glucagon-like-peptide-1 and Neoplasms

Glucagon-like peptide-1 (GLP-1) receptor agonists are effective glucose-lowering drugs, but there is concern that they may increase the risk of malignant neoplasia. The present meta-analysis examined the safety of GLP-1 receptor agonists with regard to malignant neoplasia.. We analyzed data from randomized controlled trials with a minimum duration of 24 weeks that assessed the incidence of neoplasms in type 2 diabetes patients receiving GLP-1 receptor agonists compared with placebo or other hypoglycemic drugs. We searched the MEDLINE, Embase, and Cochrane databases with a language restriction of English through October 1, 2018, and carried out a meta-analysis of the available trial data using a fixed effects model to calculate odds ratios (ORs) for neoplasia.. Thirty-four relevant articles, providing data for 50452 patients, were included in the meta-analysis. Compared with the incidence of malignant neoplasia with placebo or other interventions, no increase in malignant neoplasm formation was observed with the use of GLP-1 receptor agonists (OR 1.04, 95% confidence interval (CI) 0.94-1.15;. GLP-1 receptor agonists can be used without safety concerns related to malignant neoplasia in patients with type 2 diabetes.

Topics: Diabetes Mellitus, Type 2; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Incidence; Liraglutide; Neoplasms; Risk Factors

Diabetes mellitus affects over 20% of people aged > 65 years. With the population of older people living with diabetes growing, the condition may be only one of a number of significant comorbidities that increases the complexity of their care, reduces functional status and inhibits their ability to self-care. Coexisting comorbidities may compete for the attention of the patient and their healthcare team, and therapies to manage comorbidities may adversely affect a person's diabetes. The presence of renal or liver disease reduces the types of antihyperglycemic therapies available for use. As a result, insulin and sulfonylurea-based therapies may have to be used, but with caution. There may be a growing role for sodium-glucose co-transporter 2 (SGLT-2) inhibitors in diabetic renal disease and for glucagon-like peptide (GLP)-1 therapy in renal and liver disease (nonalcoholic steatohepatitis). Cancer treatments pose considerable challenges in glucose therapy, especially the use of cyclical chemotherapy or glucocorticoids, and cyclical antihyperglycemic regimens may be required. Clinical trials of glucose lowering show reductions in microvascular and, to a lesser extent, cardiovascular complications of diabetes, but these benefits take many years to accrue, and evidence specifically in older people is lacking. Guidelines recognize that clinicians managing patients with type 2 diabetes mellitus need to be mindful of comorbidity, particularly the risks of hypoglycemia, and ensure that patient-centered therapeutic management of diabetes is offered. Targets for glucose control need to be carefully considered in the context of comorbidity, life expectancy, quality of life, and patient wishes and expectations. This review discusses the role of chronic kidney disease, chronic liver disease, cancer, severe mental illness, ischemic heart disease, and frailty as comorbidities in the therapeutic management of hyperglycemia in patients with type 2 diabetes mellitus.

Topics: Comorbidity; Diabetes Mellitus, Type 2; Drug Therapy, Combination; End Stage Liver Disease; Frailty; Glucagon-Like Peptide 1; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Insulin; Mental Disorders; Myocardial Ischemia; Neoplasms; Quality of Life; Renal Insufficiency, Chronic; Sodium-Glucose Transporter 2 Inhibitors

Apoptosis is a complicated process that involves activation of a series of intracellular signaling. Tissue injuries from diabetes mellitus mostly occur as a consequence of higher rate of apoptosis process due to activation of a series of molecular mechanisms. Several classes of anti-hyperglycaemic agents have been developed which could potentially modulate the apoptotic process resulting in fewer tissue damages. Novel types of anti-hyperglycaemic medications such as sodium glucose cotransporters-2 inhibitors, glucagon like peptide-1 receptor agonists and dipeptidyl peptidase 4 inhibitors have shown to provide potent anti-hyperglycaemic effects, but their influences on diabetes-induced apoptotic injuries is largely unknown. Therefore, in the current study, we reviewed the published data about the possible effects of these anti-hyperglycaemic agents on apoptosis in diabetic milieu as well as in cancer cells.

Topics: Apoptosis; Blood Glucose; Deafness; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Mitochondrial Diseases; Neoplasms; Sodium-Glucose Transporter 2 Inhibitors

Dietary β-glucans are soluble fibers with potentially health-promoting effects. Gut peptides are important signals in the regulation of energy and glucose homeostasis. This article reviews the effects of different enriched β-glucan food consumption on immune responses, inflammation, gut hormone and cancer. Gut hormones are influenced by enriched β-glucan food consumption and levels of such peptide as YY, ghrelin, glucagon-like peptide 1 and 2 in humans influence serum glucose concentration as well as innate and adaptive immunity. Cancer cell development is also regulated by obesity and glucose dishomeostasy that are influenced by β-glucan food consumption that in turn regulated gut hormones.

Topics: Animals; beta-Glucans; Functional Food; Ghrelin; Glucagon-Like Peptide 1; Glucagon-Like Peptide 2; Humans; Inflammation; Neoplasms; Peptide YY

The proglucagon-derived peptide hormone, glucagon, comprises 29 amino acids. Its secretion from the pancreatic α cells is regulated by several factors. Glucagon increases blood glucose levels through gluconeogenesis and glycogenolysis. Elevated plasma concentrations of glucagon, hyperglucagonemia, may contribute to diabetes. However, hyperglucagonemia is also observed in other clinical conditions than diabetes, including nonalcoholic fatty liver disease, glucagon-producing tumors and after gastric bypass surgery. Here, we review the current literature on hyperglucagonemia in disease with a particular focus on diabetes, and finally speculate that the primary physiological importance of glucagon may not reside in glucose homeostasis but in regulation of amino acid metabolism exerted via a hitherto unrecognized hepato-pancreatic feedback loop.

Topics: Diabetes Mellitus; Glucagon; Glucagon-Like Peptide 1; Glucagonoma; Humans; Liver; Neoplasms; Non-alcoholic Fatty Liver Disease; Oxyntomodulin; Pancreas; Receptors, Glucagon

Chemotherapy often causes adverse effects, including pain, bloating, diarrhea, and inflammation and ulceration of the mucous membranes lining the digestive tract, which are collectively referred to as mucositis. Unfortunately, no remedy has been found yet to manage these side-effects.. The intestinal glucagon-like peptide-2 (GLP-2) is secreted from the intestinal endocrine L cells after nutrient intake, but recent findings show that the peptide concentration in the plasma also rises after intestinal injury and that GLP-2 receptor activation is crucial for intestinal healing. The antidiabetic hormone GLP-1, cosecreted with GLP-2, diminished mucositis in an animal model of the condition. Therefore, both peptides could be involved in the pathophysiology of mucositis.. The intestinal GLPs have shown beneficial effects in experimental trials and have potential for therapeutic use. In type 2 diabetic and obese patients, GLP secretion is impaired. Elucidating the role of these endogenous hormones could lead to the identification of mucositis risk factors and an alternative preventive therapy for these patients.

Topics: Animals; Antineoplastic Agents; Disease Models, Animal; Glucagon-Like Peptide 1; Glucagon-Like Peptide 2; Humans; Mucositis; Neoplasms

CD26 is a widely expressed transmembrane glycoprotein with peptidase activity in its extracellular domain and which regulates multiple biological processes. It acts mainly as catabolic enzyme for a number of circulating proteins involved in common pathological conditions such as diabetes and cardiovascular disease and may represent a target to modulate bioavailability of crucial substrates. The aim of the present review is to summarize data regarding CD26-based pharmacological interventions. Four main subtopics were identified:1) CD26 as the target of pharmacological inhibitors to increase bioavailability of glucagon-like petide-1 (GLP-1) and hence to enhance GLP-1 glucose-lowering activity in diabetic patients; 2) role of CD26 in the physiology and pathology of the cardiovascular system; 3) the adverse prognostic value of CD26 expression on cancer cells; 4) CD26 down-regulation on lymphocytes as a mechanism of TGF-beta immunomodulation.

Topics: Animals; Cardiovascular Diseases; Diabetes Mellitus; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Humans; Molecular Targeted Therapy; Neoplasms

Tumor-induced hypoglycemia (TIH) is a rare clinical entity that may occur in patients with diverse kinds of tumor lineages and that may be caused by different mechanisms. These pathogenic mechanisms include the eutopic insulin secretion by a pancreatic islet β-cell tumor, and also the ectopic tumor insulin secretion by non-islet-cell tumor, such as bronchial carcinoids and gastrointestinal stromal tumors. Insulinoma is, by far, the most common tumor associated with clinical and biochemical hypoglycemia. Insulinomas are usually single, small, sporadic, and intrapancreatic benign tumors. Only 5-10% of insulinomas are malignant. Insulinoma may be associated with the multiple endocrine neoplasia type 1 in 4-6% of patients. Medical therapy with diazoxide or somatostatin analogs has been used to control hypoglycemic symptoms in patients with insulinoma, but only surgical excision by enucleation or partial pancreatectomy is curative. Other mechanisms that may, more uncommonly, account for tumor-associated hypoglycemia without excess insulin secretion are the tumor secretion of peptides capable of causing glucose consumption by different mechanisms. These are the cases of tumors producing IGF2 precursors, IGF1, somatostatin, and glucagon-like peptide 1. Tumor autoimmune hypoglycemia occurs due to the production of insulin by tumor cells or insulin receptor autoantibodies. Lastly, massive tumor burden with glucose consumption, massive tumor liver infiltration, and pituitary or adrenal glands destruction by tumor are other mechanisms for TIH in cases of large and aggressive neoplasias.

Topics: Autoantibodies; Bronchial Neoplasms; Carcinoid Tumor; Gastrointestinal Neoplasms; Gastrointestinal Stromal Tumors; Glucagon-Like Peptide 1; Humans; Hypoglycemia; Insulin-Like Growth Factor I; Insulin-Like Growth Factor II; Insulinoma; Neoplasms; Pancreatic Neoplasms; Paraneoplastic Syndromes; Receptor, Insulin; Somatostatin

A lot of contradictory data regarding the serious side effects of incretin-based therapies are currently available, with more being prepared or published every month. Considering the widespread use of these drugs it should be considered a priority to establish both short- and long-term risks connected with incretin treatment. We performed an extensive literature search of the PubMed database looking for articles dealing with connections between incretin-based therapies and pancreatitis, pancreatic cancer, thyroid cancer and other neoplasms. Data obtained indicate that GLP-1 agonists and DPPIV inhibitors could increase the risk of pancreatitis and pancreatic cancer, possibly due to their capacity to increase ductal cell turnover, which has previously been found to be up-regulated in patients with obesity and T2DM. GLP-1 analogues exenatide and liraglutide seem to be connected with medullary thyroid carcinoma in rat models and, surprisingly, GLP-1 receptors have been found in papillary thyroid carcinoma, currently the most common neoplasm of the thyroid gland in humans. Changes in expression of DPPIV have been described in ovarian carcinoma, melanoma, endometrial adenocarcinoma, prostate cancer, non-small cell lung cancer and in certain haematological malignancies. In most cases loss of DPPIV activity is connected with a higher grading scale, more aggressive tumour behaviour and higher metastatic potential. In conclusion animal and human studies indicate that there could be a connection between incretin-based therapies and pancreatitis, pancreatic cancer, thyroid cancer and other neoplasms. Therefore whenever such therapy is started it would be wise to proceed with caution, especially if personal history of neoplasms is present.

Topics: Animals; Cell Proliferation; Diabetes Mellitus, Type 2; Drug-Related Side Effects and Adverse Reactions; Gastric Inhibitory Polypeptide; Gastrointestinal Agents; Glucagon-Like Peptide 1; Humans; Incretins; Insulin; Models, Animal; Neoplasms; Outcome Assessment, Health Care; Pancreas; Pancreatic Diseases; Randomized Controlled Trials as Topic; Rats; Risk Factors

Radiolabelled receptor-binding peptides targeting receptors (over)expressed on tumour cells are widely under investigation for tumour diagnosis and therapy. The concept of using radiolabelled receptor-binding peptides to target receptor-expressing tissues in vivo has stimulated a large body of research in nuclear medicine. The (111)In-labelled somatostatin analogue octreotide (OctreoScan) is the most successful radiopeptide for tumour imaging, and was the first to be approved for diagnostic use. Based on the success of these studies, other receptor-targeting peptides such as cholecystokinin/gastrin analogues, glucagon-like peptide-1, bombesin (BN), chemokine receptor CXCR4 targeting peptides, and RGD peptides are currently under development or undergoing clinical trials. In this review, we discuss some of these peptides and their analogues, with regard to their potential for radionuclide imaging of tumours.

Topics: Animals; Bombesin; Cholecystokinin; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Ligands; Neoplasms; Octreotide; Pentetic Acid; Peptides; Radionuclide Imaging; Radiopharmaceuticals; Receptor, Cholecystokinin B; Receptors, Bombesin; Receptors, Cholecystokinin; Receptors, CXCR4; Receptors, Glucagon

Nuclear medicine techniques are becoming more important in imaging oncological and infectious diseases. For metabolic imaging of these diseases, antibody and peptide imaging are currently used. In recent years peptide imaging has become important, therefore the rationale for the use of peptide imaging is described in this article. Criteria for a successful peptide tracer are a high target specificity, a high binding affinity, a long metabolic stability and a high target-to-background ratio. Tracer internalization is also beneficial. For oncological imaging, many tracers are available, most originating from regulatory peptides, but penetrating peptides are also being developed. Peptides for imaging inflammatory and infectious diseases include regulatory peptides, antimicrobial peptides and others. In conclusion, for the imaging of oncological, imflammatory and infectious diseases, many promising peptides are being developed. The ideal peptide probe is characterized by rapid and specific target localization and binding with a high tumour-to-background ratio.

Topics: Antimicrobial Cationic Peptides; Bombesin; Cholecystokinin; Gastrin-Releasing Peptide; Glucagon-Like Peptide 1; Humans; Infections; Inflammation; Isotope Labeling; Neoplasms; Peptides; Radionuclide Imaging; Radiopharmaceuticals; Somatostatin; Vasoactive Intestinal Peptide

The new incretin-based therapies, dipeptidyl peptidase-4 (DPP4) inhibitors and glucagon like peptide 1 (GLP1) receptor agonists are widely used for the treatment of type 2 diabetes because of their glucose-lowering capacity with low risk of hypoglycemia. As they are weight neutral or induce weight loss in this mostly overweight population, they are popular among clinicians and patients alike. Nonetheless, concerns have been raised about GLP1's trophic effects. While increased β cell mass observed in rodents sounds appealing for treatment of diabetes, there was also an increased incidence of medullary thyroid cancer (MTC) in some species. We reviewed literature available in the Medline database until March 2012. Safety signals have emerged for MTC and pancreatic carcinoma from adverse event databases in the United States and Europe. Considering the relatively short duration of these studies, it is more likely that premalignant lesions are stimulated in presence of GLP1, rather than new neoplasms induced. Moreover, interpreting results of animal studies is difficult because of species-specific differences in presence and density of GLP1 receptors. Furthermore, data are emerging suggesting beneficial effects of GLP1 on colon and breast cancer. In conclusion, presently, the benefits of using DPP4 inhibitors or GLP1 receptor agonists for treatment of type 2 diabetes outweigh the risks. Nonetheless, their safety profile should be monitored and their indications should be widened cautiously. At present they remain contra-indicated in patients with a personal or family history of MTC or multiple endocrine neoplasia type 2.

Topics: Animals; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Neoplasms; Receptors, Glucagon

The association between GLP-1 agonists, acute pancreatitis (AP), any cancer and thyroid cancer is discussed. This meta-analysis was aimed at evaluating the risk of those serious adverse events associated with GLP-1 agonists in patients with type 2 diabetes.. Medline, EMBASE, Cochrane Library and clinicaltrials.gov were searched in order to identify longitudinal studies evaluating exenatide or liraglutide use and reporting data on AP or cancer. Odds ratios (ORs) were pooled using a random-effects model. I(2) statistics assessed heterogeneity.. Twenty-five studies were included. Neither exenatide (OR 0.84 [95% CI 0.58-1.22], I(2) = 30%) nor liraglutide (OR 0.97 [95% CI 0.21-4.39], I(2) = 0%) were associated with an increased risk of AP, independent of baseline comparator. The pooled OR for cancer associated with exenatide was 0.86 (95% CI 0.29, 2.60, I(2) = 0%) and for liraglutide was 1.35 (95% CI 0.70, 2.59, I(2) = 0%). Liraglutide was not associated with an increased risk for thyroid cancer (OR 1.54 [95% CI 0.40-6.02], I(2) = 0%). For exenatide, no thyroid malignancies were reported.. Current available published evidence is insufficient to support an increased risk of AP or cancer associated with GLP-1 agonists. These rare and long-term adverse events deserve properly monitoring in future studies evaluating GLP-1 agonists.

Topics: Diabetes Mellitus, Type 2; Exenatide; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Liraglutide; Neoplasms; Pancreatitis; Peptides; Venoms

Concerns have been raised regarding a potentially increased risk of cancer associated with treatment with glucagon-like peptide-1 (GLP-1) receptor agonists. Here, we explored whether fasting and oral glucose tolerance test post-challenge glucose-dependent insulinotropic peptide (GIP) and GLP-1 levels were associated with incident first cancer. Within the cardiovascular re-examination arm of the population-based Malmö Diet Cancer study (n = 3734), 685 participants with a previous cancer diagnosis were excluded, resulting in 3049 participants (mean age 72.2 ± 5.6 years, 59.5% women), of whom 485 were diagnosed with incident first cancer (median follow-up time 9.9 years). Multivariable Cox-regression and competing risk regression (death as competing risk) were used to explore associations between incretin levels and incident first cancer. Higher levels of fasting GLP-1 (462 incident first cancer cases/2417 controls) showed lower risk of incident first cancer in competing risk regression (sub-hazard ratio 0.90; 95% confidence interval 0.82-0.99; p = 0.022). No association was seen for fasting GIP, post-challenge GIP, or post-challenge GLP-1 and incident first cancer. In this prospective study, none of the fasting and post-challenge levels of GIP and GLP-1 were associated with higher risk of incident first cancer; by contrast, higher levels of fasting GLP-1 were associated with lower risk of incident first cancer.

Topics: Aged; Blood Glucose; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Humans; Incretins; Insulin; Male; Neoplasms; Prospective Studies

We aimed to investigate how sirtuin 1 (SIRT1), a conserved mammalian Nicotinamide adenine dinucleotide. We used mice with specific Sirt1 disruption in the intestinal epithelium (VilKO, villin-Cre. In HFD-fed VilKO and NgnKO mice, an increase in EECs (42.3% and 37.2%), GLP-1- or GLP-2-producing L cells (93.0% and 61.4%), and GLP-1 (85.7% and 109.6%) was observed after glucose loading, explaining the improved metabolic phenotype of HFD-VilKO mice. These increases were associated with up-regulated expression of neurogenin 3 (EEPC marker) in crypts of HFD-VilKO and HFD-NgnKO mice, respectively. Conversely, Sir2d or 24-hour fasted mice showed a decrease in EECs (21.6%), L cells (41.6%), and proliferative progenitor cells. SIRT1 overexpression- or knockdown-mediated change in the progenitor cell proliferation was associated with Wnt/β-catenin activity changes. Notably, Wnt/β-catenin inhibitor completely suppressed EEC and L-cell increases in HFD-VilKO mice or organoids from HFD-VilKO and HFD-NgnKO mice.. Intestinal SIRT1 in EECs modulates the EEPC cycle by regulating β-catenin activity and can control the number of EECs in HFD-fed mice, which is a previously unknown role.

Topics: Animals; beta Catenin; Cell Proliferation; Diabetes Mellitus, Type 2; Diet, High-Fat; Glucagon-Like Peptide 1; Glucose; Mammals; Mice; Neoplasms; Sirtuin 1

Gastrointestinal tract function and it's integrity are controlled by a number of peptides whose secretion is influenced by severe inflammation. In stomach the main regulatory peptide is ghrelin. For upper small intestine cholecystokinin and lower small intestine glucagon-like peptide- 1 are secreted, while fibroblast growth factor-21 is secreted by several organs, including the liver, pancreas, and adipose tissue [12]. Hematopoietic stem cell transplantation causes serious mucosal damage, which can reflect on this peptides.. The aim of the study was to determine fasting plasma concentrations of ghrelin, cholecystokinin, glucagon- like peptide-1, and fibroblast growth factor-21, and their gene expressions, before and 6 months after hematopoietic stem cell transplantation.27 children were studied, control group included 26 healthy children.. Acute graft versus host disease was diagnosed in 11 patients (41%, n = 27). Median pre-transplantation concentrations of gastrointestinal peptides, as well as their gene expressions, were significantly lower in studied group compared with the control group. Only median of fibroblast growth factor-21 concentration was near-significantly higher before stem cell transplantation than in the control group. The post-hematopoietic transplant results revealed significantly higher concentrations of the studied peptides (except fibroblast growth factor-21) and respective gene expressions as compare to pre transplant results. Median glucagone like peptide-1 concentrations were significantly decreased in patients with features of acute graft versus host disease. Moreover, negative correlation between glucagone like peptide-1 concentrations and acute graft versus host disease severity was found.. Increased concentrations and gene expressions of gastrointestinal tract regulation peptides can be caused by stimulation of regeneration in the severe injured organ. Measurement of these parameters may be a useful method of assessment of severity of gastrointestinal tract complications of hematopoietic stem cell transplantation.

Topics: Adolescent; Case-Control Studies; Child; Child, Preschool; Cholecystokinin; Female; Fibroblast Growth Factors; Gene Expression Regulation, Neoplastic; Ghrelin; Glucagon-Like Peptide 1; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Infant; Male; Neoplasms; Severity of Illness Index

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Liraglutide; Neoplasms; Randomized Controlled Trials as Topic

Cancer-associated anorexia and cachexia are a multifactorial condition described by a loss of body weight and muscle with anorexia, asthenia, and anemia. Moreover, they correlate with a high mortality rate, poor response to chemotherapy, poor performance status, and poor quality of life. Cancer cachexia is regulated by proinflammatory cytokines such as interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), and tumor necrosis factor- α (TNF- α). In addition, glucagon like peptide-1 (GIP-1), peptide YY (PYY), ghrelin, and leptin plays a crucial role in food intake. In this study, we investigated the therapeutic effects of one of the traditional herbal medicines, Sipjeondaebo-tang (Juzen-taiho-to in Japanese; SJDBT), on cancer anorexia and cachexia in a fundamental mouse cancer anorexia/cachexia model, CT-26 tumor-bearing mice. SJDBT was more significantly effective in a treatment model where it was treated after anorexia and cachexia than in a prevention model where it was treated before anorexia and cachexia on the basis of parameters such as weights of muscles and whole body and food intakes. Moreover, SJDBT inhibited a production of IL-6, MCP-1, PYY, and GLP-1 and ameliorated cancer-induced anemia. Therefore, our in vivo studies provide evidence on the role of SJDBT in cancer-associated anorexia and cachexia, thereby suggesting that SJDBT may be useful for treating cancer-associated anorexia and cachexia.

Topics: Animals; Anorexia; Body Weight; Cachexia; Cell Line, Tumor; Chemokine CCL2; Drugs, Chinese Herbal; Ghrelin; Glucagon-Like Peptide 1; Inflammation; Interleukin-6; Intestinal Mucosa; Leptin; Male; Mice; Mice, Inbred BALB C; Muscles; Neoplasm Transplantation; Neoplasms; Peptide YY; Plant Preparations; Tumor Necrosis Factor-alpha

An important event in the development of the germline is the initiation of meiotic development. In Caenorhabditis elegans, the conserved GLP-1/Notch signaling pathway regulates the proliferative versus meiotic entry decision, at least in part, by spatially inhibiting genes in the gld-1 and gld-2 parallel pathways, which are proposed to either inhibit proliferation and/or promote meiotic development. Mutations that cause constitutive activation of the GLP-1 pathway, or inactivation of both the gld-1 and gld-2 parallel pathways, result in a tumorous germline in which all cells are thought to be proliferative. Here, to analyze proliferation and meiotic entry in wild-type and mutant tumorous germlines, we use anti-REC-8 and anti-HIM-3 specific antibodies as markers, which under our fixation conditions, stain proliferative and meiotic cells, respectively. Using these makers in wild-type animals, we find that the border of the switch from proliferation to meiotic entry is staggered in late-larval and adult germlines. In wild-type adults, the switch occurs between 19 and 26 cell diameters from the distal end, on average. Our analysis of mutants reveals that tumorous germlines that form when GLP-1 is constitutively active are completely proliferative, while tumors due to inactivation of the gld-1 and gld-2 pathways show evidence of meiotic entry. Genetic and time course studies suggest that a third pathway may exist, parallel to the GLD-1 and GLD-2 pathways, that promotes meiotic development.

Topics: Animals; Biomarkers; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Cell Division; Germ Cells; Glucagon; Glucagon-Like Peptide 1; Meiosis; Mitosis; Neoplasms; Peptide Fragments; Phosphoproteins; Protein Precursors; Schizosaccharomyces pombe Proteins; Signal Transduction