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Clin Cancer Res. 2014 Jun 15;20(12):3094-106. doi: 10.1158/1078-0432.CCR-13-2774. Epub 2014 Apr 15.

GM-CSF Production by Tumor Cells Is Associated with Improved Survival in Colorectal Cancer.

Author information

1
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.
2
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.
3
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.
4
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.

Abstract

PURPOSE:

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.

EXPERIMENTAL DESIGN:

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.

PMID:
24737547
DOI:
10.1158/1078-0432.CCR-13-2774
[Indexed for MEDLINE]
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