oxytocin and Neoplasms

Oxytocin (OT) is the first peptide hormone structurally assessed and chemically synthesized in biologically active form. This hormone acts as an important factor in a human reproductive system particularly during pregnancy and lactation in women. So far, different therapeutic roles for OT have been identified as a spectrum from central and peripheral actions on male and female reproductive systems, circulatory system, musculoskeletal system, etc. Some in vitro and in vivo studies also revealed that OT is responsible for bivariate biological functions involved in cancer as following. By activating OT receptor in tumoral cells, OT enacts as a growth regulator, whether activator or inhibitor. Regarding the increase of OT in some conditions such as breastfeeding, exercise, and multiparity, we can relate the effect of these conditions on cancer with OT effects. Based on this hypothesis, we present a review on the effects of this neuropeptide on various types of cancer and also the influence of these conditions on the same cancer.

Topics: Animals; Female; Humans; Male; Neoplasms; Oxytocin; Pregnancy; Receptors, Oxytocin; Signal Transduction; Treatment Outcome

Is oxytocin the hormone of happiness? Probably not. However, this small nine amino acid peptide is involved in a wide variety of physiological and pathological functions such as sexual activity, penile erection, ejaculation, pregnancy, uterus contraction, milk ejection, maternal behavior, osteoporosis, diabetes, cancer, social bonding, and stress, which makes oxytocin and its receptor potential candidates as targets for drug therapy. In this review, we address the issues of drug design and specificity and focus our discussion on recent findings on oxytocin and its heterotrimeric G protein-coupled receptor OTR. In this regard, we will highlight the following topics: (i) the role of oxytocin in behavior and affectivity, (ii) the relationship between oxytocin and stress with emphasis on the hypothalamo-pituitary-adrenal axis, (iii) the involvement of oxytocin in pain regulation and nociception, (iv) the specific action mechanisms of oxytocin on intracellular Ca²(+) in the hypothalamo neurohypophysial system (HNS) cell bodies, (v) newly generated transgenic rats tagged by a visible fluorescent protein to study the physiology of vasopressin and oxytocin, and (vi) the action of the neurohypophysial hormone outside the central nervous system, including the myometrium, heart and peripheral nervous system. As a short nine amino acid peptide, closely related to its partner peptide vasopressin, oxytocin appears to be ideal for the design of agonists and antagonists of its receptor. In addition, not only the hormone itself and its binding to OTR, but also its synthesis, storage and release can be endogenously and exogenously regulated to counteract pathophysiological states. Understanding the fundamental physiopharmacology of the effects of oxytocin is an important and necessary approach for developing a potential pharmacotherapy.

Topics: Affect; Analgesics; Animals; Brain; Diabetes Mellitus; Humans; Mental Disorders; Neoplasms; Osteoarthritis; Oxytocin; Receptors, Oxytocin; Sexual Dysfunction, Physiological; Signal Transduction; Social Behavior

Novel sites of oxytocin receptor expression have recently been detected in central nervous system, cardiomyocytes, endothelial cells, various carcinoma cells, etc. These and other discoveries have greatly expanded the classical biological roles of oxytocin, which are stimulation of uterine smooth muscle contraction at parturition and milk ejection during lactation. It is becoming clear that the great diversity of oxytocin actions in the brain and peripheral organs is paralleled by activation of a diversity of signalling pathways. On the other hand, until now only one single oxytocin receptor type has been detected. This receptor belongs to G protein-coupled receptors and in dependence on cell conditions it binds to different G proteins; this phenomenon is called receptor-G protein promiscuity. Thus, in the same cells oxytocin can activate multiple responses at the same time. Recently, the oxytocinergic system has also been implicated in the growth modulation of various neoplastic cells, where it may inhibit or stimulate cell proliferation in dependence on cell type and activated metabolic pathways. The discovery of novel oxytocin receptor-linked signalling cascades brings interesting knowledge opening new avenues for research in oncology and molecular pharmacology with perspectives of finding new therapeutic agents.

Topics: Animals; Cell Proliferation; Humans; Inositol 1,4,5-Trisphosphate; Neoplasms; Neoplastic Processes; Oxytocin; Protein Subunits; Proto-Oncogene Proteins c-akt; Receptors, Oxytocin; Signal Transduction

Nitric oxide (NO), a molecule with multidimensional effects has generated exponential amount of research since its identification as a biological messenger almost two decades back. The recent trend in NO research is to explore newer dimensions in the cellular and molecular mechanisms of actions and interactions of NO with various biomolecules and their implications in various pathophysiological states. Advances in our knowledge of the mechanisms by which this pleiotropic molecule regulates the expression of eukaryotic genes has generated considerable excitement and is paving the way for development of novel NO based therapeutic strategies. However, it is still a challenge to understand fully the paradox of beneficial and damaging effects of this exciting molecule. This review will discuss the current trends of research in this area especially highlighting the new insights gained from recent experimental and clinical studies. New approaches to reduce or augment the availability of NO to benefit a wide range of clinical conditions and avenues for future research are also briefly discussed.

Topics: Animals; Biomedical Research; Cell Adhesion Molecules; Cytokines; Estrogens; Gene Expression; Heat-Shock Proteins; Humans; Melatonin; Mitochondria; Natriuretic Peptides; Neoplasms; Neuroimmunomodulation; Neuronal Plasticity; Neuropeptide Y; Nitric Oxide; Nitric Oxide Donors; Nitric Oxide Synthase; Opioid Peptides; Oxytocin; Seizures; Steroids; Stress, Physiological

The hypothalamic nonapeptide oxytocin plays a crucial role in many reproductive and behavioural functions. However, in recent years, an additional new role for oxytocin has been identified in neoplastic pathology. In tumours, oxytocin acts as a growth regulator, through the activation of a specific G-coupled transmembrane receptor, the oxytocin receptor. In vitro, oxytocin inhibits proliferation of neoplastic cells of either epithelial (mammary and endometrial), nervous or bone origin, all expressing oxytocin receptor. Furthermore, an oxytocin growth-inhibiting effect was also tested and confirmed in vivo in mouse and rat mammary carcinomas. In neoplastic cells derived from two additional oxytocin target tissues, trophoblast and endothelium, oxytocin was found to promote cell proliferation, an effect opposite to that previously described in all other neoplastic oxytocin-responsive cells. The signal transduction pathways coupled to the biological effects of oxytocin are different in oxytocin growth-inhibited or growth-stimulated cells, and may depend on the membrane localization of the oxytocin receptor itself. The inhibitory effect of oxytocin is apparently mediated by activation of the cAMP-protein kinase A pathway, a nonconventional oxytocin signalling pathway, whereas the mitogenic effect is coupled to the increase of intracellular [Ca(2+)] and tyrosine phosphorylation, 'classical' oxytocin transducers. Moreover, the oxytocin receptor localization in lipid rafts enriched in caveolin-1 turns the inhibition of cell growth into a proliferative response, eliciting different epidermal growth factor receptor/mitogen-activated protein kinase activation patterns. This unexpected role of oxytocin (and oxytocin analogues) in regulating cell proliferation, as well as the widespread expression of oxytocin receptors in neoplastic tissues of different origin, opens up new perspectives on the biological role of the oxytocin-oxytocin receptor system in cancer.

Topics: Cell Division; Humans; Neoplasms; Oxytocin; Receptors, Oxytocin

The neurohypophysial peptide oxytocin (OT) and OT-like hormones facilitate reproduction in all vertebrates at several levels. The major site of OT gene expression is the magnocellular neurons of the hypothalamic paraventricular and supraoptic nuclei. In response to a variety of stimuli such as suckling, parturition, or certain kinds of stress, the processed OT peptide is released from the posterior pituitary into the systemic circulation. Such stimuli also lead to an intranuclear release of OT. Moreover, oxytocinergic neurons display widespread projections throughout the central nervous system. However, OT is also synthesized in peripheral tissues, e.g., uterus, placenta, amnion, corpus luteum, testis, and heart. The OT receptor is a typical class I G protein-coupled receptor that is primarily coupled via G(q) proteins to phospholipase C-beta. The high-affinity receptor state requires both Mg(2+) and cholesterol, which probably function as allosteric modulators. The agonist-binding region of the receptor has been characterized by mutagenesis and molecular modeling and is different from the antagonist binding site. The function and physiological regulation of the OT system is strongly steroid dependent. However, this is, unexpectedly, only partially reflected by the promoter sequences in the OT receptor gene. The classical actions of OT are stimulation of uterine smooth muscle contraction during labor and milk ejection during lactation. While the essential role of OT for the milk let-down reflex has been confirmed in OT-deficient mice, OT's role in parturition is obviously more complex. Before the onset of labor, uterine sensitivity to OT markedly increases concomitant with a strong upregulation of OT receptors in the myometrium and, to a lesser extent, in the decidua where OT stimulates the release of PGF(2 alpha). Experiments with transgenic mice suggest that OT acts as a luteotrophic hormone opposing the luteolytic action of PGF(2 alpha). Thus, to initiate labor, it might be essential to generate sufficient PGF(2 alpha) to overcome the luteotrophic action of OT in late gestation. OT also plays an important role in many other reproduction-related functions, such as control of the estrous cycle length, follicle luteinization in the ovary, and ovarian steroidogenesis. In the male, OT is a potent stimulator of spontaneous erections in rats and is involved in ejaculation. OT receptors have also been identified in other tissues, including the kidney, heart, t

Topics: Amino Acid Sequence; Animals; Base Sequence; Behavior; Behavior, Animal; Biological Evolution; Female; Humans; Male; Molecular Sequence Data; Neoplasms; Oxytocin; Receptors, Oxytocin; Sequence Alignment; Sequence Homology, Amino Acid; Sequence Homology, Nucleic Acid; Signal Transduction

Topics: Biomarkers, Tumor; Carcinoma, Small Cell; Humans; Inappropriate ADH Syndrome; Lung Neoplasms; Neoplasms; Neurophysins; Oxytocin; RNA, Messenger; Vasopressins

Topics: Adrenocorticotropic Hormone; Calcitonin; Erythropoietin; Gonadotropins; Growth Hormone; Hormones, Ectopic; Humans; Hypercalcemia; Hypoglycemia; Neoplasms; Neurophysins; Oxytocin; Paraneoplastic Endocrine Syndromes; Parathyroid Hormone; Peptides; Placental Lactogen; Prolactin; Radioimmunoassay; Receptors, Cell Surface; Thyrotropin; Vasopressins

Topics: Adrenocorticotropic Hormone; Arginine Vasopressin; beta-Lipotropin; Calcitonin; Gastrointestinal Hormones; Gonadotropins; Growth Hormone; Hormones, Ectopic; Humans; Hypercalcemia; Insulin; Insulin Secretion; Lung Neoplasms; Melanocyte-Stimulating Hormones; Neoplasm Proteins; Neoplasms; Neurophysins; Osteomalacia; Oxytocin; Paraneoplastic Endocrine Syndromes; Parathyroid Hormone; Phosphates; Placental Lactogen; Prolactin; Thyrotropin; Vasopressins

Cancer survivors experience high levels of distress, associated with a host of negative psychological states, including anxiety, depression, and fear of recurrence, which often lead to sleep problems and reduction in quality of life (QOL) and well-being. As a neuropeptide hormone associated with affiliation, calmness, and well-being, oxytocin may be a useful biological measure of changes in health outcomes in cancer survivors. In this exploratory study, which comprised a subset of participants from a larger study, we evaluated (a) the feasibility and reliability of salivary oxytocin (sOT) levels in cancer survivors and (b) the effects of 2 sleep-focused mind-body interventions, mind-body bridging (MBB) and mindfulness meditation (MM), compared with a sleep hygiene education (SHE) control, on changes in sOT levels in 30 cancer survivors with self-reported sleep disturbance. Interventions were conducted in 3 sessions, once per week for 3 weeks. Saliva samples were collected at baseline, postintervention (~1 week after the last session), and at the 2-month follow-up. In this cancer survivor group, we found that intra-individual sOT levels were fairly stable across the 3 time points, of about 3 months' duration, and mean baseline sOT levels did not differ between females and males and were not correlated with age. Correlations between baseline sOT and self-report measures were weak; however, several of these relationships were in the predicted direction, in which sOT levels were negatively associated with sleep problems and depression and positively associated with cancer-related QOL and well-being. Regarding intervention effects on sOT, baseline-subtracted sOT levels were significantly larger at postintervention in the MBB group as compared with those in SHE. In this sample of cancer survivors assessed for sOT, at postintervention, greater reductions in sleep problems were noted for MBB and MM compared with that of SHE, and increases in mindfulness and self-compassion were observed in the MBB group compared with those in SHE. The findings in this exploratory study suggest that sOT may be a reliable biological measure over time that may provide insight into the effects of mind-body interventions on health outcomes in cancer survivors.

Topics: Adult; Aged; Feasibility Studies; Female; Follow-Up Studies; Humans; Male; Meditation; Middle Aged; Mind-Body Therapies; Mindfulness; Neoplasms; Oxytocin; Prospective Studies; Quality of Life; Reproducibility of Results; Saliva; Sleep Wake Disorders; Survivors; Time Factors

Little is known about cancer incidence among patients with a history of suicide attempt. Suicide attempters have lower levels of oxytocin, a hormone related to lactation, stress, social functioning, and well-being, and recent research indicates influence on carcinogenesis. We hypothesized that the low oxytocin levels among suicide attempters results in an increased risk of cancer in general and in organs with oxytocin receptors in particular.. A nationwide cohort study of patients aged 15 years or older with hospitalization for self-inflicted injury or attempted suicide was identified from the Swedish patient register in 1968-2011. The cancer outcomes were identified from the Swedish cancer register. Cancer risk in suicide attempters was compared with the risk in the background population of the corresponding age, sex, and calendar period by calculating standardized incidence ratios (SIRs) with 95 % confidence intervals (95 % CI).. The 186,627 patients (83,637 men and 102,990 women) hospitalized for self-inflicted injury or attempted suicide contributed with 2.6 million person-years at risk. The SIR for all cancer was 1.3 (95 % CI 1.27-1.33) in men and 1.25 (1.22-1.28) in women. For cancers in organs rich in oxytocin receptors (uterus, breast, and brain), the corresponding SIRs were 1.02 (0.87-1.19) and 1.13 (1.09-1.17), respectively. There was a particularly increased risk of cancers related to alcohol and tobacco in both sexes.. Patients attempting suicide have an increased risk of cancer. However, this increase does not seem to be associated with low oxytocin levels, but rather to exposures like tobacco smoking and alcohol consumption.

Topics: Adolescent; Adult; Aged; Cohort Studies; Female; Humans; Incidence; Male; Middle Aged; Neoplasms; Oxytocin; Receptors, Oxytocin; Registries; Risk; Risk Factors; Suicide Prevention; Suicide, Attempted; Sweden

We measured the short-circuit current (Isc) in rat ileum mucosa to identify the effect of oxytocin (OT) on mucosal secretion in small intestine. We identified a COX-2-derived pulsatile PGE2 release triggered by OT in rat ileum mucosa. OT receptors (OTR) are expressed in intestine crypt epithelial cells. Notably, OT evoked a dynamic change of [Ca(2+)]i in ileum crypts, which was responsible for this pulsatile release of PGE2. OT ameliorated 5-FU-, radiation- or DSS- induced injury in vivo, including the improvement of weight loss, reduced villus height and impaired survival of crypt transit-amplifying cells as well as crypt. Moreover, these protective effects of OT against intestinal injury were eliminated by coadministration of a selective inhibitor of PGE2, AH6809. Our findings strongly suggest that OT, a novel and important regulator of intestine mucosa barrier, is required for repair of intestinal epithelium after injury. Considering that OT is an FDA-approved drug, this work reveals a potential novel and safe way to combat or prevent chemo-radiotherapy induced intestine injury or to treat IBD.

Topics: Animals; Antineoplastic Agents; Calcium; Cyclooxygenase 2; Dextran Sulfate; Dinoprostone; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Evoked Potentials; Fluorouracil; Ileum; Immunohistochemistry; Indomethacin; Intestinal Diseases; Intestinal Mucosa; Ions; Male; Mice; Mice, Inbred C57BL; Microscopy, Fluorescence; Neoplasms; Oxytocin; Rats; Rats, Wistar; Receptors, Oxytocin; Wound Healing; Xanthones

Long-term implications of the exposure to traumatizing experiences during childhood or adolescence, such as sexual abuse, or cancer, have been documented, namely the subjects' response to an acute stress in adulthood. Several indicators of the stress response have been considered (e.g. cortisol, heart rate). Oxytocin (OT) response to an acute stress of individuals exposed to trauma has not been documented. Eighty subjects (n=26 women who had experienced episodes of child abuse, n=25 men and women healthy survivors of cancer in childhood or adolescence, and 29 controls) have been submitted to a laboratory session involving an experimental stress challenge, the Trier social stress test. Overall, there was a clear OT response to the psychosocial challenge. Subjects having experienced a childhood/adolescence life-threatening illness had higher mean levels of OT than both abused and control subjects. There was a moderate negative relationship between OT and salivary cortisol. It is suggested that an acute stress stimulates OT secretion, and that the exposure to enduring life-threatening experiences in childhood/adolescence has long-lasting consequences regarding the stress system and connected functions, namely the activation of OT secretion. Better knowledge of such long-term implications is important so that to prevent dysregulations of the stress responses, which have been shown to be associated to the individual's mental health.

Topics: Acute Disease; Adolescent; Adult; Aging; Child; Child Abuse, Sexual; Female; Humans; Hydrocortisone; Hypothalamo-Hypophyseal System; Male; Middle Aged; Mood Disorders; Neoplasms; Neuropsychological Tests; Oxytocin; Psychology; Sex Characteristics; Sex Factors; Stress Disorders, Post-Traumatic; Stress, Psychological; Time; Young Adult

Oxytocin receptors (OTR) have been described in a number of tumours of different origin, and represent a new target for specific radiolabelled oxytocin (OT) analogues in cancer diagnosis and therapy. By linking the DOTA chelating agent to position 8 of the deamino derivative of Lys(8)-vasotocin (dLVT), we obtained a new compound (DOTA-dLVT) with the following characteristics: (1) it forms a monomeric and stable compound that binds to OTR with an affinity comparable to that of the endogenous OT ligand; (2) it is characterised by a very good selectivity profile for the human OTR, with a low affinity binding to the closely related V1a, V1b and V2 vasopressin receptor subtypes; (3) it induces rapid and persistent receptor internalisation and (4) when radiolabelled, [(111)In]-DOTA-dLVT is efficiently and selectively taken up by OTR-positive tumours grown in mice. These features makes radiolabelled DOTA-dLVT a very good candidate for the radiotargeting of OTR-expressing tumours.

Topics: Animals; Breast Neoplasms; Carcinoma; Chelating Agents; COS Cells; Glioblastoma; Heterocyclic Compounds, 1-Ring; Humans; Indium Radioisotopes; Isotope Labeling; Mice; Neoplasms; Oxytocin; Protein Binding; Radioactive Tracers; Radioligand Assay; Radionuclide Imaging; Radiopharmaceuticals; Receptors, Oxytocin; Sensitivity and Specificity; Stomach Neoplasms; Tissue Distribution; Transfection; Tumor Cells, Cultured; Vasotocin

The presence of 3 different neuropeptide mRNAs with a strict cell-specific expression in vivo was investigated in 13 tumor cell lines from neuroendocrine and in 23 tumor cell lines from non-neuroendocrine origin. Northern blots showed no expression of mRNA for vasopressin (VP) in the 36 tested cell lines. Very low oxytocin (OT) mRNA hybridization signals were detected in the rat pituitary tumor cell line GH4C2 and the rat pancreas tumor cell line RIN5. Both the rat pituitary tumor cell line AtT-20 and the human myeloid leukemia cell line K562, contained proopiomelanocortin (POMC) mRNA. The low incidence of VP, OT and POMC gene expression in the tested tumor cell lines was not influenced by treatments inducing differentiation. In contrast, the cholecystokinin (CCK) gene which is widely present in nervous and endocrine systems was abundantly expressed in the human primitive neuroepithelioma cell line SK-N-MC and its clonal derivative SK-N-MC-IX-C. The results indicate that the expression of neuropeptide genes is very rare in tumor cell lines. The lack of expression in undifferentiated cells agrees with the appearance of expression after day 13 of the embryogenesis when maturation of neurons begins.

Topics: Animals; Blotting, Northern; Cell Differentiation; Cholecystokinin; Gene Expression Regulation, Neoplastic; Humans; Mice; Neoplasms; Neoplasms, Experimental; Neoplasms, Nerve Tissue; Neuropeptides; Oxytocin; Paraneoplastic Endocrine Syndromes; Pro-Opiomelanocortin; Rats; RNA, Messenger; RNA, Neoplasm; Swine; Tumor Cells, Cultured; Vasopressins

The analgesic effect of intraventricular somatostatin-14 (SOM-14), arginine vasopressin (AVP), and oxytocin (OT) were tested in one terminally ill cancer patient with a diffuse mesothelioma suffering intractable continuous and incapacitating thoracic pain. SOM-14 reduced pain by 90% for 48 min; AVP reduced pain by 95% for 75 min, and OT reduced pain by 88% for 77 min. The only notable side effects were seen after the administration of AVP, which induced anesthesia and flaccid paralysis of the lower limbs, from which the patient fully recovered after 20 h.

Topics: Arginine Vasopressin; Drug Combinations; Humans; Injections, Intraventricular; Male; Middle Aged; Neoplasms; Oxytocin; Pain, Intractable; Somatostatin

Topics: Adrenal Glands; Adrenalectomy; Animals; Female; Gonads; Male; Mammary Glands, Animal; Mice; Mice, Inbred C3H; Neoplasms; Oxytocin; Pituitary Gland; Rodent Diseases

Topics: Adrenal Cortex Hormones; Adrenocorticotropic Hormone; Adult; Aged; Brain Diseases; Endocrine System Diseases; Female; Humans; Male; Middle Aged; Neoplasms; Oxytocin; Vasopressins; Water-Electrolyte Balance

Topics: Anabolic Agents; Breast Neoplasms; Dihydrotestosterone; Gastrointestinal Diseases; Humans; Neoplasms; Oxytocin; Steroids; Toxicology

Topics: Adrenocorticotropic Hormone; Aldosterone; Arginine Vasopressin; Ascites; Blood; Bradykinin; Cell Division; Cell Nucleus; Cortisone; Cricetinae; Estrone; Follicle Stimulating Hormone; Histamine; Hydrocortisone; In Vitro Techniques; Luteinizing Hormone; Microscopy; Microscopy, Phase-Contrast; Neoplasms; Neoplasms, Experimental; Oxytocin; Peptides; Pharmacology; Progesterone; Research; Serotonin; Testosterone; Tissue Culture Techniques; Vasopressins