title: GM-CSF Production by Tumor Cells Is Associated with Improved Survival in Colorectal Cancer.
abstract: OBJECTIVE
  Colorectal cancer infiltration by CD16(+) myeloid cells correlates with improved prognosis. We addressed mechanistic clues and gene and protein expression of cytokines potentially associated with macrophage polarization.
  
  
  METHODS
  GM-CSF or M-CSF-stimulated peripheral blood CD14(+) cells from healthy donors were cocultured with colorectal cancer cells. Tumor cell proliferation was assessed by (3)H-thymidine incorporation. Expression of cytokine genes in colorectal cancer and autologous healthy mucosa was tested by quantitative, real-time PCR. A tumor microarray (TMA) including >1,200 colorectal cancer specimens was stained with GM-CSF- and M-CSF-specific antibodies. Clinicopathological features and overall survival were analyzed.
  
  
  RESULTS
  GM-CSF induced CD16 expression in 66% ± 8% of monocytes, as compared with 28% ± 1% in cells stimulated by M-CSF (P = 0.011). GM-CSF but not M-CSF-stimulated macrophages significantly (P < 0.02) inhibited colorectal cancer cell proliferation. GM-CSF gene was expressed to significantly (n = 45, P < 0.0001) higher extents in colorectal cancer than in healthy mucosa, whereas M-CSF gene expression was similar in healthy mucosa and colorectal cancer. Accordingly, IL1β and IL23 genes, typically expressed by M1 macrophages, were expressed to significantly (P < 0.001) higher extents in colorectal cancer than in healthy mucosa. TMA staining revealed that GM-CSF production by tumor cells is associated with lower T stage (P = 0.02), "pushing" growth pattern (P = 0.004) and significantly (P = 0.0002) longer survival in mismatch-repair proficient colorectal cancer. Favorable prognostic effect of GM-CSF production by colorectal cancer cells was confirmed by multivariate analysis and was independent from CD16(+) and CD8(+) cell colorectal cancer infiltration. M-CSF expression had no significant prognostic relevance.
  
  
  CONCLUSIONS
  GM-CSF production by tumor cells is an independent favorable prognostic factor in colorectal cancer.
authors.affiliation: Authors' Affiliations: Department of Biomedicine, Institute for Surgical Research; Institute of Pathology, University of Basel; Department of Surgery, University Hospital, Basel; Ospedale Regionale, Lugano; Ospedale Regionale "San Giovanni," Bellinzona; Department of Surgery, Kantonsspital, St Gallen; Department of Surgery, Kantonsspital, Olten, Switzerland; Departments of General Surgery and Gastroenterology, Shanghai East Hospital, Tongji University, Shanghai, P.R. China; and Institute of Translational Pharmacology, National Research Council, Rome, Italy.
authors.forename: Christian A
authors.initials: CA
authors.lastname: Nebiker
authors.affiliation: Authors' Affiliations: Department of Biomedicine, Institute for Surgical Research; Institute of Pathology, University of Basel; Department of Surgery, University Hospital, Basel; Ospedale Regionale, Lugano; Ospedale Regionale "San Giovanni," Bellinzona; Department of Surgery, Kantonsspital, St Gallen; Department of Surgery, Kantonsspital, Olten, Switzerland; Departments of General Surgery and Gastroenterology, Shanghai East Hospital, Tongji University, Shanghai, P.R. China; and Institute of Translational Pharmacology, National Research Council, Rome, ItalyAuthors' Affiliations: Department of Biomedicine, Institute for Surgical Research; Institute of Pathology, University of Basel; Department of Surgery, University Hospital, Basel; Ospedale Regionale, Lugano; Ospedale Regionale "San Giovanni," Bellinzona; Department of Surgery, Kantonsspital, St Gallen; Department of Surgery, Kantonsspital, Olten, Switzerland; Departments of General Surgery and Gastroenterology, Shanghai East Hospital, Tongji University, Shanghai, P.R. China; and Institute of Translational Pharmacology, National Research Council, Rome, ItalyAuthors' Affiliations: Department of Biomedicine, Institute for Surgical Research; Institute of Pathology, University of Basel; Department of Surgery, University Hospital, Basel; Ospedale Regionale, Lugano; Ospedale Regionale "San Giovanni," Bellinzona; Department of Surgery, Kantonsspital, St Gallen; Department of Surgery, Kantonsspital, Olten, Switzerland; Departments of General Surgery and Gastroenterology, Shanghai East Hospital, Tongji University, Shanghai, P.R. China; and Institute of Translational Pharmacology, National Research Council, Rome, Italy.
authors.forename: Junyi
authors.initials: J
authors.lastname: Han
authors.affiliation: Authors' Affiliations: Department of Biomedicine, Institute for Surgical Research; Institute of Pathology, University of Basel; Department of Surgery, University Hospital, Basel; Ospedale Regionale, Lugano; Ospedale Regionale "San Giovanni," Bellinzona; Department of Surgery, Kantonsspital, St Gallen; Department of Surgery, Kantonsspital, Olten, Switzerland; Departments of General Surgery and Gastroenterology, Shanghai East Hospital, Tongji University, Shanghai, P.R. China; and Institute of Translational Pharmacology, National Research Council, Rome, Italy.
authors.forename: Serenella
authors.initials: S
authors.lastname: Eppenberger-Castori
authors.affiliation: Authors' Affiliations: Department of Biomedicine, Institute for Surgical Research; Institute of Pathology, University of Basel; Department of Surgery, University Hospital, Basel; Ospedale Regionale, Lugano; Ospedale Regionale "San Giovanni," Bellinzona; Department of Surgery, Kantonsspital, St Gallen; Department of Surgery, Kantonsspital, Olten, Switzerland; Departments of General Surgery and Gastroenterology, Shanghai East Hospital, Tongji University, Shanghai, P.R. China; and Institute of Translational Pharmacology, National Research Council, Rome, Italy.
authors.forename: Giandomenica
authors.initials: G
authors.lastname: Iezzi
authors.affiliation: Authors' Affiliations: Department of Biomedicine, Institute for Surgical Research; Institute of Pathology, University of Basel; Department of Surgery, University Hospital, Basel; Ospedale Regionale, Lugano; Ospedale Regionale "San Giovanni," Bellinzona; Department of Surgery, Kantonsspital, St Gallen; Department of Surgery, Kantonsspital, Olten, Switzerland; Departments of General Surgery and Gastroenterology, Shanghai East Hospital, Tongji University, Shanghai, P.R. China; and Institute of Translational Pharmacology, National Research Council, Rome, Italy.
authors.forename: Christian
authors.initials: C
authors.lastname: Hirt
authors.affiliation: Authors' Affiliations: Department of Biomedicine, Institute for Surgical Research; Institute of Pathology, University of Basel; Department of Surgery, University Hospital, Basel; Ospedale Regionale, Lugano; Ospedale Regionale "San Giovanni," Bellinzona; Department of Surgery, Kantonsspital, St Gallen; Department of Surgery, Kantonsspital, Olten, Switzerland; Departments of General Surgery and Gastroenterology, Shanghai East Hospital, Tongji University, Shanghai, P.R. China; and Institute of Translational Pharmacology, National Research Council, Rome, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Amicarella
authors.affiliation: Authors' Affiliations: Department of Biomedicine, Institute for Surgical Research; Institute of Pathology, University of Basel; Department of Surgery, University Hospital, Basel; Ospedale Regionale, Lugano; Ospedale Regionale "San Giovanni," Bellinzona; Department of Surgery, Kantonsspital, St Gallen; Department of Surgery, Kantonsspital, Olten, Switzerland; Departments of General Surgery and Gastroenterology, Shanghai East Hospital, Tongji University, Shanghai, P.R. China; and Institute of Translational Pharmacology, National Research Council, Rome, Italy.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Cremonesi
authors.affiliation: Authors' Affiliations: Department of Biomedicine, Institute for Surgical Research; Institute of Pathology, University of Basel; Department of Surgery, University Hospital, Basel; Ospedale Regionale, Lugano; Ospedale Regionale "San Giovanni," Bellinzona; Department of Surgery, Kantonsspital, St Gallen; Department of Surgery, Kantonsspital, Olten, Switzerland; Departments of General Surgery and Gastroenterology, Shanghai East Hospital, Tongji University, Shanghai, P.R. China; and Institute of Translational Pharmacology, National Research Council, Rome, ItalyAuthors' Affiliations: Department of Biomedicine, Institute for Surgical Research; Institute of Pathology, University of Basel; Department of Surgery, University Hospital, Basel; Ospedale Regionale, Lugano; Ospedale Regionale "San Giovanni," Bellinzona; Department of Surgery, Kantonsspital, St Gallen; Department of Surgery, Kantonsspital, Olten, Switzerland; Departments of General Surgery and Gastroenterology, Shanghai East Hospital, Tongji University, Shanghai, P.R. China; and Institute of Translational Pharmacology, National Research Council, Rome, Italy.
authors.forename: Xaver
authors.initials: X
authors.lastname: Huber
authors.affiliation: Authors' Affiliations: Department of Biomedicine, Institute for Surgical Research; Institute of Pathology, University of Basel; Department of Surgery, University Hospital, Basel; Ospedale Regionale, Lugano; Ospedale Regionale "San Giovanni," Bellinzona; Department of Surgery, Kantonsspital, St Gallen; Department of Surgery, Kantonsspital, Olten, Switzerland; Departments of General Surgery and Gastroenterology, Shanghai East Hospital, Tongji University, Shanghai, P.R. China; and Institute of Translational Pharmacology, National Research Council, Rome, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Padovan
authors.affiliation: Authors' Affiliations: Department of Biomedicine, Institute for Surgical Research; Institute of Pathology, University of Basel; Department of Surgery, University Hospital, Basel; Ospedale Regionale, Lugano; Ospedale Regionale "San Giovanni," Bellinzona; Department of Surgery, Kantonsspital, St Gallen; Department of Surgery, Kantonsspital, Olten, Switzerland; Departments of General Surgery and Gastroenterology, Shanghai East Hospital, Tongji University, Shanghai, P.R. China; and Institute of Translational Pharmacology, National Research Council, Rome, Italy.
authors.forename: Basilio
authors.initials: B
authors.lastname: Angrisani
authors.affiliation: Authors' Affiliations: Department of Biomedicine, Institute for Surgical Research; Institute of Pathology, University of Basel; Department of Surgery, University Hospital, Basel; Ospedale Regionale, Lugano; Ospedale Regionale "San Giovanni," Bellinzona; Department of Surgery, Kantonsspital, St Gallen; Department of Surgery, Kantonsspital, Olten, Switzerland; Departments of General Surgery and Gastroenterology, Shanghai East Hospital, Tongji University, Shanghai, P.R. China; and Institute of Translational Pharmacology, National Research Council, Rome, ItalyAuthors' Affiliations: Department of Biomedicine, Institute for Surgical Research; Institute of Pathology, University of Basel; Department of Surgery, University Hospital, Basel; Ospedale Regionale, Lugano; Ospedale Regionale "San Giovanni," Bellinzona; Department of Surgery, Kantonsspital, St Gallen; Department of Surgery, Kantonsspital, Olten, Switzerland; Departments of General Surgery and Gastroenterology, Shanghai East Hospital, Tongji University, Shanghai, P.R. China; and Institute of Translational Pharmacology, National Research Council, Rome, Italy.
authors.forename: Raoul A
authors.initials: RA
authors.lastname: Droeser
authors.affiliation: Authors' Affiliations: Department of Biomedicine, Institute for Surgical Research; Institute of Pathology, University of Basel; Department of Surgery, University Hospital, Basel; Ospedale Regionale, Lugano; Ospedale Regionale "San Giovanni," Bellinzona; Department of Surgery, Kantonsspital, St Gallen; Department of Surgery, Kantonsspital, Olten, Switzerland; Departments of General Surgery and Gastroenterology, Shanghai East Hospital, Tongji University, Shanghai, P.R. China; and Institute of Translational Pharmacology, National Research Council, Rome, Italy.
authors.forename: Raffaele
authors.initials: R
authors.lastname: Rosso
authors.affiliation: Authors' Affiliations: Department of Biomedicine, Institute for Surgical Research; Institute of Pathology, University of Basel; Department of Surgery, University Hospital, Basel; Ospedale Regionale, Lugano; Ospedale Regionale "San Giovanni," Bellinzona; Department of Surgery, Kantonsspital, St Gallen; Department of Surgery, Kantonsspital, Olten, Switzerland; Departments of General Surgery and Gastroenterology, Shanghai East Hospital, Tongji University, Shanghai, P.R. China; and Institute of Translational Pharmacology, National Research Council, Rome, Italy.
authors.forename: Martin
authors.initials: M
authors.lastname: Bolli
authors.affiliation: Authors' Affiliations: Department of Biomedicine, Institute for Surgical Research; Institute of Pathology, University of Basel; Department of Surgery, University Hospital, Basel; Ospedale Regionale, Lugano; Ospedale Regionale "San Giovanni," Bellinzona; Department of Surgery, Kantonsspital, St Gallen; Department of Surgery, Kantonsspital, Olten, Switzerland; Departments of General Surgery and Gastroenterology, Shanghai East Hospital, Tongji University, Shanghai, P.R. China; and Institute of Translational Pharmacology, National Research Council, Rome, Italy.
authors.forename: Daniel
authors.initials: D
authors.lastname: Oertli
authors.affiliation: Authors' Affiliations: Department of Biomedicine, Institute for Surgical Research; Institute of Pathology, University of Basel; Department of Surgery, University Hospital, Basel; Ospedale Regionale, Lugano; Ospedale Regionale "San Giovanni," Bellinzona; Department of Surgery, Kantonsspital, St Gallen; Department of Surgery, Kantonsspital, Olten, Switzerland; Departments of General Surgery and Gastroenterology, Shanghai East Hospital, Tongji University, Shanghai, P.R. China; and Institute of Translational Pharmacology, National Research Council, Rome, Italy.
authors.forename: Urs
authors.initials: U
authors.lastname: von Holzen
authors.affiliation: Authors' Affiliations: Department of Biomedicine, Institute for Surgical Research; Institute of Pathology, University of Basel; Department of Surgery, University Hospital, Basel; Ospedale Regionale, Lugano; Ospedale Regionale "San Giovanni," Bellinzona; Department of Surgery, Kantonsspital, St Gallen; Department of Surgery, Kantonsspital, Olten, Switzerland; Departments of General Surgery and Gastroenterology, Shanghai East Hospital, Tongji University, Shanghai, P.R. China; and Institute of Translational Pharmacology, National Research Council, Rome, Italy.
authors.forename: Michel
authors.initials: M
authors.lastname: Adamina
authors.affiliation: Authors' Affiliations: Department of Biomedicine, Institute for Surgical Research; Institute of Pathology, University of Basel; Department of Surgery, University Hospital, Basel; Ospedale Regionale, Lugano; Ospedale Regionale "San Giovanni," Bellinzona; Department of Surgery, Kantonsspital, St Gallen; Department of Surgery, Kantonsspital, Olten, Switzerland; Departments of General Surgery and Gastroenterology, Shanghai East Hospital, Tongji University, Shanghai, P.R. China; and Institute of Translational Pharmacology, National Research Council, Rome, Italy.
authors.forename: Manuele G
authors.initials: MG
authors.lastname: Muraro
authors.affiliation: Authors' Affiliations: Department of Biomedicine, Institute for Surgical Research; Institute of Pathology, University of Basel; Department of Surgery, University Hospital, Basel; Ospedale Regionale, Lugano; Ospedale Regionale "San Giovanni," Bellinzona; Department of Surgery, Kantonsspital, St Gallen; Department of Surgery, Kantonsspital, Olten, Switzerland; Departments of General Surgery and Gastroenterology, Shanghai East Hospital, Tongji University, Shanghai, P.R. China; and Institute of Translational Pharmacology, National Research Council, Rome, Italy.
authors.forename: Chantal
authors.initials: C
authors.lastname: Mengus
authors.affiliation: Authors' Affiliations: Department of Biomedicine, Institute for Surgical Research; Institute of Pathology, University of Basel; Department of Surgery, University Hospital, Basel; Ospedale Regionale, Lugano; Ospedale Regionale "San Giovanni," Bellinzona; Department of Surgery, Kantonsspital, St Gallen; Department of Surgery, Kantonsspital, Olten, Switzerland; Departments of General Surgery and Gastroenterology, Shanghai East Hospital, Tongji University, Shanghai, P.R. China; and Institute of Translational Pharmacology, National Research Council, Rome, Italy.
authors.forename: Paul
authors.initials: P
authors.lastname: Zajac
authors.affiliation: Authors' Affiliations: Department of Biomedicine, Institute for Surgical Research; Institute of Pathology, University of Basel; Department of Surgery, University Hospital, Basel; Ospedale Regionale, Lugano; Ospedale Regionale "San Giovanni," Bellinzona; Department of Surgery, Kantonsspital, St Gallen; Department of Surgery, Kantonsspital, Olten, Switzerland; Departments of General Surgery and Gastroenterology, Shanghai East Hospital, Tongji University, Shanghai, P.R. China; and Institute of Translational Pharmacology, National Research Council, Rome, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Sconocchia
authors.affiliation: Authors' Affiliations: Department of Biomedicine, Institute for Surgical Research; Institute of Pathology, University of Basel; Department of Surgery, University Hospital, Basel; Ospedale Regionale, Lugano; Ospedale Regionale "San Giovanni," Bellinzona; Department of Surgery, Kantonsspital, St Gallen; Department of Surgery, Kantonsspital, Olten, Switzerland; Departments of General Surgery and Gastroenterology, Shanghai East Hospital, Tongji University, Shanghai, P.R. China; and Institute of Translational Pharmacology, National Research Council, Rome, Italy.
authors.forename: Markus
authors.initials: M
authors.lastname: Zuber
authors.affiliation: Authors' Affiliations: Department of Biomedicine, Institute for Surgical Research; Institute of Pathology, University of Basel; Department of Surgery, University Hospital, Basel; Ospedale Regionale, Lugano; Ospedale Regionale "San Giovanni," Bellinzona; Department of Surgery, Kantonsspital, St Gallen; Department of Surgery, Kantonsspital, Olten, Switzerland; Departments of General Surgery and Gastroenterology, Shanghai East Hospital, Tongji University, Shanghai, P.R. China; and Institute of Translational Pharmacology, National Research Council, Rome, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Tornillo
authors.affiliation: Authors' Affiliations: Department of Biomedicine, Institute for Surgical Research; Institute of Pathology, University of Basel; Department of Surgery, University Hospital, Basel; Ospedale Regionale, Lugano; Ospedale Regionale "San Giovanni," Bellinzona; Department of Surgery, Kantonsspital, St Gallen; Department of Surgery, Kantonsspital, Olten, Switzerland; Departments of General Surgery and Gastroenterology, Shanghai East Hospital, Tongji University, Shanghai, P.R. China; and Institute of Translational Pharmacology, National Research Council, Rome, Italy giulio.spagnoli@usb.ch lterracciano@uhbs.ch.
authors.forename: Luigi
authors.initials: L
authors.lastname: Terracciano
authors.affiliation: Authors' Affiliations: Department of Biomedicine, Institute for Surgical Research; Institute of Pathology, University of Basel; Department of Surgery, University Hospital, Basel; Ospedale Regionale, Lugano; Ospedale Regionale "San Giovanni," Bellinzona; Department of Surgery, Kantonsspital, St Gallen; Department of Surgery, Kantonsspital, Olten, Switzerland; Departments of General Surgery and Gastroenterology, Shanghai East Hospital, Tongji University, Shanghai, P.R. China; and Institute of Translational Pharmacology, National Research Council, Rome, Italy giulio.spagnoli@usb.ch lterracciano@uhbs.ch.
authors.forename: Giulio C
authors.initials: GC
authors.lastname: Spagnoli
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D016022:Case-Control Studies; D049109:Cell Proliferation; D018925:Chemokines / Q000235:genetics / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000401:mortality* / Q000473:pathology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D005260:Female; D005500:Follow-Up Studies; D020869:Gene Expression Profiling; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism*; D006801:Humans; D007121:Immunocompetence; D007124:Immunoenzyme Techniques; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism / Q000473:pathology*; D060787:Neoplasm Grading; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D011379:Prognosis; D060888:Real-Time Polymerase Chain Reaction; D015996:Survival Rate; D046888:Tissue Array Analysis
chemical_list: D014408:Biomarkers, Tumor; D018925:Chemokines; D016207:Cytokines; D016173:Macrophage Colony-Stimulating Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor