肿瘤细胞产生 GM-CSF 与结直肠癌患者的生存改善相关。

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

机构信息

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.

出版信息

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

DOI:10.1158/1078-0432.CCR-13-2774

PMID:24737547

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.

摘要

目的

CD16(+) 髓系细胞浸润结直肠癌与改善预后相关。我们探讨了与巨噬细胞极化相关的潜在细胞因子的机制线索和基因及蛋白表达。

实验设计

从健康供者的外周血 CD14(+)细胞中用 GM-CSF 或 M-CSF 刺激，然后与结直肠癌细胞共培养。通过 (3)H-胸腺嘧啶掺入来评估肿瘤细胞增殖。用定量实时 PCR 检测结直肠癌和自体健康黏膜中的细胞因子基因表达。用 GM-CSF 和 M-CSF 特异性抗体对包括 >1200 个结直肠癌症标本的肿瘤微阵列（TMA）进行染色。分析临床病理特征和总生存期。

结果

与 M-CSF 刺激的细胞（28% ± 1%）相比，GM-CSF 诱导 66% ± 8%单核细胞中 CD16 表达（P = 0.011）。GM-CSF 而非 M-CSF 刺激的巨噬细胞显著（P < 0.02）抑制结直肠癌细胞增殖。GM-CSF 基因在结直肠癌中的表达显著（n = 45，P < 0.0001）高于健康黏膜，而 M-CSF 基因在健康黏膜和结直肠癌中表达相似。相应地，通常由 M1 巨噬细胞表达的 IL1β 和 IL23 基因在结直肠癌中表达显著（P < 0.001）高于健康黏膜。TMA 染色显示肿瘤细胞产生 GM-CSF 与较低的 T 分期（P = 0.02）、“推动”生长模式（P = 0.004）相关，并与错配修复功能正常的结直肠癌患者显著（P = 0.0002）更长的生存时间相关。GM-CSF 产生与结直肠癌浸润的 CD16(+)和 CD8(+)细胞无关，通过多变量分析证实了肿瘤细胞产生 GM-CSF 是结直肠癌的独立有利预后因素。M-CSF 表达与预后无关。