The neuroendocrine phenotype of gastric myofibroblasts and its loss with cancer progression

Balabanova, Silvia; Holmberg, Chris; Steele, Islay; Ebrahimi, Bahram; Rainbow, Lucille; Burdyga, Theodor; McCaig, Cathy; Tiszlavicz, L; Lertkowit, Nantaporn; Giger, Olivier; Oliver, Simon; Prior, Ian A.; Dimaline, R.; Simpson, Deborah M.; Beynon, Rob; Hegyi, Péter; Wang, Yichen; Dockray, Graham J.; Varró, Andrea

doi:10.1093/carcin/bgu086

Cited by 17 publications

(23 citation statements)

References 38 publications

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“…the growth factors, VEGFC and CTGF) and growth factor-associated proteins ( e.g. IGFBP3, -4, -5, -6), some of which have already been characterized in previous studies of myofibroblast secretomes ( 14 , 22 , 25 ). When flux is plotted against estimated k , this subset is readily distinguishable ( Fig.…”

Section: Resultsmentioning

confidence: 96%

“…Constitutively secreted proteins predominate in the secretomes of the two cells studied here. However, stromal myofibroblasts including CAMs may exhibit a modest regulated secretory pathway ( 22 ) and in this context it is interesting that a marker of the pathway, secretogranin-2 (SCG2), was identified and exhibited rapid label incorporation ( k = 0.274/h). Immunoblotting confirmed that secretion of SCG2 was stimulated by a short (30 min) stimulation with ionomycin, consistent with calcium-evoked exocytosis and the response was resistant to cycloheximide and BFA, consistent with release from storage vesicles ( Fig.…”

Section: Resultsmentioning

confidence: 99%

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Stable Isotope Dynamic Labeling of Secretomes (SIDLS) Identifies Authentic Secretory Proteins Released by Cancer and Stromal Cells

Hammond

Kumar

Raymond

et al. 2018

Molecular & Cellular Proteomics

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Analysis of secretomes critically underpins the capacity to understand the mechanisms determining interactions between cells and between cells and their environment. In the context of cancer cell micro-environments, the relevant interactions are recognized to be an important determinant of tumor progression. Global proteomic analyses of secretomes are often performed at a single time point and frequently identify both classical secreted proteins (possessing an N-terminal signal sequence), as well as many intracellular proteins, the release of which is of uncertain biological significance. Here, we describe a mass spectrometry-based method for stable isotope dynamic labeling of secretomes (SIDLS) that, by dynamic SILAC, discriminates the secretion kinetics of classical secretory proteins and intracellular proteins released from cancer and stromal cells in culture. SIDLS is a robust classifier of the different cellular origins of proteins within the secretome and should be broadly applicable to nonproliferating cells and cells grown in short term culture.

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Section: Resultsmentioning

confidence: 96%

Section: Resultsmentioning

confidence: 99%

Stable Isotope Dynamic Labeling of Secretomes (SIDLS) Identifies Authentic Secretory Proteins Released by Cancer and Stromal Cells

Hammond

Kumar

Raymond

et al. 2018

Molecular & Cellular Proteomics

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“…; Balabanova et al. ). The present analysis therefore focused on a comparison of CCK2R expression in these two groups.…”

Section: Methodsmentioning

confidence: 96%

“…Microarray data on pairs of CAMs and corresponding ATMs from 13 gastric cancer patients have previously been deposited at http://www.ncbi.nlm.nih.gov/geo/query/ acc.cgi?acc=GSE44740. The TNM classification system (Sobin et al 2009) had been applied to these tumors which had shown that patients with early stage disease indicated by low lymph node involvement (pN0-1) had significantly longer survival than those with advanced disease indicated by high lymph node involvement (pN2-4) (51 vs. 12 months, respectively, P < 0.01) (Holmberg et al 2012;Balabanova et al 2014). The present analysis therefore focused on a comparison of CCK2R expression in these two groups.…”

Section: Microarray Datamentioning

confidence: 99%

Cell cycle dependent expression of the CCK2 receptor by gastrointestinal myofibroblasts: putative role in determining cell migration

et al. 2017

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The well‐known action of the gastric hormone gastrin in stimulating gastric acid secretion is mediated by activation of cholecystokinin‐2 receptors (CCK2R). The latter are expressed by a variety of cell types suggesting that gastrin is implicated in multiple functions. During wound healing in the stomach CCK2R may be expressed by myofibroblasts. We have now characterized CCK2R expression in cultured myofibroblasts. Immunocytochemistry showed that a relatively small proportion (1–6%) of myofibroblasts expressed the receptor regardless of the region of the gut from which they were derived, or whether from cancer or control tissue. Activation of CCK2R by human heptadecapeptide gastrin (hG17) increased intracellular calcium concentrations in a small subset of myofibroblasts indicating the presence of a functional receptor. Unexpectedly, we found over 80% of cells expressing CCK2R were also labeled with 5‐ethynyl‐2′‐deoxyuridine (EdU) which is incorporated into DNA during S‐phase of the cell cycle. hG17 did not stimulate EdU incorporation but increased migration of both EdU‐labeled and unlabelled myofibroblasts; the migratory response was inhibited by a CCK2R antagonist and by an inhibitor of IGF receptor tyrosine kinase; hG17 also increased IGF‐2 transcript abundance. The data suggest myofibroblasts express CCK2R in a restricted period of the cell cycle during S‐phase, and that gastrin accelerates migration of these cells; it also stimulates migration of adjacent cells probably through paracrine release of IGF. Together with previous findings, the results raise the prospect that gastrin controls the position of dividing myofibroblasts which may be relevant in wound healing and cancer progression in the gastrointestinal tract.

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“…Microarray 12 months, respectively, P < 0.01) (Holmberg et al 2012;Balabanova et al 2014). The present analysis therefore focused on a comparison of CCK2R expression in these two groups.…”

Section: Microarray Datamentioning

confidence: 93%

Novel sites of CCK2R expression

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APC Adenomatous polyposis coli ARID2 AT-rich interaction domain 2 ASI Acid secretion inhibitor ATM Adjacent tissue myofibroblast ATP Adenosine-5'-triphosphate BabA Blood group antigen binding adhesion BCC Basal cell cancer BCH Basal cell hyperplasia BD Boyden insert BMP Bone morphogenetic protein BRAF B-Raf proto-oncogene BSA Bovine serum albumin CAF Cancer-associated fibroblasts CagA Cytotoxin associated gene A CAM Cancer-associated myofibroblasts xviii cAMP Cyclic adenosine monophosphate CCK Cholecystokinin CCK2R/CCKB Cholecystokinin-2 /-B / gastrin receptor CCK2Ri4sv CCK2 receptor intron 4-containing splice variant CCK-8 / CeCo Cell counting Kit-8 CCK8 Cholecystokinin-8 CCL17 (22, 24) Chemokin (C-C motif) ligand 17 (22, 24) Cdc42 Cell division control protein 42 CDK Cyclin-dependent kinase CDKI2A cyclin-dependent kinase inhibitor CDKN2A Cyclin-dependent kinase inhibitor 2A CgA Chromogranin A CM Conditioned media CMLR1 Chemokine like-receptor 1 CNS Central nervous system COX Cyclooxygenase CPE Carboxypeptidase E CRE cAMP response element CREB cAMP response element binging protein Ct Cycle threshold CTFP C-terminal flanking peptide CTLA-4 Cytotoxic T lymphocyte-associated antigen CuSO4 Copper sulphate CXCL12 C-X-C motif chemokine ligand 12 CXCR Chemokine receptor CXCR3 C-X-C Motif Chemokine Receptor 3 xxvii substitution of TIMP-3 reverted these changes. Serum MMP-2 and TIMP-3 concentration showed no correlation with disease progression. In conclusion the metastasising capacity of in situ melanomas may be significantly influenced by gastrin, and suggesting the need for closer surveillance in those patients with hypergastrinaemia. Moreover, CCK2R may provide a putative therapeutic target. Future research could usefully focus on these issues. Due to lack of experimental data the significance of infections in the origin of cancer was dismissed for almost half of a century. With the development of microbiology, the concept of tumour viruses and viral oncogenes were introduced in the early 20th century. Peyton Rous was amongst the first one to discover that avian sarcoma could be transmitted into healthy animals by a virus (later named Rous sarcoma virus (RSV)) generated from tumour extracts (Rous 1911). RSV was recognised later as the first identified tumour virus capable of inducing cancer. Intense research in this field led to the immunochemistry which identified scattered endocrine cells (G-cells) in the epithelium of the antral mucosa. Since the local concentration of former is 15-20 fold higher than the other, stimulatory effect of gastrin is mainly mediated through the amidated version containing 17 amino acid residues (Dockray et al. 1996). It should be noted however, that precursor forms have also been shown to have a proliferative effect on GI mucosa mainly observed with colonic cancers (Nemeth et al. 1993). * ** Figure 1.1. Schematic representation of gastrin synthesis. Preprogastrin is cleaved and converted to progastrin by SPC2,3 and CPE. After phosphorylation and sulphation, Gly extended gastrines (G34Gl...

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The neuroendocrine phenotype of gastric myofibroblasts and its loss with cancer progression

Cited by 17 publications

References 38 publications

Stable Isotope Dynamic Labeling of Secretomes (SIDLS) Identifies Authentic Secretory Proteins Released by Cancer and Stromal Cells

Stable Isotope Dynamic Labeling of Secretomes (SIDLS) Identifies Authentic Secretory Proteins Released by Cancer and Stromal Cells

Cell cycle dependent expression of the CCK2 receptor by gastrointestinal myofibroblasts: putative role in determining cell migration

Novel sites of CCK2R expression

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