title: Smad4 loss is associated with fewer S100A8-positive monocytes in colorectal tumors and attenuated response to S100A8 in colorectal and pancreatic cancer cells.
abstract: S100A8 and its dimerization partner S100A9 are emerging as important chemokines in cancer. We previously reported that Smad4-negative pancreatic tumors contain fewer stromal S100A8-positive monocytes than their Smad4-positive counterparts. Here, we studied S100A8/A9-expressing cells in colorectal tumors relating their presence to clinicopathological parameters and Smad4 status. Two-dimensional gel electrophoresis (n = 12) revealed variation in the levels of S100A8 protein in colorectal cancer tumors, whereas immunohistochemical analysis (n = 313) showed variation in the numbers of stromal S100A8-positive and S100A9-positive cells. Loss of Smad4 expression was observed in 42/304 (14%) colorectal tumors and was associated with reduced numbers of S100A8-positive (P = 0.03) but not S100A9-positive stromal cells (P = 0.26). High S100A9 cell counts were associated with large tumor sizes (P = 0.0006) and poor differentiation grade (P = 0.036). However, neither S100A8 nor S100A9 cell counts predicted poor survival, except for patients with Smad4-negative tumors (P = 0.02). To address the impact of environmental S100A8/A9 chemokines on tumor cells, we examined the effects of exogenously added S100A8 and S100A9 proteins on cellular migration and proliferation of colorectal and pancreatic cancer cells. S100A8 and S100A9 enhanced migration and proliferation in Smad4-positive and Smad4-negative cancer cells. However, transient depletion of Smad4 resulted in loss of responsiveness to exogenous S100A8, but not S100A9. S100A8 and S100A9 activated Smad4 signaling as evidenced by phosphorylation of Smad2/3; blockade of the receptor for the advanced glycation end products inhibited this response. In conclusion, Smad4 loss alters the tumor's interaction with stromal myeloid cells and the tumor cells' response to the stromal chemokine, S100A8.
authors.affiliation: The Liverpool Cancer Research-UK Centre, Division of Surgery and Oncology, School of Cancer Studies, University of Liverpool, Liverpool L69 3GA, UK.
authors.forename: Chin Wee
authors.initials: CW
authors.lastname: Ang
authors.forename: Taoufik
authors.initials: T
authors.lastname: Nedjadi
authors.forename: Adnan A
authors.initials: AA
authors.lastname: Sheikh
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Tweedle
authors.forename: Sarah
authors.initials: S
authors.lastname: Tonack
authors.forename: Sailish
authors.initials: S
authors.lastname: Honap
authors.forename: Rosalind E
authors.initials: RE
authors.lastname: Jenkins
authors.forename: B Kevin
authors.initials: BK
authors.lastname: Park
authors.forename: Irmgard
authors.initials: I
authors.lastname: Schwarte-Waldhoff
authors.forename: Ilyas
authors.initials: I
authors.lastname: Khattak
authors.forename: Bahram
authors.initials: B
authors.lastname: Azadeh
authors.forename: Andrew
authors.initials: A
authors.lastname: Dodson
authors.forename: Helen
authors.initials: H
authors.lastname: Kalirai
authors.forename: John P
authors.initials: JP
authors.lastname: Neoptolemos
authors.forename: Paul S
authors.initials: PS
authors.lastname: Rooney
authors.forename: Eithne
authors.initials: E
authors.lastname: Costello
mesh_terms: D000368:Aged; D015153:Blotting, Western; D040501:Calgranulin A / Q000378:metabolism*; D040502:Calgranulin B / Q000378:metabolism; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000473:pathology; D019281:Dimerization; D015180:Electrophoresis, Gel, Two-Dimensional; D005260:Female; D005455:Fluorescent Antibody Technique; D017127:Glycation End Products, Advanced / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000166:cytology / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D034741:RNA, Small Interfering / Q000494:pharmacology; D015398:Signal Transduction; D051901:Smad4 Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology
chemical_list: D040501:Calgranulin A; D040502:Calgranulin B; D017127:Glycation End Products, Advanced; D034741:RNA, Small Interfering; C497796:SMAD4 protein, human; D051901:Smad4 Protein