Publikation
GM-CSF Production by Tumor Cells Is Associated with Improved Survival in Colorectal Cancer
Wissenschaftlicher Artikel/Review - 15.04.2014
Nebiker Christian A, Oertli Daniel, von Holzen Urs, Adamina Michel, Muraro Manuele G, Mengus Chantal, Zajac Paul, Sconocchia Giuseppe, Zuber Markus, Tornillo Luigi, Terracciano Luigi, Bolli Martin, Rosso Raffaele, Han Junyi, Eppenberger-Castori Serenella, Iezzi Giandomenica, Hirt Christian, Amicarella Francesca, Cremonesi Eleonora, Huber Xaver, Padovan Elisabetta, Angrisani Basilio, Droeser Raoul A, Spagnoli Giulio C
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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.