title: Mesenchymal-epithelial signalling in tumour microenvironment: role of high-mobility group Box 1.
abstract: Glucose deprivation, hypoxia and acidosis are characteristic features of the central core of most solid tumours. Myofibroblasts are stromal cells present in many such solid tumours, including those of the colon, and are known to be involved in all stages of tumour progression. HMGB1 is a nuclear protein with an important role in nucleosome stabilisation and gene transcription; it is also released from immune cells and is involved in the inflammatory process. We report that the microenvironmental condition of glucose deprivation is responsible for the active release of HMGB1 from various types of cancer cell lines (HT-29, MCF-7 and A549) under normoxic conditions. Recombinant HMGB1 (10 ng/ml) triggered proliferation in myofibroblast cells via activation of PI3K and MEK1/2. Conditioned medium collected from glucose-deprived HT-29 colon cancer cells stimulated the migration and invasion of colonic myofibroblasts, and these processes were significantly inhibited by immunoneutralising antibodies to HMGB1, RAGE and TLR4, together with specific inhibitors of PI3K and MEK1/2. Our data suggest that HMGB1 released from cancer cells under glucose deprivation is involved in stimulating colonic myofibroblast migration and invasion and that this occurs through the activation of RAGE and TLR4, resulting in the activation of the MAPK and PI3K signalling pathways. Thus, HMGB1 might be released by cancer cells in areas of low glucose in solid tumours with the resulting activation of myofibroblasts and is a potential therapeutic target to inhibit solid tumour growth.
authors.affiliation: Biomolecular Sciences, School of Pharmacy and Bimolecular Sciences, Liverpool John Moores University, Liverpool, L3 3AF, UK.
authors.forename: Sikander
authors.initials: S
authors.lastname: Sharma
authors.affiliation: Biomolecular Sciences, School of Pharmacy and Bimolecular Sciences, Liverpool John Moores University, Liverpool, L3 3AF, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Evans
authors.affiliation: Biomolecular Sciences, School of Pharmacy and Bimolecular Sciences, Liverpool John Moores University, Liverpool, L3 3AF, UK. a.r.evans@ljmu.ac.uk.
authors.forename: Elaine
authors.initials: E
authors.lastname: Hemers
mesh_terms: D000230:Adenocarcinoma / Q000473:pathology; D000951:Antigens, Neoplasm / Q000378:metabolism; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003094:Collagen / Q000494:pharmacology; D003110:Colonic Neoplasms / Q000473:pathology; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004338:Drug Combinations; D004789:Enzyme Activation / Q000187:drug effects; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism*; D005947:Glucose / Q000172:deficiency; D024243:HMGB1 Protein / Q000378:metabolism*; D006801:Humans; D007797:Laminin / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008648:Mesoderm / Q000187:drug effects / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D058628:Myofibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D011509:Proteoglycans / Q000494:pharmacology; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D059016:Tumor Microenvironment / Q000187:drug effects
chemical_list: D000951:Antigens, Neoplasm; D017077:Culture Media, Conditioned; D004338:Drug Combinations; D024243:HMGB1 Protein; D007797:Laminin; D011509:Proteoglycans; D011994:Recombinant Proteins; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; C059485:matrigel; D003094:Collagen; D019869:Phosphatidylinositol 3-Kinases; C498978:MOK protein, human; D020928:Mitogen-Activated Protein Kinases; D005947:Glucose
keywords: Glucose deprivation; HMGB1; Invasion; Myofibroblasts; Tumour microenvironment