非小细胞肺癌中巨噬细胞集落刺激因子表达及CD163+巨噬细胞浸润与预后的关系
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摘要
研究背景
肺癌是最常见的恶性肿瘤之一,其中约80%为非小细胞肺癌。肺癌患者的死亡率高,仅有15%左右患者生存期超过五年。许多临床和实验证据表明肿瘤浸润巨噬细胞(TIMs)有促进肿瘤生长和转移的作用。巨噬细胞在巨噬细胞集落刺激因子(M-CSF)诱导下分化为高表达CD163等分子的表型。因此探讨非小细胞肺癌(NSCLC)中M-CSF的表达及巨噬细胞浸润与肿瘤的进展、转移的关系和影响患者预后的关系,有利于提高NSCLC患者的预后。
材料与方法
收集广西医科大学第一附属医院心胸外科2005年至2006年间手术切除并经病理证实的NSCLC标本47例,其中男28例,女19例,年龄29-75岁,中位年龄58岁。临床分期I期18例,II期5例,III期21例,IV期3例。鳞癌19例,腺癌28例。病理分级参照WHO标准,1级7例,2级22例,3级18例。
采用免疫组化的方法检测肿瘤组织、癌旁肺组织的M-CSF表达情况和CD163+巨噬细胞浸润情况以及它们的分布规律。
分析M-CSF表达情况、CD163+巨噬细胞浸润情况与患者临床病理参数的关系以及预后的关系。
结果
1. NSCLC中M-CSF表达和分布
M-CSF蛋白主要表达在肺癌细胞胞浆内,癌旁肺组织支气管上皮胞浆部分表达,肺泡上皮少量或无表达,间质中巨噬细胞、淋巴细胞、浆细胞部分表达。NSCLC中肿瘤组织M-CSF密度(0.026±0.023)高于癌旁肺组织(0.006±0.004)。(t=6.436,P <0.05)。
2. NSCLC中CD163+巨噬细胞分布
CD163特异性表达在巨噬细胞的胞浆、胞膜处,未见淋巴细胞、内皮细胞、成纤维细胞及肿瘤细胞表达。肿瘤的癌巢、癌内间质、癌正常交界区及癌旁肺组织均可以见到CD163+巨噬细胞浸润,癌正常交界区TIMs密度(67.95±42.56)高于癌内间质(58.28±33.36)、癌巢(45.38±29.10)及癌旁肺组织(11.02±8.54),t=2.203,t=3.055,t=9.056,P <0.05。
3. NSCLC中M-CSF的表达与CD163+巨噬细胞密度的关系
肿瘤内M-CSF密度与癌巢、癌内间质、癌与正常交界区CD163+TIMs密度正相关,随着肿瘤内M-CSF密度增加,癌巢、癌内间质或癌与正常交界区CD163+TIMs密度增高(r=0.701, r=0.361,r=0.364,P <0.05)。
4. NSCLC中M-CSF的表达及CD163+TIM密度与临床病理参数的关系
M-CSF高密度者(≥0.021平均光密度值)在1+2级分化NSCLC的比率35%(10/29),在3级分化NSCLC的比率78%(14/18),低分化癌的M-CSF密度明显高于中高分化癌(χ~2=8.331, P <0.05)。而M-CSF蛋白密度与患者性别、年龄、肿瘤大小、组织学类型、临床分期等无关(P>0.05)。交界区CD163+TIMs高密度者(≥70.00个)在I+II期的比率33%(7/21),III+IV期的比率68%(15/22),淋巴结无受累的比率30%(6/20),淋巴结受累的比率70%(16/23)。临床分期越高或淋巴结受累,交界区CD163+TIMs密度越高(χ~2=5.222,χ~2=6.702,P <0.05)。而癌巢、癌内间质CD163+TIMs密度与临床病理参数无关(P>0.05)。
5. NSCLC中M-CSF的表达及CD163+TIM密度与患者生存时间的关系
单因素分析结果显示,交界区CD163+TIMs密度高的患者平均生存时间(684d)少于CD163+TIM密度低的(1615d,χ~2=15.776,P <0.05)。癌巢、癌内间质CD163+TIM密度及肿瘤内M-CSF密度与生存期无明显关系,P >0.05。Cox风险比例回归模型多因素分析结果显示,交界区CD163+TIM密度和临床分期可以作为非小细胞肺癌患者预后的独立预测指标(CD163,HR 3.96;95%CI,1.70～9.23; P<0.05)。
结论
肺癌组织中及癌旁肺组织中均存在M-CSF的表达及CD163+TIMs,癌组织的M-CSF的表达及CD163+TIMs明显高于癌旁肺组织,且随着癌组织的M-CSF的表达增高肿瘤不同部位的CD163+TIMs明显增高。交界区CD163+TIM密度可以作为非小细胞肺癌患者预后的独立预测指标。
Background
Lung cancer is one of the most common malignance tumor,and has a high mortality in the globe world.Non-small cell lung cancer accounts for about 80% of all lung cancer.Many clinic and experiment study have suggested tumor infiltrated macrophages(TIMs) may promote the tumor invasion and matastasis. Macrophages are attracted by macrophages colony-stimulating factors(M-CSF) and induced to a phenotype which highly express CD163 and other moleculars.The objective of the present study is to evaluate relationship between the expression of macrophage-colony stimulating factors and the infiltration of the CD163+ macrophages and prognosis in non-small cell lung cancer. Materials and Methods
The paraffin-embedded specimens from 47 patients who had undergone surgery for NSCLC at the first affiliated hospital of guangxi medical university from 2005 to 2006 were included in this study ,which contains 28 cases of males,19 cases of females,median age was 58 years(range,29 to 75 years).18 cases were stage I,5 stage II,21 stage III,3 stage IV.19 tumors were squamous,28 adenicarcinoma.7 cases were grade 1,22 grade 2,18 grade 3.
Immunohistochemistry was performed to test the expression of M-CSF and infiltration of the CD163+ macrophages.
The correlations between M-CSF/CD163+ macrophages and linicopathologic features and survival time were analysed by SolutionsStatistical Package for the Social Sciences(SPSS).
Results
1. The expression and distribution of M-CSF in NSCLC
The positive staining of M-CSF was mainly found on the cytoplasm of tumor cells or some of the bronchiole epithelial cells in the peritumoral tissues .Most of the alveolar epitheliums and stroma cells were negative ,although sporadic positive staining on lymphocyte、macrophage or plasmocyte.The M-CSF staining density in tumor was higher than in peritumoral lung tissue(0.026±0.023,0.006±0.004 P <0.05).
2.The distribution of CD163+macrophages in NSCLC
The positive staining of CD163 was found on the membrane or cytoplasm of macrophages,but not on the tumor cells、lymphocytes、plasmocytes or fibroblasts. The mean member of macrophages in tumor margin(67.95±42.56)was higher than in tumor stroma(58.28±33.36), tumor nest(45.38±29.10)and peritumoral lung tissues(11.02±8.54), P <0.05.
3.The correlations between M-CSF and CD163+ macrophages
The M-CSF density in tumor was positively correlated with the density of CD163+ macrophages in tumor nest,tumor stroma and margin. (r=0.701, r=0.361,r=0.364,P <0.05)
4.The correlations between M-CSF/CD163+ macrophages and clinicopathologic features
The M-CSF density in tumor was correlated with the tumor grade,the ratio of high M-CSF density (≥0.021 IOD)in poorly differentiated grade was 78% (14/18),significantly higher than well and moderate differentiated grades( 35% 10/29).The ratio of high density of CD163+ macrophage(≥70.00 /field) in tumor margin was 68%(15/22)in III+IV stages,higher than 33%(7/21)in I+II stages ,and with lymphnode metastasis was 70%(16/23),higher than without lymphnode metastasis 30%(6/20).CD163+ macrophage infiltration in tumor margin increased with the development of clinic stage and metastasis of lymphnode(χ~2=5.222,χ~2=6.702,P <0.05). In tumor nest and stroma there was no statistically significant association between CD163+ macrophages and clinicopathologic features(P>0.05).
5.The correlations between M-CSF/CD163+ macrophages and survival time
The median survival time of those patients with a high CD163+ macrophages density in tumor margin was 684 days compared to 1615 days with a low CD163+ macrpphages density, CD163+ macrophage infiltration in tumor margin increased with the reduction of patient survival time(χ~2=15.776,P <0.05).Multivariate Cox proportional harzards assumption was to used to assess that CD163+ macrophage infiltration in tumor margin may serve as potential markers for independent predicting prognosis in NSCLC.
Conclusions
1. There were M-CSF expression and CD163+ TIMs both in lung cancer and peritumoral lung tissues.The M-CSF expression and CD163+ TIMs in lung cancer were higher than in peritumoral lung tissues, M-CSF density in tumor was positively correlated with the density of CD163+macrophages in tumor nest、tumor stroma and margin.
2. CD163+ macrophage infiltration in tumor margin may serve as potential markers for independent predicting prognosis in NSCLC.
肺癌是最常见的恶性肿瘤之一,其中约80%为非小细胞肺癌。肺癌患者的死亡率高,仅有15%左右患者生存期超过五年。许多临床和实验证据表明肿瘤浸润巨噬细胞(TIMs)有促进肿瘤生长和转移的作用。巨噬细胞在巨噬细胞集落刺激因子(M-CSF)诱导下分化为高表达CD163等分子的表型。因此探讨非小细胞肺癌(NSCLC)中M-CSF的表达及巨噬细胞浸润与肿瘤的进展、转移的关系和影响患者预后的关系,有利于提高NSCLC患者的预后。
材料与方法
收集广西医科大学第一附属医院心胸外科2005年至2006年间手术切除并经病理证实的NSCLC标本47例,其中男28例,女19例,年龄29-75岁,中位年龄58岁。临床分期I期18例,II期5例,III期21例,IV期3例。鳞癌19例,腺癌28例。病理分级参照WHO标准,1级7例,2级22例,3级18例。
采用免疫组化的方法检测肿瘤组织、癌旁肺组织的M-CSF表达情况和CD163+巨噬细胞浸润情况以及它们的分布规律。
分析M-CSF表达情况、CD163+巨噬细胞浸润情况与患者临床病理参数的关系以及预后的关系。
结果
1. NSCLC中M-CSF表达和分布
M-CSF蛋白主要表达在肺癌细胞胞浆内,癌旁肺组织支气管上皮胞浆部分表达,肺泡上皮少量或无表达,间质中巨噬细胞、淋巴细胞、浆细胞部分表达。NSCLC中肿瘤组织M-CSF密度(0.026±0.023)高于癌旁肺组织(0.006±0.004)。(t=6.436,P <0.05)。
2. NSCLC中CD163+巨噬细胞分布
CD163特异性表达在巨噬细胞的胞浆、胞膜处,未见淋巴细胞、内皮细胞、成纤维细胞及肿瘤细胞表达。肿瘤的癌巢、癌内间质、癌正常交界区及癌旁肺组织均可以见到CD163+巨噬细胞浸润,癌正常交界区TIMs密度(67.95±42.56)高于癌内间质(58.28±33.36)、癌巢(45.38±29.10)及癌旁肺组织(11.02±8.54),t=2.203,t=3.055,t=9.056,P <0.05。
3. NSCLC中M-CSF的表达与CD163+巨噬细胞密度的关系
肿瘤内M-CSF密度与癌巢、癌内间质、癌与正常交界区CD163+TIMs密度正相关,随着肿瘤内M-CSF密度增加,癌巢、癌内间质或癌与正常交界区CD163+TIMs密度增高(r=0.701, r=0.361,r=0.364,P <0.05)。
4. NSCLC中M-CSF的表达及CD163+TIM密度与临床病理参数的关系
M-CSF高密度者(≥0.021平均光密度值)在1+2级分化NSCLC的比率35%(10/29),在3级分化NSCLC的比率78%(14/18),低分化癌的M-CSF密度明显高于中高分化癌(χ~2=8.331, P <0.05)。而M-CSF蛋白密度与患者性别、年龄、肿瘤大小、组织学类型、临床分期等无关(P>0.05)。交界区CD163+TIMs高密度者(≥70.00个)在I+II期的比率33%(7/21),III+IV期的比率68%(15/22),淋巴结无受累的比率30%(6/20),淋巴结受累的比率70%(16/23)。临床分期越高或淋巴结受累,交界区CD163+TIMs密度越高(χ~2=5.222,χ~2=6.702,P <0.05)。而癌巢、癌内间质CD163+TIMs密度与临床病理参数无关(P>0.05)。
5. NSCLC中M-CSF的表达及CD163+TIM密度与患者生存时间的关系
单因素分析结果显示,交界区CD163+TIMs密度高的患者平均生存时间(684d)少于CD163+TIM密度低的(1615d,χ~2=15.776,P <0.05)。癌巢、癌内间质CD163+TIM密度及肿瘤内M-CSF密度与生存期无明显关系,P >0.05。Cox风险比例回归模型多因素分析结果显示,交界区CD163+TIM密度和临床分期可以作为非小细胞肺癌患者预后的独立预测指标(CD163,HR 3.96;95%CI,1.70～9.23; P<0.05)。
结论
肺癌组织中及癌旁肺组织中均存在M-CSF的表达及CD163+TIMs,癌组织的M-CSF的表达及CD163+TIMs明显高于癌旁肺组织,且随着癌组织的M-CSF的表达增高肿瘤不同部位的CD163+TIMs明显增高。交界区CD163+TIM密度可以作为非小细胞肺癌患者预后的独立预测指标。
Background
Lung cancer is one of the most common malignance tumor,and has a high mortality in the globe world.Non-small cell lung cancer accounts for about 80% of all lung cancer.Many clinic and experiment study have suggested tumor infiltrated macrophages(TIMs) may promote the tumor invasion and matastasis. Macrophages are attracted by macrophages colony-stimulating factors(M-CSF) and induced to a phenotype which highly express CD163 and other moleculars.The objective of the present study is to evaluate relationship between the expression of macrophage-colony stimulating factors and the infiltration of the CD163+ macrophages and prognosis in non-small cell lung cancer. Materials and Methods
The paraffin-embedded specimens from 47 patients who had undergone surgery for NSCLC at the first affiliated hospital of guangxi medical university from 2005 to 2006 were included in this study ,which contains 28 cases of males,19 cases of females,median age was 58 years(range,29 to 75 years).18 cases were stage I,5 stage II,21 stage III,3 stage IV.19 tumors were squamous,28 adenicarcinoma.7 cases were grade 1,22 grade 2,18 grade 3.
Immunohistochemistry was performed to test the expression of M-CSF and infiltration of the CD163+ macrophages.
The correlations between M-CSF/CD163+ macrophages and linicopathologic features and survival time were analysed by SolutionsStatistical Package for the Social Sciences(SPSS).
Results
1. The expression and distribution of M-CSF in NSCLC
The positive staining of M-CSF was mainly found on the cytoplasm of tumor cells or some of the bronchiole epithelial cells in the peritumoral tissues .Most of the alveolar epitheliums and stroma cells were negative ,although sporadic positive staining on lymphocyte、macrophage or plasmocyte.The M-CSF staining density in tumor was higher than in peritumoral lung tissue(0.026±0.023,0.006±0.004 P <0.05).
2.The distribution of CD163+macrophages in NSCLC
The positive staining of CD163 was found on the membrane or cytoplasm of macrophages,but not on the tumor cells、lymphocytes、plasmocytes or fibroblasts. The mean member of macrophages in tumor margin(67.95±42.56)was higher than in tumor stroma(58.28±33.36), tumor nest(45.38±29.10)and peritumoral lung tissues(11.02±8.54), P <0.05.
3.The correlations between M-CSF and CD163+ macrophages
The M-CSF density in tumor was positively correlated with the density of CD163+ macrophages in tumor nest,tumor stroma and margin. (r=0.701, r=0.361,r=0.364,P <0.05)
4.The correlations between M-CSF/CD163+ macrophages and clinicopathologic features
The M-CSF density in tumor was correlated with the tumor grade,the ratio of high M-CSF density (≥0.021 IOD)in poorly differentiated grade was 78% (14/18),significantly higher than well and moderate differentiated grades( 35% 10/29).The ratio of high density of CD163+ macrophage(≥70.00 /field) in tumor margin was 68%(15/22)in III+IV stages,higher than 33%(7/21)in I+II stages ,and with lymphnode metastasis was 70%(16/23),higher than without lymphnode metastasis 30%(6/20).CD163+ macrophage infiltration in tumor margin increased with the development of clinic stage and metastasis of lymphnode(χ~2=5.222,χ~2=6.702,P <0.05). In tumor nest and stroma there was no statistically significant association between CD163+ macrophages and clinicopathologic features(P>0.05).
5.The correlations between M-CSF/CD163+ macrophages and survival time
The median survival time of those patients with a high CD163+ macrophages density in tumor margin was 684 days compared to 1615 days with a low CD163+ macrpphages density, CD163+ macrophage infiltration in tumor margin increased with the reduction of patient survival time(χ~2=15.776,P <0.05).Multivariate Cox proportional harzards assumption was to used to assess that CD163+ macrophage infiltration in tumor margin may serve as potential markers for independent predicting prognosis in NSCLC.
Conclusions
1. There were M-CSF expression and CD163+ TIMs both in lung cancer and peritumoral lung tissues.The M-CSF expression and CD163+ TIMs in lung cancer were higher than in peritumoral lung tissues, M-CSF density in tumor was positively correlated with the density of CD163+macrophages in tumor nest、tumor stroma and margin.
2. CD163+ macrophage infiltration in tumor margin may serve as potential markers for independent predicting prognosis in NSCLC.
引文
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[37] Denardo D G, Barreto J B, Andreu P, et al. CD4(+) T cells regulate pulmonary metastasis of mammary carcinomas by enhancing protumor properties of macrophages[J]. Cancer Cell,2009,16(2):91-102.
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[41] Egeblad M, Werb Z. New functions for the matrix metalloproteinases in cancer progression[J]. Nat Rev Cancer,2002,2(3):161-174.
[42] Almholt K, Lund L R, Rygaard J, et al. Reduced metastasis of transgenic mammary cancer in urokinase-deficient mice[J]. Int J Cancer,2005,113(4):525-532.
[43] Kuang D M, Zhao Q, Peng C, et al. Activated monocytes in peritumoral stroma of hepatocellular carcinoma foster immune privilege and disease progression through PD-L1[J]. J Exp Med,2009,206(6):1327-1337.
[1] Qian B Z, Pollard J W. Macrophage diversity enhances tumor progression and metastasis[J]. 2010,141(1):39-51.
[2] Miyamoto T, Suda T. [Differentiation and function of monocyte/macrophage lineage cells and osteoblasts][J]. Nippon Rinsho,2005,63(9):1511-1516.
[3] Radzun H J. [Differentiation pathways in the monocyte/macrophage system][J]. Verh Dtsch Ges Pathol,1988,72:50-56.
[4] Tacke F, Randolph G J. Migratory fate and differentiation of blood monocyte subsets[J]. Immunobiology,2006,211(6-8):609-618.
[5] Gordon S, Taylor P R. Monocyte and macrophage heterogeneity[J]. 2005,5(12):953-964.
[6] Treves A J. The origin of monocyte-macrophage heterogeneity: possible alternatives[J]. 1984,14(4):335-346.
[7] Nowicki A, Szenajch J, Ostrowska G, et al. Impaired tumor growth in colony-stimulating factor 1 (CSF-1)-deficient, macrophage-deficient op/op mouse: evidence for a role of CSF-1-dependent macrophages in formation of tumor stroma[J]. 1996,65(1):112-119.
[8] Stanley E R, Berg K L, Einstein D B, et al. Biology and action of colony--stimulating factor-1[J]. Mol Reprod Dev,1997,46(1):4-10.
[9] Sweet M J, Hume D A. CSF-1 as a regulator of macrophage activation andimmune responses[J]. Arch Immunol Ther Exp (Warsz),2003,51(3):169-177.
[10] Aharinejad S, Abraham D, Paulus P, et al. Colony-stimulating factor-1 antisense treatment suppresses growth of human tumor xenografts in mice[J]. 2002,62(18):5317-5324.
[11] Kuropkat C, Duenne A A, Herz U, et al. Significant correlation of matrix metalloproteinase and macrophage colony-stimulating factor serum concentrations in patients with head and neck cancer[J]. 2004,51(5):375-378.
[12] Mroczko B, Szmitkowski M. [Macrophage-colony stimulating factor (M-csf) in diagnostic and monitoring of non-small-cell lung cancer (NSCLC)][J]. Pol Arch Med Wewn,2001,105(3):203-209.
[13] Rollins B J. Inflammatory chemokines in cancer growth and progression[J]. 2006,42(6):760-767.
[14] Barleon B, Sozzani S, Zhou D, et al. Migration of human monocytes in response to vascular endothelial growth factor (VEGF) is mediated via the VEGF receptor flt-1[J]. 1996,87(8):3336-3343.
[15] Uutela M, Wirzenius M, Paavonen K, et al. PDGF-D induces macrophage recruitment, increased interstitial pressure, and blood vessel maturation during angiogenesis[J]. 2004,104(10):3198-3204.
[16] Chen J J, Lin Y C, Yao P L, et al. Tumor-associated macrophages: the double-edged sword in cancer progression[J]. J Clin Oncol,2005,23(5):953-964.
[17] Mantovani A, Sozzani S, Locati M, et al. Macrophage polarization:tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes[J]. Trends Immunol,2002,23(11):549-555.
[18] Mantovani A, Sica A. Macrophages, innate immunity and cancer: balance, tolerance, and diversity[J]. 2010,22(2):231-237.
[19] Mantovani A, Allavena P, Sica A, et al. Cancer-related inflammation[J]. 2008,454(7203):436-444.
[20] Biswas S K, Gangi L, Paul S, et al. A distinct and unique transcriptional program expressed by tumor-associated macrophages (defective NF-kappaB and enhanced IRF-3/STAT1 activation)[J]. 2006,107(5):2112-2122.
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[22] Pang B, Zhou X, Yu H, et al. Lipid peroxidation dominates the chemistry of DNA adduct formation in a mouse model of inflammation[J]. 2007,28(8):1807-1813.
[23] Colotta F, Allavena P, Sica A, et al. Cancer-related inflammation, the seventh hallmark of cancer: links to genetic instability[J]. 2009,30(7):1073-1081.
[24] Balkwill F. Tumour necrosis factor and cancer[J]. 2009,9(5):361-371.
[25] Greten F R, Eckmann L, Greten T F, et al. IKKbeta links inflammation andtumorigenesis in a mouse model of colitis-associated cancer[J]. 2004,118(3):285-296.
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[29] Wang S, Yuan Y, Liao L, et al. Disruption of the SRC-1 gene in mice suppresses breast cancer metastasis without affecting primary tumor formation[J]. Proc Natl Acad Sci U S A,2009,106(1):151-156.
[30] Denardo D G, Barreto J B, Andreu P, et al. CD4(+) T cells regulate pulmonary metastasis of mammary carcinomas by enhancing protumor properties of macrophages[J]. Cancer Cell,2009,16(2):91-102.
[31] Gocheva V, Wang H W, Gadea B B, et al. IL-4 induces cathepsin protease activity in tumor-associated macrophages to promote cancer growth and invasion[J]. Genes Dev,2010,24(3):241-255.
[32] Lin E Y, Nguyen A V, Russell R G, et al. Colony-stimulating factor 1 promotes progression of mammary tumors to malignancy[J]. J ExpMed,2001,193(6):727-740.
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[36] Vasiljeva O, Papazoglou A, Kruger A, et al. Tumor cell-derived and macrophage-derived cathepsin B promotes progression and lung metastasis of mammary cancer[J]. 2006,66(10):5242-5250.
[37] Lewis C E, Pollard J W. Distinct role of macrophages in different tumor microenvironments[J]. Cancer Res,2006,66(2):605-612.
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[40] Lin E Y, Li J F, Gnatovskiy L, et al. Macrophages regulate the angiogenicswitch in a mouse model of breast cancer[J]. 2006,66(23):11238-11246.
[41] Lin E Y, Pollard J W. Tumor-associated macrophages press the angiogenic switch in breast cancer[J]. 2007,67(11):5064-5066.
[42] Murdoch C, Muthana M, Coffelt S B, et al. The role of myeloid cells in the promotion of tumour angiogenesis[J]. 2008,8(8):618-631.
[43] De Palma M, Venneri M A, Galli R, et al. Tie2 identifies a hematopoietic lineage of proangiogenic monocytes required for tumor vessel formation and a mesenchymal population of pericyte progenitors[J]. 2005,8(3):211-226.
[44] Leek R D, Harris A L. Tumor-associated macrophages in breast cancer[J]. 2002,7(2):177-189.
[45] Schoppmann S F, Birner P, Stockl J, et al. Tumor-associated macrophages express lymphatic endothelial growth factors and are related to peritumoral lymphangiogenesis[J]. 2002,161(3):947-956.
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[1] Qian B Z, Pollard J W. Macrophage diversity enhances tumor progression and metastasis[J]. 2010,141(1):39-51.
[2] Miyamoto T, Suda T. [Differentiation and function of monocyte/macrophage lineage cells and osteoblasts][J]. Nippon Rinsho,2005,63(9):1511-1516.
[3] Radzun H J. [Differentiation pathways in the monocyte/macrophage system][J]. Verh Dtsch Ges Pathol,1988,72:50-56.
[4] Tacke F, Randolph G J. Migratory fate and differentiation of blood monocyte subsets[J]. Immunobiology,2006,211(6-8):609-618.
[5] Gordon S, Taylor P R. Monocyte and macrophage heterogeneity[J]. 2005,5(12):953-964.
[6] Treves A J. The origin of monocyte-macrophage heterogeneity: possible alternatives[J]. 1984,14(4):335-346.
[7] Nowicki A, Szenajch J, Ostrowska G, et al. Impaired tumor growth in colony-stimulating factor 1 (CSF-1)-deficient, macrophage-deficient op/op mouse: evidence for a role of CSF-1-dependent macrophages in formation of tumor stroma[J]. 1996,65(1):112-119.
[8] Stanley E R, Berg K L, Einstein D B, et al. Biology and action of colony--stimulating factor-1[J]. Mol Reprod Dev,1997,46(1):4-10.
[9] Sweet M J, Hume D A. CSF-1 as a regulator of macrophage activation andimmune responses[J]. Arch Immunol Ther Exp (Warsz),2003,51(3):169-177.
[10] Aharinejad S, Abraham D, Paulus P, et al. Colony-stimulating factor-1 antisense treatment suppresses growth of human tumor xenografts in mice[J]. 2002,62(18):5317-5324.
[11] Kuropkat C, Duenne A A, Herz U, et al. Significant correlation of matrix metalloproteinase and macrophage colony-stimulating factor serum concentrations in patients with head and neck cancer[J]. 2004,51(5):375-378.
[12] Mroczko B, Szmitkowski M. [Macrophage-colony stimulating factor (M-csf) in diagnostic and monitoring of non-small-cell lung cancer (NSCLC)][J]. Pol Arch Med Wewn,2001,105(3):203-209.
[13] Rollins B J. Inflammatory chemokines in cancer growth and progression[J]. 2006,42(6):760-767.
[14] Barleon B, Sozzani S, Zhou D, et al. Migration of human monocytes in response to vascular endothelial growth factor (VEGF) is mediated via the VEGF receptor flt-1[J]. 1996,87(8):3336-3343.
[15] Uutela M, Wirzenius M, Paavonen K, et al. PDGF-D induces macrophage recruitment, increased interstitial pressure, and blood vessel maturation during angiogenesis[J]. 2004,104(10):3198-3204.
[16] Chen J J, Lin Y C, Yao P L, et al. Tumor-associated macrophages: the double-edged sword in cancer progression[J]. J Clin Oncol,2005,23(5):953-964.
[17] Mantovani A, Sozzani S, Locati M, et al. Macrophage polarization:tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes[J]. Trends Immunol,2002,23(11):549-555.
[18] Mantovani A, Sica A. Macrophages, innate immunity and cancer: balance, tolerance, and diversity[J]. 2010,22(2):231-237.
[19] Mantovani A, Allavena P, Sica A, et al. Cancer-related inflammation[J]. 2008,454(7203):436-444.
[20] Biswas S K, Gangi L, Paul S, et al. A distinct and unique transcriptional program expressed by tumor-associated macrophages (defective NF-kappaB and enhanced IRF-3/STAT1 activation)[J]. 2006,107(5):2112-2122.
[21] Deng L, Zhou J F, Sellers R S, et al. A novel mouse model of inflammatory bowel disease links mammalian target of rapamycin-dependent hyperproliferation of colonic epithelium to inflammation-associated tumorigenesis[J]. 2010,176(2):952-967.
[22] Pang B, Zhou X, Yu H, et al. Lipid peroxidation dominates the chemistry of DNA adduct formation in a mouse model of inflammation[J]. 2007,28(8):1807-1813.
[23] Colotta F, Allavena P, Sica A, et al. Cancer-related inflammation, the seventh hallmark of cancer: links to genetic instability[J]. 2009,30(7):1073-1081.
[24] Balkwill F. Tumour necrosis factor and cancer[J]. 2009,9(5):361-371.
[25] Greten F R, Eckmann L, Greten T F, et al. IKKbeta links inflammation andtumorigenesis in a mouse model of colitis-associated cancer[J]. 2004,118(3):285-296.
[26] Condeelis J, Pollard J W. Macrophages: obligate partners for tumor cell migration, invasion, and metastasis[J]. Cell,2006,124(2):263-266.
[27] Wyckoff J, Wang W, Lin E Y, et al. A paracrine loop between tumor cells and macrophages is required for tumor cell migration in mammary tumors[J]. Cancer Res,2004,64(19):7022-7029.
[28] Wyckoff J B, Wang Y, Lin E Y, et al. Direct visualization of macrophage-assisted tumor cell intravasation in mammary tumors[J]. Cancer Res,2007,67(6):2649-2656.
[29] Wang S, Yuan Y, Liao L, et al. Disruption of the SRC-1 gene in mice suppresses breast cancer metastasis without affecting primary tumor formation[J]. Proc Natl Acad Sci U S A,2009,106(1):151-156.
[30] Denardo D G, Barreto J B, Andreu P, et al. CD4(+) T cells regulate pulmonary metastasis of mammary carcinomas by enhancing protumor properties of macrophages[J]. Cancer Cell,2009,16(2):91-102.
[31] Gocheva V, Wang H W, Gadea B B, et al. IL-4 induces cathepsin protease activity in tumor-associated macrophages to promote cancer growth and invasion[J]. Genes Dev,2010,24(3):241-255.
[32] Lin E Y, Nguyen A V, Russell R G, et al. Colony-stimulating factor 1 promotes progression of mammary tumors to malignancy[J]. J ExpMed,2001,193(6):727-740.
[33] Zhu X D, Zhang J B, Zhuang P Y, et al. High expression of macrophage colony-stimulating factor in peritumoral liver tissue is associated with poor survival after curative resection of hepatocellular carcinoma[J]. J Clin Oncol,2008,26(16):2707-2716.
[34] Egeblad M, Werb Z. New functions for the matrix metalloproteinases in cancer progression[J]. Nat Rev Cancer,2002,2(3):161-174.
[35] Almholt K, Lund L R, Rygaard J, et al. Reduced metastasis of transgenic mammary cancer in urokinase-deficient mice[J]. Int J Cancer,2005,113(4):525-532.
[36] Vasiljeva O, Papazoglou A, Kruger A, et al. Tumor cell-derived and macrophage-derived cathepsin B promotes progression and lung metastasis of mammary cancer[J]. 2006,66(10):5242-5250.
[37] Lewis C E, Pollard J W. Distinct role of macrophages in different tumor microenvironments[J]. Cancer Res,2006,66(2):605-612.
[38] Hanahan D, Christofori G, Naik P, et al. Transgenic mouse models of tumour angiogenesis: the angiogenic switch, its molecular controls, and prospects for preclinical therapeutic models[J]. 1996,32A(14):2386-2393.
[39] Zumsteg A, Christofori G. Corrupt policemen: inflammatory cells promote tumor angiogenesis[J]. 2009,21(1):60-70.
[40] Lin E Y, Li J F, Gnatovskiy L, et al. Macrophages regulate the angiogenicswitch in a mouse model of breast cancer[J]. 2006,66(23):11238-11246.
[41] Lin E Y, Pollard J W. Tumor-associated macrophages press the angiogenic switch in breast cancer[J]. 2007,67(11):5064-5066.
[42] Murdoch C, Muthana M, Coffelt S B, et al. The role of myeloid cells in the promotion of tumour angiogenesis[J]. 2008,8(8):618-631.
[43] De Palma M, Venneri M A, Galli R, et al. Tie2 identifies a hematopoietic lineage of proangiogenic monocytes required for tumor vessel formation and a mesenchymal population of pericyte progenitors[J]. 2005,8(3):211-226.
[44] Leek R D, Harris A L. Tumor-associated macrophages in breast cancer[J]. 2002,7(2):177-189.
[45] Schoppmann S F, Birner P, Stockl J, et al. Tumor-associated macrophages express lymphatic endothelial growth factors and are related to peritumoral lymphangiogenesis[J]. 2002,161(3):947-956.
[46] Ojalvo L S, King W, Cox D, et al. High-density gene expression analysis of tumor-associated macrophages from mouse mammary tumors[J]. 2009,174(3):1048-1064.
[47] Kaminska J, Kowalska M, Kotowicz B, et al. Pretreatment serum levels of cytokines and cytokine receptors in patients with non-small cell lung cancer, and correlations with clinicopathological features and prognosis. M-CSF - an independent prognostic factor[J]. Oncology,2006,70(2):115-125.
[48] Curiel T J, Coukos G, Zou L, et al. Specific recruitment of regulatory Tcells in ovarian carcinoma fosters immune privilege and predicts reduced survival[J]. 2004,10(9):942-949.