title: Stromal genes discriminate preinvasive from invasive disease, predict outcome, and highlight inflammatory pathways in digestive cancers.
abstract: The stromal compartment is increasingly recognized to play a role in cancer. However, its role in the transition from preinvasive to invasive disease is unknown. Most gastrointestinal tumors have clearly defined premalignant stages, and Barrett's esophagus (BE) is an ideal research model. Supervised clustering of gene expression profiles from microdissected stroma identified a gene signature that could distinguish between BE metaplasia, dysplasia, and esophageal adenocarcinoma (EAC). EAC patients overexpressing any of the five genes (TMEPAI, JMY, TSP1, FAPalpha, and BCL6) identified from this stromal signature had a significantly poorer outcome. Gene ontology analysis identified a strong inflammatory component in BE disease progression, and key pathways included cytokine-cytokine receptor interactions and TGF-beta. Increased protein levels of inflammatory-related genes significantly up-regulated in EAC compared with preinvasive stages were confirmed in the stroma of independent samples, and in vitro assays confirmed functional relevance of these genes. Gene set enrichment analysis of external datasets demonstrated that the stromal signature was also relevant in the preinvasive to invasive transition of the stomach, colon, and pancreas. These data implicate inflammatory pathways in the genesis of gastrointestinal tract cancers, which can affect prognosis.
authors.affiliation: Medical Research Council Cancer Cell Unit, Hutchison Medical Research Council Research Centre, Cambridge CB22 0XZ, United Kingdom.
authors.forename: Amel
authors.initials: A
authors.lastname: Saadi
authors.forename: Nicholas B
authors.initials: NB
authors.lastname: Shannon
authors.forename: Pierre
authors.initials: P
authors.lastname: Lao-Sirieix
authors.forename: Maria
authors.initials: M
authors.lastname: O'Donovan
authors.forename: Elaine
authors.initials: E
authors.lastname: Walker
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Clemons
authors.forename: James S
authors.initials: JS
authors.lastname: Hardwick
authors.forename: Chunsheng
authors.initials: C
authors.lastname: Zhang
authors.forename: Madhumita
authors.initials: M
authors.lastname: Das
authors.forename: Vicki
authors.initials: V
authors.lastname: Save
authors.forename: Marco
authors.initials: M
authors.lastname: Novelli
authors.forename: Frances
authors.initials: F
authors.lastname: Balkwill
authors.forename: Rebecca C
authors.initials: RC
authors.lastname: Fitzgerald
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000276:immunology / Q000473:pathology; D001471:Barrett Esophagus / Q000235:genetics / Q000276:immunology / Q000473:pathology; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics; D016207:Cytokines / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D004067:Digestive System Neoplasms / Q000235:genetics* / Q000276:immunology / Q000473:pathology*; D010450:Endopeptidases; D004938:Esophageal Neoplasms / Q000235:genetics / Q000276:immunology / Q000473:pathology; D018093:Gelatinases / Q000235:genetics; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics; D008679:Metaplasia; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics; D009857:Oncogenes; D011230:Precancerous Conditions / Q000235:genetics / Q000276:immunology / Q000473:pathology; D011379:Prognosis; D051560:Proto-Oncogene Proteins c-bcl-6; D018121:Receptors, Cytokine / Q000235:genetics; D012697:Serine Endopeptidases / Q000235:genetics; D017154:Stromal Cells / Q000276:immunology / Q000473:pathology; D015534:Trans-Activators / Q000235:genetics; D000099167:Fibroblast Activation Protein Alpha
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D016207:Cytokines; D004268:DNA-Binding Proteins; D010450:Endopeptidases; D018093:Gelatinases; D008565:Membrane Proteins; D009687:Nuclear Proteins; D051560:Proto-Oncogene Proteins c-bcl-6; D018121:Receptors, Cytokine; D012697:Serine Endopeptidases; D015534:Trans-Activators; D000099167:Fibroblast Activation Protein Alpha; C084103:BCL6 protein, human; C121977:JMY protein, human; C412868:PMEPA1 protein, human; C481348:SPZ1 protein, human