neuropeptide-y and Colorectal-Neoplasms

Currently available data on the involvement of neuropeptide Y (NPY), peptide YY (PYY), and pancreatic polypeptide (PP) and their receptors (YRs) in cancer are updated. The structure and dynamics of YRs and their intracellular signaling pathways are also studied. The roles played by these peptides in 22 different cancer types are reviewed (e.g., breast cancer, colorectal cancer, Ewing sarcoma, liver cancer, melanoma, neuroblastoma, pancreatic cancer, pheochromocytoma, and prostate cancer). YRs could be used as cancer diagnostic markers and therapeutic targets. A high Y1R expression has been correlated with lymph node metastasis, advanced stages, and perineural invasion; an increased Y5R expression with survival and tumor growth; and a high serum NPY level with relapse, metastasis, and poor survival. YRs mediate tumor cell proliferation, migration, invasion, metastasis, and angiogenesis; YR antagonists block the previous actions and promote the death of cancer cells. NPY favors tumor cell growth, migration, and metastasis and promotes angiogenesis in some tumors (e.g., breast cancer, colorectal cancer, neuroblastoma, pancreatic cancer), whereas in others it exerts an antitumor effect (e.g., cholangiocarcinoma, Ewing sarcoma, liver cancer). PYY or its fragments block tumor cell growth, migration, and invasion in breast, colorectal, esophageal, liver, pancreatic, and prostate cancer. Current data show the peptidergic system's high potential for cancer diagnosis, treatment, and support using Y2R/Y5R antagonists and NPY or PYY agonists as promising antitumor therapeutic strategies. Some important research lines to be developed in the future will also be suggested.

Topics: Breast Neoplasms; Colorectal Neoplasms; Humans; Liver Neoplasms; Male; Neoplasm Recurrence, Local; Neuroblastoma; Neuropeptide Y; Pancreatic Neoplasms; Peptide YY; Prostatic Neoplasms; Receptors, Neuropeptide Y; Sarcoma, Ewing

In oncology, liquid biopsy is of major relevance from theranostic point of view. The searching for mutations in circulating tumor DNA (ctDNA) in case of colorectal cancers (CRCs) allows the optimization of patient care. In this context, independent of mutation status biomarkers are required for its detection to confirm the presence of ctDNA in liquid biopsies. Indeed, the hypermethylation of NPY and WIF1 genes appear to be an ideal biomarker for the specific detection of ctDNA in CRCs. The objective of this work is to develop the research of hypermethylation of NPY and WIF1 by Crystal Digital PCR™ for the detection of ctDNA in CRCs.. Detection of hypermethylated NPY and WIF1 was developed on Cristal digital PCR™. Biological validation was performed from a local cohort of 22 liquid biopsies and 23 tissue samples from patients with CRC. These patients were treated at the University Hospital of Besancon (France).. The local cohort study confirmed that NPY and WIF1 were significantly hypermethylated in tumor tissues compared to adjacent non-tumor tissues (WIF1 p < 0.001; NPY p < 0.001; non-parametric Wilcoxon paired-series test). Histological characteristics, tumor stages or mutation status were not correlated to the methylation profiles. On the other hand, hypermethylation of NPY or WIF1 in liquid biopsy had a 95.5% [95%CI 77-100%] sensitivity and 100% [95%CI 69-100%] specificity.. Using Crystal digital PCR™, this study shows that hypermethylation of NPY and WIF1 are constant specific biomarkers of CRCs regardless of a potential role in carcinogenesis.

Topics: Adaptor Proteins, Signal Transducing; Adult; Aged; Aged, 80 and over; Circulating Tumor DNA; Colorectal Neoplasms; Confidence Intervals; DNA Methylation; Female; Genetic Markers; Humans; Liquid Biopsy; Male; Middle Aged; Neuropeptide Y; Polymerase Chain Reaction; Sensitivity and Specificity

Circulating tumor DNA (ctDNA) has emerged as a good candidate for tracking tumor dynamics in different cancer types, potentially avoiding repeated tumor biopsies. Many different genes can be mutated within a tumor, complicating procedures for tumor monitoring, even with highly sensitive next-generation sequencing (NGS) strategies. Droplet-based digital PCR (dPCR) is a highly sensitive and quantitative procedure, allowing detection of very low amounts of circulating tumor genetic material, but can be limited in the total number of target loci monitored.. We analyzed hypermethylation of 3 genes, by use of droplet-based dPCR in different stages of colorectal cancer (CRC), to identify universal markers for tumor follow-up.. Hypermethylation of WIF1 (WNT inhibitory factor 1) and NPY (neuropeptide Y) genes was significantly higher in tumor tissue compared to normal tissue, independently of tumor stage. All tumor tissues appeared positive for one of the 2 markers. Methylated ctDNA (MetctDNA) was detected in 80% of metastatic CRC and 45% of localized CRC. For samples with detectable mutations in ctDNA, MetctDNA and mutant ctDNA (MutctDNA) fractions were correlated. During follow-up of different stage CRC patients, MetctDNA changes allowed monitoring of tumor evolution.. These results indicate that MetctDNA could be used as a universal surrogate marker for tumor follow-up in CRC patients, and monitoring MetctDNA by droplet-based dPCR could avoid the need for monitoring mutations.

Topics: Adaptor Proteins, Signal Transducing; Aged; Biomarkers, Tumor; Colorectal Neoplasms; DNA Methylation; DNA, Neoplasm; Female; Humans; Male; Neuropeptide Y; Polymerase Chain Reaction; Repressor Proteins

DNA methylation is a well-known epigenetic mechanism involved in epigenetic gene regulation. Several genes were reported hypermethylated in CRC, althought no gene marker was proven to be individually of sufficient sensitivity or specificity in routine clinical practice. Here, we identified novel epigenetic markers and assessed their combined use for diagnostic accuracy.. We used methylation arrays on samples from several effluents to characterize methylation profiles in CRC samples and controls, as established by colonoscopy and pathology findings, and selected two differentially methylated candidate epigenetic genes (NPY, PENK). To this gene panel we added WIF, on the basis of being reported in literature as silenced by promoter hypermethylation in several cancers, including CRC. We measured their methylation degrees by quantitative multiplex-methylation specific PCR (QM-MSP) on 15 paired carcinomas and adjacent non-cancerous colorectal tissues and we subsequently performed a clinical validation on two different series of 266 serums, subdivided in 32 CRC, 26 polyps, 47 other cancers and 161 with normal colonoscopy. We assessed the results by receiver operating characteristic curve (ROC), using cumulative methylation index (CMI) as variable threshold.. We obtained CRC detection on tissues with both sensitivity and specificity of 100%. On serum CRC samples, we obtained sensitivity/specificity values of, e.g., 87%/80%, 78%/90% and 59%/95%, and negative predictive value/positive predictive value figures of 97%/47%, 95%/61% and 92%/70%. On serum samples from other cancers we obtained sensitivity/specificity of, e.g, 89%/25%, 43%/80% and 28%/91%.. We showed the potential of NPY, PENK, and WIF1 as combined epigenetic markers for CRC diagnosis, both in tissue and serum and tested their use as serum biomarkers in other cancers. We optimized a QM-MSP for simultaneously quantifying their methylation levels. Our assay can be an effective blood test for patients where CRC risk is present but difficult to assess (e.g. mild symptoms with no CRC family history) and who would therefore not necessarily choose to go for further examination. This panel of markers, if validated, can also be a cost effective screening tool for the detection of asymptomatic cancer patients for colonoscopy.

Topics: Adaptor Proteins, Signal Transducing; Adenocarcinoma; Aged; Aged, 80 and over; Biomarkers, Tumor; Case-Control Studies; Colorectal Neoplasms; DNA; DNA Methylation; Enkephalins; Female; Humans; Male; Middle Aged; Molecular Diagnostic Techniques; Multiplex Polymerase Chain Reaction; Neoplasm Staging; Neuropeptide Y; Promoter Regions, Genetic; Protein Precursors; Repressor Proteins; ROC Curve; Sequence Analysis, DNA

The perivascular innervation of arterioles in colorectal cancer and adjacent submucosa was investigated.. Neurotransmitter markers, neuropeptide Y (NPY), vasoactive intestinal peptide (VIP), substance P (SP), calcitonin gene-related peptide (CGRP) and tyrosine hydroxylase (TH), were studied and immunoreactivity was compared with that of control normal tissue.. There was absence of perivascular nerves within tumours and loss of perivascular innervation in the submucosa adjacent to the tumour. The pattern of loss varied for different transmitters. The loss was progressively greater with advancing tumour stage for NPY (controls 95%, Dukes' A 68%, Dukes>> B 13%, Dukes' C 6%) and VIP (50%, 23%, 20%, 17%). For TH there was extensive loss of innervation around tumours of all stages (69%, 5%, 7%, 0%). SP immunoreactive peri-arteriolar nerves were similar in control tissue (39%) and tissue adjacent to Dukes' A tumours (40%) but diminished to 19% and 0% in tissue adjacent to Dukes' B and C tumours, respectively. In none of the tissues was CGRP immunoreactivity above 4%. The mean distance over which there was reduced NPY immunoreactivity from the tumour edge was 2.43 mm for Dukes' A/B tumours compared with 7.20 mm for Dukes' C tumours; for VIP immunoreactivity this distance was 5.22 mm for Dukes' A/B tumours and 5.52 mm for Dukes' C tumours.. The progressive loss, both in terms of vascular nerve immunoreactivity and distance from the tumour edge with tumour grade, suggests that the tumour itself may influence neural integrity in perivascular plexuses, perhaps via the secretion of an inhibitory factor.

Topics: Aged; Aged, 80 and over; Arterioles; Biomarkers, Tumor; Calcitonin Gene-Related Peptide; Colon; Colorectal Neoplasms; Female; Humans; Male; Neoplasm Staging; Neuropeptide Y; Rectum; Substance P; Tyrosine 3-Monooxygenase; Vasoactive Intestinal Peptide

Specimens of the sigmoid colon were obtained from male and female patients (n = 11) with carcinoma of the colon or rectum and studied immunohistochemically for vasoactive intestinal polypeptide-, somatostatin-, substance P-, neuropeptide Y-, calcitonin gene-related peptide-, met- and leu-enkephalin-, 5-hydroxytryptamine-, and dopamine beta-hydroxylase-containing nerves. In the subdivisions of the submucous plexus (namely, Schabadasch's, Meissner's, and the intermediate plexuses), substance P- and vasoactive intestinal polypeptide-immunoreactive nerve fibers were the most numerous, and equal densities of these nerves were found in all three layers. In contrast, few neuropeptide Y-, met-enkephalin-, leu-enkephalin-, calcitonin gene-related peptide-, somatostatin-, 5-hydroxytryptamine-, and dopamine beta-hydroxylase-immunoreactive nerves were found in these regions. The nerve cell bodies of the submucous plexus contained vasoactive intestinal polypeptide, substance P, leu-enkephalin, somatostatin, and 5-hydroxytryptamine but not neuropeptide Y, met-enkephalin, calcitonin gene-related peptide, and dopamine beta-hydroxylase. Vasoactive intestinal polypeptide-containing nerve cell bodies were found in all three subdivisions. Substance P-, leu-enkephalin-, and somatostatin-immunoreactive nerve cell bodies were found in Schabadasch's plexus and the intermediate region of the submucous plexus, but they were absent from Meissner's plexus; 5-hydroxytryptamine-containing nerve cell bodies were only observed in Schabadasch's plexus. The possible function of the neuropeptide-, dopamine beta-hydroxylase-, and 5-hydroxytryptamine-containing neurons in the different layers of the submucous plexus is discussed.

Topics: Adult; Aged; Calcitonin Gene-Related Peptide; Colon, Sigmoid; Colorectal Neoplasms; Dopamine beta-Hydroxylase; Enkephalins; Female; Fluorescent Antibody Technique; Humans; Male; Middle Aged; Neurons; Neuropeptide Y; Neuropeptides; Serotonin; Somatostatin; Submucous Plexus; Substance P; Vasoactive Intestinal Peptide