title: PI3K/AKT signaling is essential for communication between tissue-infiltrating mast cells, macrophages, and epithelial cells in colitis-induced cancer.
abstract: OBJECTIVE
  To understand signaling pathways that shape inflamed tissue and predispose to cancer is critical for effective prevention and therapy for chronic inflammatory diseases. We have explored phosphoinositide 3-kinase (PI3K) activity in human inflammatory bowel diseases and mouse colitis models.
  
  
  METHODS
  We conducted immunostaining of phosphorylated AKT (pAKT) and unbiased high-throughput image acquisition and quantitative analysis of samples of noninflamed normal colon, colitis, dysplasia, and colorectal cancer. Mechanistic insights were gained from ex vivo studies of cell interactions, the piroxicam/IL-10(-/-) mouse model of progressive colitis, and use of the PI3K inhibitor LY294002.
  
  
  RESULTS
  Progressive increase in densities of pAKT-positive tumor-associated macrophages (TAM) and increase in densities of mast cells in the colonic submucosa were noted with colitis and progression to dysplasia and cancer. Mast cells recruited macrophages in ex vivo migration assays, and both mast cells and TAMs promoted invasion of cancer cells. Pretreatment of mast cells with LY294002 blocked recruitment of TAMs. LY294002 inhibited mast cell and TAM-mediated tumor invasion, and in mice, blocked stromal PI3K, colitis, and cancer.
  
  
  CONCLUSIONS
  The PI3K/AKT pathway is active in cells infiltrating inflamed human colon tissue. This pathway sustains the recruitment of inflammatory cells through a positive feedback loop. The PI3K/AKT pathway is essential for tumor invasion and the malignant features of the piroxicam/IL-10(-/-) mouse model. LY294002 targets the PI3K pathway and hinders progressive colitis. These findings indicate that colitis and progression to cancer are dependent on stromal PI3K and sensitive to treatment with LY294002.
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Feinberg School of Medicine, Chicago, Illinois 60611, USA.
authors.forename: Mohammad W
authors.initials: MW
authors.lastname: Khan
authors.forename: Ali
authors.initials: A
authors.lastname: Keshavarzian
authors.forename: Elias
authors.initials: E
authors.lastname: Gounaris
authors.forename: Joshua E
authors.initials: JE
authors.lastname: Melson
authors.forename: Eric C
authors.initials: EC
authors.lastname: Cheon
authors.forename: Nichole R
authors.initials: NR
authors.lastname: Blatner
authors.forename: Zongmin E
authors.initials: ZE
authors.lastname: Chen
authors.forename: Fu-Nien
authors.initials: FN
authors.lastname: Tsai
authors.forename: Goo
authors.initials: G
authors.lastname: Lee
authors.forename: Hyunji
authors.initials: H
authors.lastname: Ryu
authors.forename: Terrence A
authors.initials: TA
authors.lastname: Barrett
authors.forename: David J
authors.initials: DJ
authors.lastname: Bentrem
authors.forename: Philipp
authors.initials: P
authors.lastname: Beckhove
authors.forename: Khashayarsha
authors.initials: K
authors.lastname: Khazaie
mesh_terms: D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology; D015550:Cell Degranulation / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D002867:Chromones / Q000494:pharmacology; D003092:Colitis / Q000150:complications / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D003106:Colon / Q000473:pathology; D015179:Colorectal Neoplasms / Q000209:etiology / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D004847:Epithelial Cells / Q000201:enzymology*; D019073:HT29 Cells; D006801:Humans; D007413:Intestinal Mucosa / Q000473:pathology; D008264:Macrophages / Q000201:enzymology*; D008407:Mast Cells / Q000201:enzymology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009025:Morpholines / Q000494:pharmacology; D009361:Neoplasm Invasiveness; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010894:Piroxicam / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction; D053802:Tryptases / Q000378:metabolism
chemical_list: D016588:Anticarcinogenic Agents; D002867:Chromones; D016861:Cyclooxygenase Inhibitors; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010894:Piroxicam; D051057:Proto-Oncogene Proteins c-akt; D053802:Tryptases; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one