neuropeptide-y and Neoplasm-Metastasis

Neurotransmitters are identified to be endogenous chemicals and act on neurons to transmit signals to each other or to a target cell across synapse. They are involved in many brain functions including analgesia, reward, food intake, metabolism, reproduction, social behaviors, learning, and memory. Recently, sympathetic nerve fibers were detected in many solid tumors including gastrointestinal cancer, supporting the idea that neural system has effects on tumor progression. Neurotransmitters were secreted from the sympathetic nerve fibers and subsequently infiltrated into tumor tissues. Further studies disclosed the different mechanisms of various kinds of neurotransmitters in the progression of carcinogenesis, including tumor cell proliferation, angiogenesis, and tumor invasion and metastasis. Neurotransmitters are mainly subdivided into four types, amino acids, monoamines, peptides, and others, each of which contains multiple chemicals. For this reason, we cannot describe each in detail. In this review, we will focus on several important neurotransmitters including tachykinis, neuropeptide Y, and b-adrenergic receptors. How they function and their crosstalks with the immune system in the progression, especially the metastasis of gastrointestinal cancer, will be described. Finally, we will summarize the clinical implications in the treatment of gastrointestinal cancer.

Topics: Adrenergic Fibers; Cell Proliferation; Disease Progression; Gastrointestinal Neoplasms; Humans; Neoplasm Invasiveness; Neoplasm Metastasis; Neovascularization, Pathologic; Neuropeptide Y; Neurotransmitter Agents; Receptors, Adrenergic, beta; Tachykinins

Ewing sarcoma (ES) develops in bones or soft tissues of children and adolescents. The presence of bone metastases is one of the most adverse prognostic factors, yet the mechanisms governing their formation remain unclear. As a transcriptional target of EWS-FLI1, the fusion protein driving ES transformation, neuropeptide Y (NPY) is highly expressed and released from ES tumors. Hypoxia up-regulates NPY and activates its pro-metastatic functions. To test the impact of NPY on ES metastatic pattern, ES cell lines, SK-ES1 and TC71, with high and low peptide release, respectively, were used in an orthotopic xenograft model. ES cells were injected into gastrocnemius muscles of SCID/beige mice, the primary tumors excised, and mice monitored for the presence of metastases. SK-ES1 xenografts resulted in thoracic extra-osseous metastases (67%) and dissemination to bone (50%) and brain (25%), while TC71 tumors metastasized to the lungs (70%). Bone dissemination in SK-ES1 xenografts associated with increased NPY expression in bone metastases and its accumulation in bone invasion areas. The genetic silencing of NPY in SK-ES1 cells reduced bone degradation. Our study supports the role for NPY in ES bone invasion and provides new models for identifying pathways driving ES metastases to specific niches and testing anti-metastatic therapeutics.

Topics: Animals; Bone Neoplasms; Brain Neoplasms; Cell Line, Tumor; Cell Movement; Culture Media, Conditioned; Disease Models, Animal; Female; Gene Silencing; Humans; Hypoxia; Lung Neoplasms; Mice; Mice, SCID; Neoplasm Metastasis; Neoplasm Transplantation; Neuropeptide Y; Oncogene Proteins, Fusion; Phenotype; Proto-Oncogene Protein c-fli-1; RNA-Binding Protein EWS; Sarcoma, Ewing

Neuroblastoma represents one of the most frequently developing malignant solid tumours in children. At the time of diagnosis, in more than half of the cases, metastatic cells are also present in the bone marrow. The present study was aimed at immunocytochemical analysis of selected neuropeptide manifestation in metastatic cells of neuroblastoma in bone marrow and at comparing the obtained results with the immunophenotype of parental neuroblastoma cells. The studies were performed on bone marrow material obtained from children treated at the Department of Paediatric Haematology and Oncology, University of Medical Sciences, Poznań, Poland, in 1998-2000. Immunocytochemical analysis of nervous tissue markers (employing the immunomax technique) involved 36 bone marrow preparations obtained from 27 children. The analysis included expression of neuron-specific enolase (NSE), PGP 9.5 protein, substance P (SP), chromogranin A (ChA), bombesin (B), galanin (G), neuropeptide Y (NPY) and vasoactive intestinal peptide (VIP). Close to 90% metastatic cells in bone marrow were found to exhibit NSE+SP+B+ phenotype and over a half of the cells manifested additionally expression of PGP 9.5+ChA+NPY+. Comparison of the obtained results with the immunophenotype of neuroblastoma cells obtained directly from the primary tumour demonstrated high correlation of NSE, SP and PGP 9.5 expression. Due to the relative ease of obtaining the bone marrow material and absence of neuromarkers in bone marrow metastatic cells in solid tumours other than neuroblastoma, determination of immunophenotype of the cells may represent a valuable supplementation in preliminary diagnosis of this tumour in children.

Topics: Adolescent; Biomarkers, Tumor; Biopsy, Needle; Bone Marrow; Child; Child, Preschool; Chromogranin A; Chromogranins; Female; Galanin; Humans; Immunohistochemistry; Immunophenotyping; Male; Neoplasm Metastasis; Neoplasm Staging; Neuroblastoma; Neuropeptide Y; Substance P; Vasoactive Intestinal Peptide

A case of a renin-producing paraganglioma of adrenal origin with metastases to the retroperitoneal area, paravaginal area, and the ovary is reported with immunohistochemical findings indicating expression of multiple neuropeptide immunoreactivities. The patient was 23 years old at the time of diagnosis, and died from metastatic spread of the tumor 7 years later.. Tumor tissue was examined by light microscopy, indirect immunohistochemistry, and electron microscopy.. The tumor tissue investigated contained several cells exhibiting opioid peptide-like immunoreactivities (i.e., enkephalin and dynorphin-like immunoreactivity [LI]). A lower number of cells displayed neuropeptide Y-, galanin-, somatostatin-, neurotensin-, substance P-, peptide histidine-isoleucine-, cholecystokinin-, renin-, and calbindin-LI.. To the authors' knowledge, galanin, dynorphin, peptide histidine-isoleucine, cholecystokinin, and calbindin have not been reported previously to occur in paraganglioma, and renin has been reported to occur very rarely. A review of recent literature suggest that enkephalin-, neuropeptide Y-, and somatostatin-like immunoreactivities may be useful as diagnostic markers for paragangliomas.

Topics: Adrenal Gland Neoplasms; Adult; Biomarkers, Tumor; Catecholamines; Enkephalins; Female; Humans; Immunohistochemistry; Neoplasm Metastasis; Neuropeptide Y; Neuropeptides; Pheochromocytoma; Renin; Somatostatin

Twenty patients, 16 males and 4 females, aged 11-76 yr, were treated for a metastatic pheochromocytoma at our institution between 1985 and 1990. A neurofibromatosis was associated in 4. Thirteen patients had a unilateral adrenal tumor, 3 had an extraadrenal retroperitoneal tumor, 2 had a bilateral adrenal pheochromocytoma, one had a unilateral tumor with a contralateral medullary hyperplasia and one an adrenal and an extraadrenal pheochromocytoma. Metastases occurred in all patients, at presentation in 11, 10 to 30 months later in 7, and 9 and 28 yr later, respectively in two. Histology did not afford conclusive evidence for malignancy. Catecholamine hyperproduction was present in all, predominantly affecting norepinephrine. Neuron Specific Enolase level was elevated in 11, Neuro-Peptide Y level in 9 and procalcitonin level in 11/18. High dopamine, methoxytyramine and homovanillic acid excretion levels seemed to correlate with large tumors or terminal stage. MIBG uptake was found in 16 after a diagnostic dose and in 1 only after a therapeutic dose. Surgery was performed on primary tumor in 18 and on distant metastase in 10. Iodine-131 MIBG therapy was performed in 11, among whom 9 were evaluable. Cumulative activity ranged from 100 to 711 mCi, in 1 to 6 courses. Symptomatic improvement occurred in 5 patients, stabilization was observed in 3 and tumor partial response in two, which lasted for 28 and 9 months, respectively terminating in a rapidly progressing disease with bone marrow involvement. Moderate myelosuppression occurred in 4 patients. Chemotherapy gave no response in 7 evaluable patients. Fourteen patients died with a median survival of 16 months from diagnosis of metastases (range 3-60). Response to therapy was poor and warrants further cooperative trials.

Topics: 3-Iodobenzylguanidine; Adolescent; Adrenal Gland Neoplasms; Adult; Aged; Antineoplastic Agents; Biomarkers, Tumor; Calcitonin; Calcitonin Gene-Related Peptide; Catecholamines; Child; Chromogranin A; Chromogranins; Female; Follow-Up Studies; Humans; Iodine Radioisotopes; Iodobenzenes; Male; Middle Aged; Neoplasm Metastasis; Neuropeptide Y; Pheochromocytoma; Phosphopyruvate Hydratase; Protein Precursors; S100 Proteins; Tomography, Emission-Computed; Treatment Outcome