasion [123][160]. Increased Y5R expression correlated with survival and tumor growth [123][160]. NPY decreases PD-1+ T cells/PD-1 expression/cell in T cells and augments T cell proliferation and tumor cell eradication [124][162]. PYY blocks tumor cell growth, volume/weight, and cAMP level [125][164].
Lung	NPY gene expression upregulated in patients with TP53 mutation [126][165]. High PYY/PP levels [127][128][129][130][166,167,168,169].
Melanoma	Higher NPY expression in melanoma than in melanocytic nevi or nodular melanoma [131][170]. Melanoma metastases and lentigo malign melanomas: no NPY expression [131][170]. High NPY expression is associated with invasiveness [131][170]. Y2R antagonist BIIE0246: decrease in tumor weight and angiogenesis [132][171]. Tumors of sympathectomized animals: NPY gene expression and hypoxic and apoptotic factors increase [133][172]. Uveal melanoma: Y6R gene expression associated with tumor development and used as a biomarker [134][173]. Low NPY expression is associated with high cell proliferation [135][174]. High NPY expression is linked to better outcomes [135][174].
Neuroblastoma	High serum NPY levels correlated with relapse, metastasis, and poor survival [136][188]. ProNPY processing is associated with poor outcomes/clinically advanced stages [137][189]. NPY/Y1R/Y2R/Y4R/Y5R expression [138][178]. NPY favors cancer cell proliferation [10][139][10,175]. NPY increases the survival of tumor cells by exerting an anti-apoptotic effect [140][141][190,191]. NPY, via Y2R, promotes the proliferation of endothelial cells and increases vascularization; Y2R antagonists, but not Y5R antagonists, decrease vascularization [10][139][142][10,175,179]. Ganglioneuroblastoma: NPY expression [143][177]. NPY release is stimulated by protein kinase C-coupled M3 muscarinic receptors [144][145][180,181]. 17 beta-estradiol favors Y1R gene transcription [146][182]. Valproate increases NPY expression [147][187]. BDNF promotes NPY/Y5R expressions that are positively correlated with TrkB expression [10][148][10,185]. High TrkB expression correlated with a worse prognosis [10]. Retinoic acid decreases NPY gene expression and YR expression [149][150][183,184]. The Y2R antagonist BIIE0246 inhibits MAPK activation, decreases cell proliferation, promotes apoptosis, and exerts an anti-angiogenic action [10][139][142][10,175,179]. Y2R mediates glycolysis [151][186]. Chemotherapy: increase in Y5R expression [148][185]. Y5R blockade: promotes apoptosis in tumor cells and sensitizes resistant cancer cells to chemotherapy [148][185]. Metastasis is associated with a high NPY release [62][68]. NPY promotes motility and invasiveness in tumor cells [62][68]. Y5R is highly expressed in migratory cells [62][68].
Ovarian	Y1R/Y2R expressions [42][47]. NPY exerts a protective action against cisplatin [152][197]. PYY expression [153][154][155][198,199,200].
Pancreatic	NPY/Y1R expressions and Y2R overexpression [156][201]. NPY promotes tumor cell growth [157][202]. NPY released from tumors: high serum NPY level [158][203]. PYY decreases the growth/cAMP level in tumor cells [159][160][206,207]. BIM-43004-1 (PYY22-36 Y2R synthetic agonist): decreases tumor cell growth and cAMP level [160][161][207,208]. PYY14-36 exerts the highest antitumor action [162][209]. PYY/vitamin E co-administration: increase in antitumor action [163][210]. PYY increased the growth of Capan-2 tumor cells [157][202]. PP is located in the pancreatic head region and insulinoma [164][213]. Pancreatic ductal adenocarcinoma: low plasma PP level [165][211]. Endocrine pancreatic tumor: elevated plasma PP level [166][212]. Pancreatic neuroendocrine tumor: high PP level and peptide release [167][168][215,216]. Carbachol promotes PP release from tumor cells [169][219].
Parathyroid adenoma	Some tumors show numerous NPY nerve fibers, whereas others have a few scattered NPY fibers [170][221].
Pheochromocytoma	High plasma NPY level [171][222]. Plasma NPY increased during surgical tumor removal; the level remained high until tumor resection [172][223]. Y1R/Y2R/Y5R expressions [10]. Adrenal pheochromocytoma: NPY1-36 is the predominant molecule found in plasma/tissue [171][222]. Extra-adrenal pheochromocytoma: many NPY fragments [171][222]. NPY mRNA expression is more frequently observed in adrenal than in extra-adrenal tumors [171][222]. NPY mRNA level increased when tumor cells were treated with nerve growth factor, protein kinase modulators (Bu)(2)cAMP, or staurosporine, but it was reduced when treated with dexamethasone or insulin-like growth factor II [173][227]. NPY expression is not associated with malignancy [173][227]. NPY release from tumor cells: nitric oxide, bradykinin, and angiotensin II favor its release, and dopamine blocks NPY release [174][175][176][177][178][228,229,230,231,232]. NPY promotes left ventricular hypertrophy [179][226]. Plasma NPY level is higher in patients with left ventricular hypertrophy [179][226].
Pituitary adenoma	Protein/mRNA NPY and mRNA Y1R/Y2R expressions [180][181][234,235]. Positive correlation between Y2R and NPY level [180][234]. NPY favors growth hormone release and blocks prolactin release [182][183][236,237]. NPY not detected in normal pituitary cells [181][235].
Prostate	Low NPY expression is associated with aggressive grade, higher genomic risk, and shorter metastases-free survival/progression-free survival [184][238]. Transcriptional changes in ERG rearrangement-positive cancer cells promote metabolic changes by activating metabolic signaling molecules such as NPY [185][240]. Plasma NPY level: biomarker [186][241]. NPY, Y1R, Y2R and Y5R upregulation [187][242]. Y1R/Y5R: high expression in bone metastases [187][242]. NPY, released from nerve terminals, regulates therapy resistance and oncogenesis [188][243]. NPY blockade: increased apoptosis in cancer cells, changes in energetic metabolic pathways, and decreased cell motility [188][243]. NPY decreases tumor cell proliferation (DU145 and LNCaP cells) or promotes cell proliferation (PC3 cells): actions mediated by Y1R [189][244]. Depression favors NPY release from tumor cells, and NPY recruits myeloid-derived suppressor cells [190][191][246,247]. PYY blocks tumor cell growth and increases VEGF production in tumor cells [192][248].
Thymus	NPY expression [193][249].