人成釉细胞瘤中TAMs及EP3的表达与意义
摘要
目的
本研究探讨肿瘤相关巨噬细胞(TAMs)在人成釉细胞瘤(ABs)组织中的浸润及对ABs组织血管生成的影响,探讨前列腺素2 (PGE2)受体EP3蛋白在ABs组织中的表达与意义。
材料与方法
实验标本来自中国医科大学附属口腔医院和第一临床医院2001-2007年存档蜡块,其中ABs101例(其中原发66例、复发35例),正常口腔黏膜26例。
应用HE常规染色法,在镜下观察人ABs中的中性粒细胞,巨噬细胞,淋巴细胞,浆细胞的浸润表达情况；应用免疫组化SP法及CD68, CD34鼠抗人单克隆抗体,EP3兔抗人多克隆抗体,对TAMs,微血管密度(MVD), PGE2受体EP3蛋白进行检测,通过结果判定,统计学处理进行分析。
结果
1、应用HE常规染色法观察ABs临床病理切片,发现人ABs中淋巴细胞,中性粒细胞,巨噬细胞浸润明显,有少量的浆细胞的浸润表达,这些炎性细胞有的位于靠近肿瘤上皮团的间质内,有的直接浸润于肿瘤上皮团内。ABs炎性细胞计数明显高于正常口腔粘膜(P值分别为0.000,P<0.05),具有统计学意义。
2、ABs巨噬细胞计数与微血管记数明显高于正常口腔粘膜(P值分别为0.000,0.003,P<0.05)。巨噬细胞计数与MVD之间呈正相关(r=0.194,P值为0.026,P<0.05)。
3、ABs中EP3表达主要在胞浆,以中度阳性强阳性为主,位于牙源性上皮的外周柱状或立方状细胞及中心星网状层细胞浆中；EP3表达具有异质性,分化较好的角化细胞中表达为强阳性,而在原始胚胎细胞中表达往往呈阴性或弱阳性；EP3蛋白部分视野下核阳性率较高,占总数的60.38%(64／106)。在炎细胞、血管内皮细胞、纤维细胞胞浆中EP3也为阳性表达。正常粘膜中EP3主要表达在表层和棘浅层。人类原发ABs、复发ABs中都有EP3的明显表达,阳性率依次为复发ABs 85.71%、原发ABs 80.30%；正常口腔粘膜也有表达其阳性率为42.31%。采用秩和检验,EP3蛋白在ABs与正常口腔粘膜有显著差异(P=0.000,P<0.05)；原发组,复发组与正常黏膜组间有显著差异,具有统计学意义(P值分别为0.000,0.029,P<0.05)。
结论
1、人ABs中巨噬细胞,淋巴细胞,中性粒细胞浸润明显,有少量浆细胞的浸润表达。炎性细胞构成了人ABs的肿瘤微环境。
2、人ABs组织中有明显的TAMs的浸润且与ABs的血管生成有关。
3、人ABs中炎性介质EP3在蛋白质水平上高表达且明显高于正常粘膜。
Objective
This study was to investigate the influence of Tumor-associated macrophages (TAMs) infiltration in the human ameloblastomas(ABs), the correlation between TAMs and angiogenesis in ABs, to investigate the expression and significance of prostaglandin E2(PGE2) receptor EP3 in the ABs.
Materials and Methdods
All of the samples were selected from department of oral pathology, school of stomotology, China Medical University in the period of 2001 to 2007. Include: ameloblastomas (n=101, including 66 primary ABs,35 recurring ABs), normal oral mucosa(n=26).
Using the HE convention dyeing, Under microscope observes the neutral granular cell, the macrophage,the lymphocyte, acidophilia granular cell, cytoplasmic cell in human ABs. TAMs, MCD and EP3 were detected by streptavidin peroxidase method and avidin-biotin peroxidose complex technique of immunohistochemistry using monoclonal mouse anti-human CD68 and CD34 antibody, polyclonal rabbit anti-human EP3 antibody.
Results
1. Observes the ABs clinical pathological section using the HE convention dyeing, discovers in person ABs the macrophage, the lymphocyte, the neutral granular cell obvious infiltration, has the few cytoplasmic cells's infiltration expression, these inflammatory cell some infiltrations in near tumor mesenchymal, some direct infiltrations in tumor epidermis group. Compare the infiltration with the normal mucous membrane to be remarkable, the P value respectively is 0.000, has statistics significance.
2. The mean macrophage counts in ABs was significantly higher than the counts in normal mucosa (P<0.05). The mean macrophage counts in primary ABs, recurring ABs were different. The mean microvessel counts in ABs were higher than that in normal mucosa (P<0.05). The mean microvessel were strongly correlated with TAMs counts in ABs (P<0.01).
3. EP3 was expressed in the plasma of peripheral columnar or cuboidal cells and central polyhedral cells of odontogenic epithelium, most of which were moderately positive and strongly positive. The expressions of EP3 had heterogenicity.It was strong positive in well differentiated keratinocytes, while in primary embryonic cells, It was negative or weakly positive..EP3 protein expressed strongly in the nuclus of ABs, and its nuclear positive rate was 60.38%(64/106).The expressions of EP3 in the plasm of phlogotic cells, vascular endothelial cells and fibrocytes were also positive. In normal mucosas, EP3 was expressed in surface layer and the superficial layer of stratum spinosum. The immunohistochemical staining of EP3 was obviously expressed in human primary ABs, recurrent ABs. the positive rate was recurrent ABs (85.71%), primary Abs (80.30%).And EP3 also expressed in NOMs, the positive rate of which was 42.31%. Using Rank sum test, we found that there were significant differences between NOMs and Abs (P=0.000).
Conclusions
1. In human ABs the macrophage, the lymphocyte, the neutral granular cell obvious infiltration, has the few cytoplasmic cell's infiltration expression. The inflammatory cell constituted the ABs tumor microenvironment.
2. The expression of TAMs in ABs was stronger than in normal mucosas, and it may play a major role in the regulation of angiogenesis in ABs.
3. The protein expressions of EP3 in ABs was higner than that of normal mucosas.
本研究探讨肿瘤相关巨噬细胞(TAMs)在人成釉细胞瘤(ABs)组织中的浸润及对ABs组织血管生成的影响,探讨前列腺素2 (PGE2)受体EP3蛋白在ABs组织中的表达与意义。
材料与方法
实验标本来自中国医科大学附属口腔医院和第一临床医院2001-2007年存档蜡块,其中ABs101例(其中原发66例、复发35例),正常口腔黏膜26例。
应用HE常规染色法,在镜下观察人ABs中的中性粒细胞,巨噬细胞,淋巴细胞,浆细胞的浸润表达情况；应用免疫组化SP法及CD68, CD34鼠抗人单克隆抗体,EP3兔抗人多克隆抗体,对TAMs,微血管密度(MVD), PGE2受体EP3蛋白进行检测,通过结果判定,统计学处理进行分析。
结果
1、应用HE常规染色法观察ABs临床病理切片,发现人ABs中淋巴细胞,中性粒细胞,巨噬细胞浸润明显,有少量的浆细胞的浸润表达,这些炎性细胞有的位于靠近肿瘤上皮团的间质内,有的直接浸润于肿瘤上皮团内。ABs炎性细胞计数明显高于正常口腔粘膜(P值分别为0.000,P<0.05),具有统计学意义。
2、ABs巨噬细胞计数与微血管记数明显高于正常口腔粘膜(P值分别为0.000,0.003,P<0.05)。巨噬细胞计数与MVD之间呈正相关(r=0.194,P值为0.026,P<0.05)。
3、ABs中EP3表达主要在胞浆,以中度阳性强阳性为主,位于牙源性上皮的外周柱状或立方状细胞及中心星网状层细胞浆中；EP3表达具有异质性,分化较好的角化细胞中表达为强阳性,而在原始胚胎细胞中表达往往呈阴性或弱阳性；EP3蛋白部分视野下核阳性率较高,占总数的60.38%(64／106)。在炎细胞、血管内皮细胞、纤维细胞胞浆中EP3也为阳性表达。正常粘膜中EP3主要表达在表层和棘浅层。人类原发ABs、复发ABs中都有EP3的明显表达,阳性率依次为复发ABs 85.71%、原发ABs 80.30%；正常口腔粘膜也有表达其阳性率为42.31%。采用秩和检验,EP3蛋白在ABs与正常口腔粘膜有显著差异(P=0.000,P<0.05)；原发组,复发组与正常黏膜组间有显著差异,具有统计学意义(P值分别为0.000,0.029,P<0.05)。
结论
1、人ABs中巨噬细胞,淋巴细胞,中性粒细胞浸润明显,有少量浆细胞的浸润表达。炎性细胞构成了人ABs的肿瘤微环境。
2、人ABs组织中有明显的TAMs的浸润且与ABs的血管生成有关。
3、人ABs中炎性介质EP3在蛋白质水平上高表达且明显高于正常粘膜。
Objective
This study was to investigate the influence of Tumor-associated macrophages (TAMs) infiltration in the human ameloblastomas(ABs), the correlation between TAMs and angiogenesis in ABs, to investigate the expression and significance of prostaglandin E2(PGE2) receptor EP3 in the ABs.
Materials and Methdods
All of the samples were selected from department of oral pathology, school of stomotology, China Medical University in the period of 2001 to 2007. Include: ameloblastomas (n=101, including 66 primary ABs,35 recurring ABs), normal oral mucosa(n=26).
Using the HE convention dyeing, Under microscope observes the neutral granular cell, the macrophage,the lymphocyte, acidophilia granular cell, cytoplasmic cell in human ABs. TAMs, MCD and EP3 were detected by streptavidin peroxidase method and avidin-biotin peroxidose complex technique of immunohistochemistry using monoclonal mouse anti-human CD68 and CD34 antibody, polyclonal rabbit anti-human EP3 antibody.
Results
1. Observes the ABs clinical pathological section using the HE convention dyeing, discovers in person ABs the macrophage, the lymphocyte, the neutral granular cell obvious infiltration, has the few cytoplasmic cells's infiltration expression, these inflammatory cell some infiltrations in near tumor mesenchymal, some direct infiltrations in tumor epidermis group. Compare the infiltration with the normal mucous membrane to be remarkable, the P value respectively is 0.000, has statistics significance.
2. The mean macrophage counts in ABs was significantly higher than the counts in normal mucosa (P<0.05). The mean macrophage counts in primary ABs, recurring ABs were different. The mean microvessel counts in ABs were higher than that in normal mucosa (P<0.05). The mean microvessel were strongly correlated with TAMs counts in ABs (P<0.01).
3. EP3 was expressed in the plasma of peripheral columnar or cuboidal cells and central polyhedral cells of odontogenic epithelium, most of which were moderately positive and strongly positive. The expressions of EP3 had heterogenicity.It was strong positive in well differentiated keratinocytes, while in primary embryonic cells, It was negative or weakly positive..EP3 protein expressed strongly in the nuclus of ABs, and its nuclear positive rate was 60.38%(64/106).The expressions of EP3 in the plasm of phlogotic cells, vascular endothelial cells and fibrocytes were also positive. In normal mucosas, EP3 was expressed in surface layer and the superficial layer of stratum spinosum. The immunohistochemical staining of EP3 was obviously expressed in human primary ABs, recurrent ABs. the positive rate was recurrent ABs (85.71%), primary Abs (80.30%).And EP3 also expressed in NOMs, the positive rate of which was 42.31%. Using Rank sum test, we found that there were significant differences between NOMs and Abs (P=0.000).
Conclusions
1. In human ABs the macrophage, the lymphocyte, the neutral granular cell obvious infiltration, has the few cytoplasmic cell's infiltration expression. The inflammatory cell constituted the ABs tumor microenvironment.
2. The expression of TAMs in ABs was stronger than in normal mucosas, and it may play a major role in the regulation of angiogenesis in ABs.
3. The protein expressions of EP3 in ABs was higner than that of normal mucosas.
引文
1 Hanahan D, Weinderg RA. The hallmarks of cancer. [J] Cell.2000; 100:57-70.
2 Da Fano C. A cytological analysis of the reaction in animals resistant to implanted carcinomata. Fifth Sci Rep ICRF.1911;5:57-75.
3 Van Ravenswaay Claasen HH, Kluin PM, Fleuren GJ. Tumor infiltrating cell in human cancer on the possible role of CD16+macrophage in antitumor cytotoxity. [J] Lab Invest.1992;67 (2):166-174.
4 Taskinen M, Karjalainen-Lindsberg ML, Leppa S. Prognostic influence of tumor-infiltrating mast cells in patients with follicular lymphoma treated with rituximab and chop. [J] Blood. 2008; 111:4664-4667
5 Sunderkotter C, Goebeler M, Schulze Osthoff K, et al. Macrophage-derived angiogenesis factors. [J]. Pharmacol Ther.1991;51(2):195-216.
6 Folkman J. Tumor angiogenesis:therapeutic implications. [J]. N Engl Med.1971;285 (21): 1182-1186.
7 蔡方,赵勇,赵文丽.肿瘤相关巨噬细胞与胃癌血管生成及转移关系.中国肿瘤,2006；15(7)：476-477.
8 Ng D, Poon RT, Lee JM, et al. Microvessel density, vascular endothelial growth factor and its receptors Flt-1 and Flk-1/KDR in hepatocellular carcinoma. [J]Am J Clin Pathol.2001;116 (6): 838-845.
9 Hisai H, Kato J, Kobune M, et al. Increased expression of angiogenin in hepatocellular carcinoma in correlation with tumor vascularity.[J] Clin Cancer Res.2003; 9(13):4852-4859.
10 Ueno T, Suzuki T, Oikawa A, et al. Recruited bone marrow cells expressing the EP3 prostaglandin E receptor subtype enhance angiogenesis during chronic inflammation. [J]Biomed Pharmacother.2009; 10(17).
11 Bartz H, Buning Pfaue F, Turkel O, et al. Respiratory syncytial virus induces prostaglandin E2, IL-10 and IL-11 generation in antigenpresenting cells.[J]Clin Exp Immunol.2002; 129(3): 438-45.
12 Huang SH, Cao XJ, Wei W. Melat on indecreases TLR3-mediated inflammatory factor expression via inhibition of NF-kappa B activation in respiratory syncytial virus-infected RAW264.7 macrophages.[J]Pineal Res.2008;45(1):93-100.
13 Morris on PT, Thomas LH, Sharland, et al. MRSV-infected air way epithelial cells cause biphasic up-regulation of CCR1 expression on human monocytes.[J] Leukoc Biol.2007;81(6): 1487-95.
14 Margarita B, Barbar SF. Prostaglandin E2 inhibits production of Thl lymphokines but not of Th2 lymphokines. [J] Immunol.1991;146:108-113.
15 Tsuyoshi Tajima, Takahisa Murata, Kosuke Aritake, et al. Lipopolysaccharide induces macrophage migration via prostaglandin D and prostaglandin E2. [J] PET.2008;326(2): 493-501.
16 Han C, Wu T. Cyclooxygenase-2-derived prostaglandin E2 promotes human cholangiocarcinoma cell growth and invasion through EP1 receptor-mediated activation of the epidermal growth factor recrptor and Akt. [J]Biol Chem.2005; 80:24053-24063.
17 Kubo H, Hosono K, Suzuki T. Host prostaglandin EP3 receptor signaling relevant to tumor-associated lymphangiogenesis. [J] Biomed Pharmacother.2010; 64(2):101-6.
18 T. Lawrence, D. A. Willoughby, D. W. Gilroy. Anti-inflammatory lipid mediators and insights into the resolution of inflammation. [J] Nat. Rev. Immunol.2002;2:787-795.
19 Devanand Sarkar, Paul B, Fisher. Molecular mechanisms of aging-associated inflammation. [J] Caner Letters.2006;236(1):13-23.
20 Virchow R. Die krankhaften Geschwulste. DreiBig Vorlesungen, gehalten wahrend des Wintersemesters 1862-1863 an der Universitat zu Berlin Vorlesungen uber Pathologie Berlin: Verlag von August Hirschwald; 1863.
21 Ehrlich P. Experimentelle studien an maustumoren. zeitschr f Krebsforschung 1907,5:59-81.
22 Balwill F, Charles KA, Mantovani A. Smoldering and polarized inflammation in the initiation and promotion of malignant disease. [J] Cancer Cell.2005;7; 3:211-7.
23 Pollard JW. Tumour-educated macrophages promote tumour progression and metastasis. [J] Nat Rev Cancer.2004;4:71-8.
24 T. Lawrence, D. A. Willoughby, D. W. Gilroy, Anti-inflammatory lipid mediators and insights into the resolution of inflammation. [J] Nat. Rev. Immunol.2002;2:787-795.
25 Tlsty TD. Stomal cells can contribute oncogenic signals. Semin Cancer Biol.2001; 11:97-104.
26 Van Kempen LC, Ruiter DJ, van Muijen GN, Coussens LM. The tumor microenvironment:a critical determinant of neoplastic evolution. [J] Eur J Cell Biol.2003;82:539-48.
27 Dvorak HF. Rous-Whipple Award Lecture. How tumors make bad blood vessels and stroma. [J] Am J Pathol.2003;162:1747-1757.
28 SP. Hussain, LJ. Hofseth, CC. Harris, Radical causes of cancer. [J] Nat. Rev, Cancer.2003;3: 276-285.
29 Funk CD. Prostaglandins and leukotrienes:advances in eicosanoid biology. [J] Science.2001;294:1871-1875.
30 O'Byrne KJ, Dalgleish AG. Chronic immune activation and inflammation as the cause of malignancy. [J] Br J Cancer.2001;85:473-483
31 Balkwill F. Cancer and the chemokine network. [J] Nat Rev Cancer.2004; 4:540-550
32 Coussens LM, Werb Z. Inflammation and cancer. [J] Nature.2002;420:860-7.
33 Thun MJ, Henley SJ, Gansler T. Inflammation and cancer:an epidemiological perspective. [J] Novartis Found Symp.2004; 256:6-21.
34 Clevrs H. At the crossroads of inflammation and cancer. [J] Cell.2004; 118:671-4.
35 Shacter E, Weitzman SA. Chronic inflammation and cancer. [J] Oncology.2002; 16:217-26.
36 Balkwill F, Charles KA, Mantovani A. Smoldering and polarized inflammation in the initiation and promotion of malignant disease. [J] Cancer Cell.2005;7:211-7.
37 Lewis CE, Murdoch C. Macrophage responses to hypoxia:implication for tumor progression and anti-cancer therapies. [J] AM J Pathol.2005;167:627-35.
38 Murdoch C, Lewis CE. Macrophage migration and gene expression in response to tumor hypoxia. [J] Int J Cancer.2005; 117:701-8.
39 G. L. Larsen, P. L. Warner, P. A. Ward, The role of cytokines and adhesion molecules in the development of inflammatory injury. [J] Mol. Med. Today.1995;1:40-45.
40 Welch DR, Schissel DJ, Howrey RP, Aeed PA. Tumor-elicited polymorphonuclear cells, in contrast to'normal'circulating polymorphonuclear cells, stimulate invasive and metastatic potentials of rat mammary adenocarcinoma cells. [J] Proc Natl Acad Sci.1989;86:5859-63.
41 Josephy PD, Coomber BL. The 1996 Veylien Henderson Award of the Society of Toxicology of Canada. Current concepts:neutrophils and the activation of carcinogens in the breast and other organs. [J] Can J Physiol Pharmacol.1999; 76:693-700.
42 Allavena P, Sica A, Solinas G, Porta C, Mantovani A. The inflammatory micro-environment in tumor progression:the role of tumor-associated macrophages. [J] Crit Rev Oncol Hematol. 2008a;66(1):1-9.
43 Allavena P, Sica A, Solinas G, Porta C, Mantovani A. The Inflammatory micro-environment in tumor progression:the role of tumor-associated macrophages. [J] Crit Rev Oncol Hematol. 2008b;66:1-9
44 Yuan A, Chen JJ, Yang PC. Pathophysiology of tumor-associated macrophages. [J]Adv Clin Chem.2008;45:199-223.
45 Lewis CE, Pollard JW. Distinct role of macrophages in different tumor microenvironments. [J] Cancer Res.2006;66(2):605-612.
46 Siveen KS, Kuttan G. Role of macrophages in tumour progression. [J] Immunol Lett. 2009; 123(2):97-102.
47 Mayumi Ono. Molecular links between tumor angiogenesis and inflammation:inflammatory stimuli of macrophages and cancer cells as targets for therapeutic strategy. [J] Cancer Sci.2008;99(8):1501-1506
48 Sica A, Schioppa T, Mantovani A, et al. Tumour-associated macrophages are a distinct M2 polarised population promoting tumour progression:potential targets of anti-cancer therapy. [J]Euro J Cancer.2006;42(6):717-727.
49 Leek RD, Lewis CE, Whitehouse R, et al. Association of macrophage infiltration with angiogenesis and prognosis in invasive breast carcinoma.[J]Cancer Res.1996;56(20): 4625-4629.
50 Bunt SK, Yang L, Sinha P, Clements VK, Leips J, Ostrand-Rosenberg S. Reduced inflammation in the tumor microenvironment delays the accumulation of myeloid-derived suppressor cells and limits tumor progression. [J] Cancer Res.2007;67:10019-10026
51 Saccni A, Schioppa T, Porta C, et al. p50 nuclesr factor-κB overexpression in tumor-associated macrophages inhibits M1 inflammatory responses and antitumor resistance.[J]Cancer Res.2006;66(23):11432-11440.
52李宏捷,张玉茹,朱晓虹.口腔鳞状细胞癌巨噬细胞浸润与VEGF表达关系的研究.现代口腔医学杂志,2007；21(5)：499-501.
53 Lewis CE, Pollard JW. Distinct role of macrophages in different tumor microenvironments. [J] Cancer Res.2006;66 (2):605-612.
54 Nyberg P, Salo T, Kalluri R. Tumor microenvironment and angiogenesis. [J] Front Biosci. 2008;13(1):6537-53.
55 Minardi D, Lucarini G, Filosa A, Milanese G, Zizzi A, Di Primio R, Montironi R, Muzzonigro G. Prognostic role of tumor necrosis, microvessel density, vascular endothelial growth factor and hypoxia inducible factor-1 alpha in patients with clear cell renal carcinoma after radical nephrectomy in a long term follow-up. Int J Immunopathol Pharmacol.2008;21(2):447-55.
56 Arbeit JM. Transgenic models of epidermal neoplasia and multi-stage carcinogenesis. [J] Cancer Surv.1996;26(1):7-34.
57 Sunderkotter C, Goebeler M, Schulze-Osthoff K, et al. Macrophage-derived angiogenesis factors. [J] Pharmaco Ther.1991; 51:195-216.
58 58Weidner N, Folkman J, Pozza F, et al. Tumor angiogenesis:a new significant and independent indicat or in early-stage breast carcinoma.[J] J Natl Cancer I nst.1992;84 (24); 1850-1851.
59 Toge H, Inagaki T, Kojimoto Y, Shinka T, Hara I. Angiogenesis in renal cell carcinoma:the role of tumor-associated macrophages. [J] Int J Urol.2009; 16(10):801-7
60李德超,陈瑶,魏良富.iNOS、VEGF和CD34在人涎腺腺样囊性癌中的表达及意义.口腔医学研究,2008；24(6)：644-646.
61 Shieh YS, Hung YJ, Hsieh CB, Chen JS, Chou KC, Liu SY Tumor-associated macrophage correlated with angiogenesis and progression of mucoepidermoid carcinoma of salivary glands. [J] Ann Surg Oncol.2009;16(3):751-60.
62钟鸣,王洁,王兆元,韩有平.CD34和血管内皮生长因子在人牙源性病损中的表达.中华口腔医学杂志,2002；37(6)：455.
63冯红超,宋宇峰.口腔鳞癌巨噬细胞和微血管的空间关系.贵阳医学院学报,2003；28(1)：12-14.
64 Sharma SD, Meeran SM, Katiyar SK. Proanthocyanidins inhibit in vitro and in vivo growth of human non-small cell lung cancer cells by inhibiting the prostaglandin E(2) and prostaglandin E(2) receptors. [J]Mol Cancer Ther.2010;9(3):569-80.
65 Chen X, Wang S, Wu N, et al. Leukot riene A4 hydrolase as a target for cancer prevention and therapy [J]. Curr Cancer Drug Targets.2004; 4 (3):267-283.
66 Yokomizo T, Izumi T, Shimizu T. Leukot riene B4:metabolism and signal transduction.[J] Arch Biochem Biophys.2001;15(2):231-241.
67 Katoh H, Hosono K, Ito Y. COX-2 and prostaglandin EP3/EP4 signaling regulate the tumor stromal proangiogenic microenvironment via CXCL12-CXCR4 chemokine systems. Am J Pathol.2010;176(3):1469-83.
68 Hiromichi FJ, Wei X, John WR. Prostaglandin E2 induced functional expression of early growth response factor-1 by EP4, but not EP2, prostanoid receptora via the phosphatidylinositol 3-kinase and extracellular signal-regulated kinases. [J]Biol Chem. 2003;278:12151-12156
69 Amano H, Ito Y, Suzuki T. Roles of a prostaglandin E-type receptor, EP3, in upregulation of matrix metalloproteinase-9 and vascular endothelial growth factor during enhancement of tumor metastasis. [J]Cancer Sci.2009; 100(12):2318-24.
70 Ogawa Y, Suzuki T, Oikawa A. Bone marrow-derived EP3-expressing stromal cells enhance tumor-associated angiogenesis and tumor growth. [J]Biochem Biophys Res Commun.2009; 15; 382(4):720-5.
71 Taniguchi T, Fujino H, Israel DD, Regan JW, Murayama T. Human EP3(I) prostanoid receptor induces VEGF and VEGF receptor-1 mRNA expression. [J]Biochem Biophys Res Commun. 2008;26; 377(4):1173-8.
72 Scharl A, Vierbuchen M, Conradt B, et al. Immunohistochemical detection of progesterone receptor in formalin-fixed and paraffin-embedded breast cancer tissue using amonoclonal antibody. [J]Arch Gynecol Obstet.1999;247(2):63-71.
73何华.如何正确地对免疫组化结果进行半定量评分.中外健康文摘·临床医师.2008；5(7)：162.
74 Kinoshita T, Takahashi Y, Sakashita T, et al. Growth stimulation and induction of epidermal growth factor receptor by overexpression of cyclooxygenase 1 and 2 in human colon carcinoma cells. [J] Biochim Biophys Acta.1999; 1438:120-130.
75羊建,刘佳佳.前列腺素EP3亚型受体的研究进展.International Journal of Immunology. 2007;30:80-83
76 Boie Y, Stocco R, Sawyer N, et al. Molecular cloning and characterization of the four rat prostaglandin E2 prostanoid receptor subtypes.[J]Eur J Pharmacol.1997;340:227-241
77 Alexander S. Endocytosis and intracellular sorting of receptor tyrosine kinase.[J]Frontiers in Bioscience reductase.1998; 3:729-738
1 Coussens LM, et al. Iflammation and cancer. [J] Nature.2002;420(6917):860-867.
2 Pollard JW. Tumour-educated macrophages promote tumour progression and metastasis. [J]. Nat Rev Cancer.2004;4:71-78.
3 Nardin A, et al. Macrophages and cancer. [J] Front Biosci.2008;13:3494-505.
4 Antonio S, et al. Cancer related inflammation:the macrophage connection. [J]Cancer Letters. 2008; 267(2):204-215.
5 Lucas T et al. Modulation of tumor associated macrophages in solid tumors. [J] Front Biosci. 2008,13:5580-5588.
6 Matsushima K, et al. Chemokines and inflammation. [J] Nippon Ronen Igakkai Zasshi.1999; 36(2):82-9.
7 Balkwill F. Cancer and the chemokine network. [J] Nat Rev Cancer.2004;4(7):540-550
8 Gordon S. Alternative activation of macrophages. [J] Nat Rev Immunol.2003;3:23-35
9 Mantovani A, et al. The chemokine system in diverse forms of macrophage activation and polarization. [J]Trends Immunol.2004;25(12):677-686
10 Gordon S, et al. Monocyte and macrophage heterogeneity. [J] Nat Rev Immunol.2005;5: 953-964
11 Sica A, Schioppa T, MantovaniA, et al. Tmour-associated macrophages are a distinct M2 polarised population promoting tumour progression:potential targets of anti-cancer therapy [J]. Eur J Cancer.2006;42 (6):717-727.
12 Mantovani A et al. Macrophage polarization:tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes.[J]Trends Immunol.2002;23(11):549-555
13 Allavena P et al. IL-10 prevents the differentiation of monocytes to dendritic cells but promotes their maturation to macrophages.[J]Eur J Immunol.1998;28:359
14 Sica A et al. Autocrine production of IL-10 mediates defective IL-12 production and NF-kappa B activation in tumor-associated macrophages.[J]Immunol.2000; 164:762-767
15 Yasuda H. Solid tumor physiology and hypoxia-induced chemo/radio-resistance:novel strategy for cancer therapy:nitric oxide donor as a therapeutic enhancer. [J]Nitric Oxide.2008;19(2):205-216
16 Weigert A et al. Nitric oxide, apoptosis and macrophage polarization during tumor progression. [J]Nitric Oxide.2008;19(2):95-102
17 Knowles H, Leek R, HarrisAL. Macrophage infiltration and angiogenesis in human malignancy.[J]Novartis Found Syrup.2004; 256:189-200.
18 Lewis CE, Pollard JW. Distinct role of macrophages in different tumormicroenvironments. [J]Cancer Res.2006;66 (2):605-612.
19 Chen JJ, Lin YC, Yao PL, et al. Tumor-associated macrophages:the double-edged sword in cancer progression. [J] Clin Oncol.2005;23 (5):953-964.
20 Oshima H, Oshima M, Inaba K, et al. Hyperp lastic gastric tumors induced by activated macrophages in COX-2 /mPGES-1 transgenic mice. [J]EMBO J.2004;23 (7):1669-1678.
21 Lewis C, Murdoch C. Macrophage responses to hypoxia:implications for tumor progression and anticancer therapies. [J]Am J Patho.2005;167 (3):627-635.
22 Van den Brule F, Califice S, Gamier F, et al. Galectin-1 accumulation in the ovary carcinoma peritumoral stroma is induced by ovary carcinoma cells and affects both cancer cell proliferation and adhesion to laminin-1 and fibronectin. [J]Lab Invest.2003;83(3):377-386.
23 Lin EY, Nguyen AV, Russell RG, et al. Colonystimulating factorl promotes progression of marmnary tumors to malignancy. [J] Exp Med.2001;193 (6):727-740.
24 Hagemann T, Wilson J, Kulbe H, et al. Macrophages induce invasiveness of epithelial cancer cells via NF-κB and JNK.[J]Immunol.2005;175 (2):1197-1205.
25 Goswami S, Sahai E, Wyckoff JB, et al. Macrophages promote the invasion of breast carcinoma cells via a colony-stimulating factor-Ⅰ/epidermal growth factor paracrine loop. [J] Cancer Res.2005;65 (12):5278-5283.
26 Wyckoff J, WangW, Lin EY, et al. A pamcfine loop between tumor cells and macrophages is required for tumor cell migration in manunary tumors. [J]Cancer Res.2004;64(19):7022-7029.
27 Oosterling SJ, van derBij GJ, Meijer GA, et al. Macrophages direct tumour histology and clinical outcome in a colon cancermodel.[J] Pathol.2005;207 (2):147-155.
28 Ben-Barnch A. Inflammation-associated immune suppression in cancer:the roles played by cytokines, chemokines and additional mediators.[J] Semin Cancer Biol.2006;16 (1):38-52.
29 Maruyama K, Ii M, Cursiefen C, et al. Inflammation-induced lymphangiogenesis in the cornea arises from CD1 lb-positive macrophages.[J] Clin Invest.2005;115 (9):2363-2372.
30 Kerjaschki D. The crucial role of macrophages in lymphangiogenesis.[J] Clin Invest.2005;115 (9):2316-2319.
31 Schoppmann SF, Birner P, Stockl J, et al. Tumor-associated macrophages express lymphatic endothelial growth factors and are related to peritumoral lymphangiogenesis. [J] Am J Pathol. 2002; 161 (3):947-956.
32 Bjorndahl MA, Cao R Burton JB, et al. Vascular endothelial growth factor-a promotes pefitumoml lymphangiogenesis and lymphaticmetastasis[J].Cancer Res.2005;65(20): 9261-9268.
33 SkobeM, Hamberg LM, Hawighorst T, et al. Concurrent induction of lymphangiogenesis, angiogenesis, and macrophage recruitment by vascular endothelial growth factor-C in melanoma.[J] Am J Pathol.2001;159 (3):893-903.
34冯红超,宋宇峰,温玉明.口腔癌组织中血管内皮生长皮生长因子2C在肿瘤相关巨噬细胞内的表达及与淋巴结转移的关系.[J]癌症,2004；23(3)：278-281.
35 ColomboMP, MantovaniA. Targetingmyelomonocytic cells to revert inflmtion-dependent cancer promotion.[J] Cancer Re.2005; 65 (20):9113-9116.
36 Guiducci C, Vicari AP, Sangaletti S, et al. Redirecting in vivo elicited tumor infiltrating macrophages and dendritic cells towards tumor rejection. [J] Cancer Res.2005; 65 (8):3437-3446.
1 Jonson JD et al. Association and phosphorylation-dependent dissociation of proteins in the insulin receptor complex. [J] Proc Natl Acad Sci USA.1993;90(23):11317-21.
2 Lai C et al. Structure and expression of the Tyro 10 receptor tyrosine kinase.[J]Oncogene.1994; 9:877
3 G. Agarwal, L. Kovac, C. Radziejewski et al. Binding of discoidin domain receptor 2 to collagen I:an atomic force microscopy investigation. [J]Biochemistry.2002;41(37):11091.
4 B. Leitinger, A. Steplewski, A. Fertala. The D2 period of collagen II contains a specific binding site for the human discoidin domain receptor, DDR2. [J]Mol Biol.2004; 344(4):993-1003.
5 W. Vogel, C. Brakebusch, R. Fassler et al. Discoidin domain receptor 1 is activated independently of beta(l) integrin. [J] Biol Chem.2000;275(8):5779-84.
6 D.L. Simpson, S.D. Rosen, S.H. Barondes. Discoidin, a developmentally regulated carbohydrate-binding protein from Dictyostelium discoideum. Purification and characterization. [J]Biochemistry.1974;13(17):3487-93.
7 Alves F, Vogel W, Mossie K et al. Distinct structural characteristics of discoidin I subfamily receptor tyrosine kinases and complementary expression in human cancer. [J]Oncogene.1995; 10 (3):609-18.
8 Leitinger B. Molecular analysis of collagen binding by the human discoidin domain receptors, DDR1 and DDR2. Identification of collagen binding sites in DDR2. [J]Biol. Chem.2003;278 (19):16761-9.
9 R. Abdulhussein, C. McFadden, P. Fuentes-Prior et al. [J]Biol. Chem.2004;279 (30):31462.
10 Vogel WF. Ligand-induced shedding of discoidin domain receptor 1. [J]FEBS Lett.2002;514 (2-3):175-80.
11 Wybenga-Groot LE, Baskin B, Ong SH, et al. Structural basis for autoinhibition of the Ephb2 receptor tyrosine kinase by the unphosphorylated juxtamembrane region. [J] Cell.2006; 106 (6): 745-57.
12 Alves F, Saupe S, Ledwon M et al.Identification of two novel, kinase-deficient variants of discoidin domain receptor 1:differential expression in human colon cancer cell lines. FASEB J. 2001;15 (7):1321-3.
13 Perez JL, Shen X, Finkernagel S et al. Identification and chromosomal mapping of a receptor tyrosine kinase with a putative phospholipid binding sequence in its ectodomain. [J]Oncogene.1994; 9 (1):211-9
14 Sakuma S, Saya H, Tada M et al. Receptor protein tyrosine kinase DDR is up-regulated by p53 protein. [J] FEBS Lett 1996;398 (2-3):165-9.
15 Foehr ED, Tatavos A, Tanabe E et al. Discoidin domain receptor 1 (DDR1) signaling in PC 12 cells:activation of juxtamembrane domains in PDGFR/DDR/TrkA chimeric receptors. [J]FASEB.2000;14 (7):973-81.
16 Wang CZ, Hsu YM, Tang MJ.Function of discoidin domain receptor I in HGF-induced branching tubulogenesis of MDCK cells in collagen gel. [J]Cell. Physiol.2005;203 (1): 295-304.
17 Barker KT et al. Expression patterns of the novel receptor-like tyrosine kinase, DDR, in human breast tumours. [J]Oncogene.1995; 10(3):569-75..
18 Matsuyama W, Watanabe M, Shirahama Y et al. Activation of discoidin domain receptor 1 on CD14-positive bronchoalveolar lavage fluid cells induces chemokine production in idiopathic pulmonary fibrosis. [J]Immunol.2005;174 (10):6490-8.
19 Matsuyama W, Kamohara H, Galligan C et al. Interaction of discoidin domain receptor 1 isoform b (DDRlb) with collagen activates p38 mitogen-activated protein kinase and promotes differentiation of macrophages. FASEB J.2003; 17 (10):1286-8.
20 Matsuyama W, Faure M, Yoshimura T.Activation of discoidin domain receptor 1 facilitates the maturation of human monocyte-derived dendritic cells through the TNF receptor associated factor 6/TGF-beta-activated protein kinase 1 binding protein 1 beta/p38 alpha mitogen-activated protein kinase signaling cascade. [J]Immunol.2003;171 (7):3520-32.
21 Matsuyama W, Wang L, Farrar WL et al. Activation of discoidin domain receptor 1 isoform b with collagen up-regulates chemokine production in human macrophages:role of p38 mitogen-activated protein kinase and NF-kappa B. [J]Immuno.2004;172 (4):2332-40.
22 Vogel W, Lammers R, Huang J et al. Activation of a phosphotyrosine phosphatase by tyrosine phosphorylation. [J]Science.1999;259(5101):1611-4
23 L'hote CG, Thomas PH, Ganesan TS.Functional analysis of discoidin domain receptor 1:effect of adhesion on DDR1 phosphorylation. FASEB J.2002;16 (2):234-6
24 Faraci-Orf E, McFadden C, Vogel WF.DDR1 signaling is essential to sustain Stat5 function during lactogenesis. [J]Cell Biochem.2006;97 (1):109-21.
25 Dejmek J, Leandersson K, Manjer J et al. Expression and signaling activity of Wnt-5a/discoidin domain receptor-1 and Syk plays distinct but decisive roles in breast cancer patient survival. [J]Clin. Cancer Res.2005;11(2 Pt 1):520-8.
26 Dejmek J, Dib K, Jonsson M et al. Wnt-5a and G-protein signaling are required for collagen-induced DDR1 receptor activation and normal mammary cell adhesion. Int. J. Cancer.2003;103 (3):344-51.
27 Ikeda K, Wang LH, Torres R et al.Discoidin domain receptor 2 interacts with Src and Shc following its activation by type I collagen. [J]Biol.Chem.2002;277 (21):19206-12.
28 Yang K, Kim JH, Kim HJ et al. Tyrosine 740 phosphorylation of discoidin domain receptor 2 by Src stimulates intramolecular autophosphorylation and Shc signaling complex formation. [J] Biol. Chem.2005;280 (47):39058-66.
29 Faraci E, Eck M, Gerstmayer B et al. An extracellular matrix-specific microarray allowed the identification of target genes downstream of discoidin domain receptors.[J]Matrix Biol.2003;22(4):373-81.
30 Zerlin M, Julius MA, Goldfarb M.NEP:a novel receptor-like tyrosine kinase expressed in proliferating neuroepithelia. [J]Oncogene.1993;8 (10):2731-9.
31 Lai C, Lemke G Structure and expression of the Tyro 10 receptor tyrosine kinase. [J]Oncogene.1994;9 (3):877-83
32 Bhatt RS, Tomoda T, Fang Y et al. Discoidin domain receptor 1 functions in axon extension of cerebellar granule neurons. [J]Genes Dev.2000;14 (17):2216-18.
33 Sakamoto O, Suga M, Suda T et al.Expression of discoidin domain receptor 1 tyrosine kinase on the human bronchial epithelium. [J]Eur. Respir.2001;17 (5):969-74.
34 Labrador JP, Azcoitia V, Tuckermann J et al. The collagen receptor DDR2 regulates proliferation and its elimination leads to dwarfism. [J]EMBO Rep.2001;2 (5):446-52.
35 Ferri N, Carragher NO, Raines EW.Role of discoidin domain receptors 1 and 2 in human smooth muscle cell-mediated collagen remodeling:potential implications in atherosclerosis and lymphangioleiomyomatosis. Am. J. Pathol.2004;164 (5):1575-85.
36 Hou G, Vogel W, Bendeck MP.The discoidin domain receptor tyrosine kinase DDR1 in arterial wound repair. [J]Clin. Invest.2001;107 (6):727-35.
37 Hou G, Vogel WF, Bendeck MP.Tyrosine kinase activity of discoidin domain receptor 1 is necessary for smooth muscle cell migration and matrix metalloproteinase expression. [J]Circ Res.2002;90(11):1147-9.
38 Shyu KG, Chao YM, Wang BW et al. Regulation of discoidin domain receptor 2 by cyclic mechanical stretch in cultured rat vascular smooth muscle cells. [J]Hypertension.2005;46 (3): 614-21.
39 Mao TK, Kimura Y, Kenny TP et al. Elevated expression of tyrosine kinase DDR2 in primary biliary cirrhosis. [J]Autoimmunity.2002;35 (8):521-9
40 Chin GS, Lee S, Hsu M et al. Discoidin domain receptors and their ligand, collagen, are temporally regulated in fetal rat fibroblasts in vitro. [J] Reconstr. Surg.2001;107 (3):769-76.
41 Johnson JD, Edman JC, Rutter WJ.A receptor tyrosine kinase found in breast carcinoma cells has an extracellular discoidin I-like domain. [J]Proc. Natl. Acad. Sci.1993;90(12):5677-81.
42 Barker KT, Martindale JE, Mitchell PJ et al. Expression patterns of the novel receptor-like tyrosine kinase, DDR, in human breast tumours. [J]Oncogene.1995; 10 (3):569-75.
43 Ongusaha PP, Kim JI, Fang L, et al. p53 induction and activation of DDR1 kinase counteract p53-mediated apoptosis and influence p53 regulation through a positive feedback loop. Lee, EMBO J.2003;22 (6):1289-301.
44 Balduino A, Hurtado SP, Frazao P et al. Bone marrow subendosteal microenvironment harbours functionally distinct haemosupportive stromal cell populations. [J]Cell Tissue Res. 2005;319 (2):255-66.
2 Da Fano C. A cytological analysis of the reaction in animals resistant to implanted carcinomata. Fifth Sci Rep ICRF.1911;5:57-75.
3 Van Ravenswaay Claasen HH, Kluin PM, Fleuren GJ. Tumor infiltrating cell in human cancer on the possible role of CD16+macrophage in antitumor cytotoxity. [J] Lab Invest.1992;67 (2):166-174.
4 Taskinen M, Karjalainen-Lindsberg ML, Leppa S. Prognostic influence of tumor-infiltrating mast cells in patients with follicular lymphoma treated with rituximab and chop. [J] Blood. 2008; 111:4664-4667
5 Sunderkotter C, Goebeler M, Schulze Osthoff K, et al. Macrophage-derived angiogenesis factors. [J]. Pharmacol Ther.1991;51(2):195-216.
6 Folkman J. Tumor angiogenesis:therapeutic implications. [J]. N Engl Med.1971;285 (21): 1182-1186.
7 蔡方,赵勇,赵文丽.肿瘤相关巨噬细胞与胃癌血管生成及转移关系.中国肿瘤,2006；15(7)：476-477.
8 Ng D, Poon RT, Lee JM, et al. Microvessel density, vascular endothelial growth factor and its receptors Flt-1 and Flk-1/KDR in hepatocellular carcinoma. [J]Am J Clin Pathol.2001;116 (6): 838-845.
9 Hisai H, Kato J, Kobune M, et al. Increased expression of angiogenin in hepatocellular carcinoma in correlation with tumor vascularity.[J] Clin Cancer Res.2003; 9(13):4852-4859.
10 Ueno T, Suzuki T, Oikawa A, et al. Recruited bone marrow cells expressing the EP3 prostaglandin E receptor subtype enhance angiogenesis during chronic inflammation. [J]Biomed Pharmacother.2009; 10(17).
11 Bartz H, Buning Pfaue F, Turkel O, et al. Respiratory syncytial virus induces prostaglandin E2, IL-10 and IL-11 generation in antigenpresenting cells.[J]Clin Exp Immunol.2002; 129(3): 438-45.
12 Huang SH, Cao XJ, Wei W. Melat on indecreases TLR3-mediated inflammatory factor expression via inhibition of NF-kappa B activation in respiratory syncytial virus-infected RAW264.7 macrophages.[J]Pineal Res.2008;45(1):93-100.
13 Morris on PT, Thomas LH, Sharland, et al. MRSV-infected air way epithelial cells cause biphasic up-regulation of CCR1 expression on human monocytes.[J] Leukoc Biol.2007;81(6): 1487-95.
14 Margarita B, Barbar SF. Prostaglandin E2 inhibits production of Thl lymphokines but not of Th2 lymphokines. [J] Immunol.1991;146:108-113.
15 Tsuyoshi Tajima, Takahisa Murata, Kosuke Aritake, et al. Lipopolysaccharide induces macrophage migration via prostaglandin D and prostaglandin E2. [J] PET.2008;326(2): 493-501.
16 Han C, Wu T. Cyclooxygenase-2-derived prostaglandin E2 promotes human cholangiocarcinoma cell growth and invasion through EP1 receptor-mediated activation of the epidermal growth factor recrptor and Akt. [J]Biol Chem.2005; 80:24053-24063.
17 Kubo H, Hosono K, Suzuki T. Host prostaglandin EP3 receptor signaling relevant to tumor-associated lymphangiogenesis. [J] Biomed Pharmacother.2010; 64(2):101-6.
18 T. Lawrence, D. A. Willoughby, D. W. Gilroy. Anti-inflammatory lipid mediators and insights into the resolution of inflammation. [J] Nat. Rev. Immunol.2002;2:787-795.
19 Devanand Sarkar, Paul B, Fisher. Molecular mechanisms of aging-associated inflammation. [J] Caner Letters.2006;236(1):13-23.
20 Virchow R. Die krankhaften Geschwulste. DreiBig Vorlesungen, gehalten wahrend des Wintersemesters 1862-1863 an der Universitat zu Berlin Vorlesungen uber Pathologie Berlin: Verlag von August Hirschwald; 1863.
21 Ehrlich P. Experimentelle studien an maustumoren. zeitschr f Krebsforschung 1907,5:59-81.
22 Balwill F, Charles KA, Mantovani A. Smoldering and polarized inflammation in the initiation and promotion of malignant disease. [J] Cancer Cell.2005;7; 3:211-7.
23 Pollard JW. Tumour-educated macrophages promote tumour progression and metastasis. [J] Nat Rev Cancer.2004;4:71-8.
24 T. Lawrence, D. A. Willoughby, D. W. Gilroy, Anti-inflammatory lipid mediators and insights into the resolution of inflammation. [J] Nat. Rev. Immunol.2002;2:787-795.
25 Tlsty TD. Stomal cells can contribute oncogenic signals. Semin Cancer Biol.2001; 11:97-104.
26 Van Kempen LC, Ruiter DJ, van Muijen GN, Coussens LM. The tumor microenvironment:a critical determinant of neoplastic evolution. [J] Eur J Cell Biol.2003;82:539-48.
27 Dvorak HF. Rous-Whipple Award Lecture. How tumors make bad blood vessels and stroma. [J] Am J Pathol.2003;162:1747-1757.
28 SP. Hussain, LJ. Hofseth, CC. Harris, Radical causes of cancer. [J] Nat. Rev, Cancer.2003;3: 276-285.
29 Funk CD. Prostaglandins and leukotrienes:advances in eicosanoid biology. [J] Science.2001;294:1871-1875.
30 O'Byrne KJ, Dalgleish AG. Chronic immune activation and inflammation as the cause of malignancy. [J] Br J Cancer.2001;85:473-483
31 Balkwill F. Cancer and the chemokine network. [J] Nat Rev Cancer.2004; 4:540-550
32 Coussens LM, Werb Z. Inflammation and cancer. [J] Nature.2002;420:860-7.
33 Thun MJ, Henley SJ, Gansler T. Inflammation and cancer:an epidemiological perspective. [J] Novartis Found Symp.2004; 256:6-21.
34 Clevrs H. At the crossroads of inflammation and cancer. [J] Cell.2004; 118:671-4.
35 Shacter E, Weitzman SA. Chronic inflammation and cancer. [J] Oncology.2002; 16:217-26.
36 Balkwill F, Charles KA, Mantovani A. Smoldering and polarized inflammation in the initiation and promotion of malignant disease. [J] Cancer Cell.2005;7:211-7.
37 Lewis CE, Murdoch C. Macrophage responses to hypoxia:implication for tumor progression and anti-cancer therapies. [J] AM J Pathol.2005;167:627-35.
38 Murdoch C, Lewis CE. Macrophage migration and gene expression in response to tumor hypoxia. [J] Int J Cancer.2005; 117:701-8.
39 G. L. Larsen, P. L. Warner, P. A. Ward, The role of cytokines and adhesion molecules in the development of inflammatory injury. [J] Mol. Med. Today.1995;1:40-45.
40 Welch DR, Schissel DJ, Howrey RP, Aeed PA. Tumor-elicited polymorphonuclear cells, in contrast to'normal'circulating polymorphonuclear cells, stimulate invasive and metastatic potentials of rat mammary adenocarcinoma cells. [J] Proc Natl Acad Sci.1989;86:5859-63.
41 Josephy PD, Coomber BL. The 1996 Veylien Henderson Award of the Society of Toxicology of Canada. Current concepts:neutrophils and the activation of carcinogens in the breast and other organs. [J] Can J Physiol Pharmacol.1999; 76:693-700.
42 Allavena P, Sica A, Solinas G, Porta C, Mantovani A. The inflammatory micro-environment in tumor progression:the role of tumor-associated macrophages. [J] Crit Rev Oncol Hematol. 2008a;66(1):1-9.
43 Allavena P, Sica A, Solinas G, Porta C, Mantovani A. The Inflammatory micro-environment in tumor progression:the role of tumor-associated macrophages. [J] Crit Rev Oncol Hematol. 2008b;66:1-9
44 Yuan A, Chen JJ, Yang PC. Pathophysiology of tumor-associated macrophages. [J]Adv Clin Chem.2008;45:199-223.
45 Lewis CE, Pollard JW. Distinct role of macrophages in different tumor microenvironments. [J] Cancer Res.2006;66(2):605-612.
46 Siveen KS, Kuttan G. Role of macrophages in tumour progression. [J] Immunol Lett. 2009; 123(2):97-102.
47 Mayumi Ono. Molecular links between tumor angiogenesis and inflammation:inflammatory stimuli of macrophages and cancer cells as targets for therapeutic strategy. [J] Cancer Sci.2008;99(8):1501-1506
48 Sica A, Schioppa T, Mantovani A, et al. Tumour-associated macrophages are a distinct M2 polarised population promoting tumour progression:potential targets of anti-cancer therapy. [J]Euro J Cancer.2006;42(6):717-727.
49 Leek RD, Lewis CE, Whitehouse R, et al. Association of macrophage infiltration with angiogenesis and prognosis in invasive breast carcinoma.[J]Cancer Res.1996;56(20): 4625-4629.
50 Bunt SK, Yang L, Sinha P, Clements VK, Leips J, Ostrand-Rosenberg S. Reduced inflammation in the tumor microenvironment delays the accumulation of myeloid-derived suppressor cells and limits tumor progression. [J] Cancer Res.2007;67:10019-10026
51 Saccni A, Schioppa T, Porta C, et al. p50 nuclesr factor-κB overexpression in tumor-associated macrophages inhibits M1 inflammatory responses and antitumor resistance.[J]Cancer Res.2006;66(23):11432-11440.
52李宏捷,张玉茹,朱晓虹.口腔鳞状细胞癌巨噬细胞浸润与VEGF表达关系的研究.现代口腔医学杂志,2007；21(5)：499-501.
53 Lewis CE, Pollard JW. Distinct role of macrophages in different tumor microenvironments. [J] Cancer Res.2006;66 (2):605-612.
54 Nyberg P, Salo T, Kalluri R. Tumor microenvironment and angiogenesis. [J] Front Biosci. 2008;13(1):6537-53.
55 Minardi D, Lucarini G, Filosa A, Milanese G, Zizzi A, Di Primio R, Montironi R, Muzzonigro G. Prognostic role of tumor necrosis, microvessel density, vascular endothelial growth factor and hypoxia inducible factor-1 alpha in patients with clear cell renal carcinoma after radical nephrectomy in a long term follow-up. Int J Immunopathol Pharmacol.2008;21(2):447-55.
56 Arbeit JM. Transgenic models of epidermal neoplasia and multi-stage carcinogenesis. [J] Cancer Surv.1996;26(1):7-34.
57 Sunderkotter C, Goebeler M, Schulze-Osthoff K, et al. Macrophage-derived angiogenesis factors. [J] Pharmaco Ther.1991; 51:195-216.
58 58Weidner N, Folkman J, Pozza F, et al. Tumor angiogenesis:a new significant and independent indicat or in early-stage breast carcinoma.[J] J Natl Cancer I nst.1992;84 (24); 1850-1851.
59 Toge H, Inagaki T, Kojimoto Y, Shinka T, Hara I. Angiogenesis in renal cell carcinoma:the role of tumor-associated macrophages. [J] Int J Urol.2009; 16(10):801-7
60李德超,陈瑶,魏良富.iNOS、VEGF和CD34在人涎腺腺样囊性癌中的表达及意义.口腔医学研究,2008；24(6)：644-646.
61 Shieh YS, Hung YJ, Hsieh CB, Chen JS, Chou KC, Liu SY Tumor-associated macrophage correlated with angiogenesis and progression of mucoepidermoid carcinoma of salivary glands. [J] Ann Surg Oncol.2009;16(3):751-60.
62钟鸣,王洁,王兆元,韩有平.CD34和血管内皮生长因子在人牙源性病损中的表达.中华口腔医学杂志,2002；37(6)：455.
63冯红超,宋宇峰.口腔鳞癌巨噬细胞和微血管的空间关系.贵阳医学院学报,2003；28(1)：12-14.
64 Sharma SD, Meeran SM, Katiyar SK. Proanthocyanidins inhibit in vitro and in vivo growth of human non-small cell lung cancer cells by inhibiting the prostaglandin E(2) and prostaglandin E(2) receptors. [J]Mol Cancer Ther.2010;9(3):569-80.
65 Chen X, Wang S, Wu N, et al. Leukot riene A4 hydrolase as a target for cancer prevention and therapy [J]. Curr Cancer Drug Targets.2004; 4 (3):267-283.
66 Yokomizo T, Izumi T, Shimizu T. Leukot riene B4:metabolism and signal transduction.[J] Arch Biochem Biophys.2001;15(2):231-241.
67 Katoh H, Hosono K, Ito Y. COX-2 and prostaglandin EP3/EP4 signaling regulate the tumor stromal proangiogenic microenvironment via CXCL12-CXCR4 chemokine systems. Am J Pathol.2010;176(3):1469-83.
68 Hiromichi FJ, Wei X, John WR. Prostaglandin E2 induced functional expression of early growth response factor-1 by EP4, but not EP2, prostanoid receptora via the phosphatidylinositol 3-kinase and extracellular signal-regulated kinases. [J]Biol Chem. 2003;278:12151-12156
69 Amano H, Ito Y, Suzuki T. Roles of a prostaglandin E-type receptor, EP3, in upregulation of matrix metalloproteinase-9 and vascular endothelial growth factor during enhancement of tumor metastasis. [J]Cancer Sci.2009; 100(12):2318-24.
70 Ogawa Y, Suzuki T, Oikawa A. Bone marrow-derived EP3-expressing stromal cells enhance tumor-associated angiogenesis and tumor growth. [J]Biochem Biophys Res Commun.2009; 15; 382(4):720-5.
71 Taniguchi T, Fujino H, Israel DD, Regan JW, Murayama T. Human EP3(I) prostanoid receptor induces VEGF and VEGF receptor-1 mRNA expression. [J]Biochem Biophys Res Commun. 2008;26; 377(4):1173-8.
72 Scharl A, Vierbuchen M, Conradt B, et al. Immunohistochemical detection of progesterone receptor in formalin-fixed and paraffin-embedded breast cancer tissue using amonoclonal antibody. [J]Arch Gynecol Obstet.1999;247(2):63-71.
73何华.如何正确地对免疫组化结果进行半定量评分.中外健康文摘·临床医师.2008；5(7)：162.
74 Kinoshita T, Takahashi Y, Sakashita T, et al. Growth stimulation and induction of epidermal growth factor receptor by overexpression of cyclooxygenase 1 and 2 in human colon carcinoma cells. [J] Biochim Biophys Acta.1999; 1438:120-130.
75羊建,刘佳佳.前列腺素EP3亚型受体的研究进展.International Journal of Immunology. 2007;30:80-83
76 Boie Y, Stocco R, Sawyer N, et al. Molecular cloning and characterization of the four rat prostaglandin E2 prostanoid receptor subtypes.[J]Eur J Pharmacol.1997;340:227-241
77 Alexander S. Endocytosis and intracellular sorting of receptor tyrosine kinase.[J]Frontiers in Bioscience reductase.1998; 3:729-738
1 Coussens LM, et al. Iflammation and cancer. [J] Nature.2002;420(6917):860-867.
2 Pollard JW. Tumour-educated macrophages promote tumour progression and metastasis. [J]. Nat Rev Cancer.2004;4:71-78.
3 Nardin A, et al. Macrophages and cancer. [J] Front Biosci.2008;13:3494-505.
4 Antonio S, et al. Cancer related inflammation:the macrophage connection. [J]Cancer Letters. 2008; 267(2):204-215.
5 Lucas T et al. Modulation of tumor associated macrophages in solid tumors. [J] Front Biosci. 2008,13:5580-5588.
6 Matsushima K, et al. Chemokines and inflammation. [J] Nippon Ronen Igakkai Zasshi.1999; 36(2):82-9.
7 Balkwill F. Cancer and the chemokine network. [J] Nat Rev Cancer.2004;4(7):540-550
8 Gordon S. Alternative activation of macrophages. [J] Nat Rev Immunol.2003;3:23-35
9 Mantovani A, et al. The chemokine system in diverse forms of macrophage activation and polarization. [J]Trends Immunol.2004;25(12):677-686
10 Gordon S, et al. Monocyte and macrophage heterogeneity. [J] Nat Rev Immunol.2005;5: 953-964
11 Sica A, Schioppa T, MantovaniA, et al. Tmour-associated macrophages are a distinct M2 polarised population promoting tumour progression:potential targets of anti-cancer therapy [J]. Eur J Cancer.2006;42 (6):717-727.
12 Mantovani A et al. Macrophage polarization:tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes.[J]Trends Immunol.2002;23(11):549-555
13 Allavena P et al. IL-10 prevents the differentiation of monocytes to dendritic cells but promotes their maturation to macrophages.[J]Eur J Immunol.1998;28:359
14 Sica A et al. Autocrine production of IL-10 mediates defective IL-12 production and NF-kappa B activation in tumor-associated macrophages.[J]Immunol.2000; 164:762-767
15 Yasuda H. Solid tumor physiology and hypoxia-induced chemo/radio-resistance:novel strategy for cancer therapy:nitric oxide donor as a therapeutic enhancer. [J]Nitric Oxide.2008;19(2):205-216
16 Weigert A et al. Nitric oxide, apoptosis and macrophage polarization during tumor progression. [J]Nitric Oxide.2008;19(2):95-102
17 Knowles H, Leek R, HarrisAL. Macrophage infiltration and angiogenesis in human malignancy.[J]Novartis Found Syrup.2004; 256:189-200.
18 Lewis CE, Pollard JW. Distinct role of macrophages in different tumormicroenvironments. [J]Cancer Res.2006;66 (2):605-612.
19 Chen JJ, Lin YC, Yao PL, et al. Tumor-associated macrophages:the double-edged sword in cancer progression. [J] Clin Oncol.2005;23 (5):953-964.
20 Oshima H, Oshima M, Inaba K, et al. Hyperp lastic gastric tumors induced by activated macrophages in COX-2 /mPGES-1 transgenic mice. [J]EMBO J.2004;23 (7):1669-1678.
21 Lewis C, Murdoch C. Macrophage responses to hypoxia:implications for tumor progression and anticancer therapies. [J]Am J Patho.2005;167 (3):627-635.
22 Van den Brule F, Califice S, Gamier F, et al. Galectin-1 accumulation in the ovary carcinoma peritumoral stroma is induced by ovary carcinoma cells and affects both cancer cell proliferation and adhesion to laminin-1 and fibronectin. [J]Lab Invest.2003;83(3):377-386.
23 Lin EY, Nguyen AV, Russell RG, et al. Colonystimulating factorl promotes progression of marmnary tumors to malignancy. [J] Exp Med.2001;193 (6):727-740.
24 Hagemann T, Wilson J, Kulbe H, et al. Macrophages induce invasiveness of epithelial cancer cells via NF-κB and JNK.[J]Immunol.2005;175 (2):1197-1205.
25 Goswami S, Sahai E, Wyckoff JB, et al. Macrophages promote the invasion of breast carcinoma cells via a colony-stimulating factor-Ⅰ/epidermal growth factor paracrine loop. [J] Cancer Res.2005;65 (12):5278-5283.
26 Wyckoff J, WangW, Lin EY, et al. A pamcfine loop between tumor cells and macrophages is required for tumor cell migration in manunary tumors. [J]Cancer Res.2004;64(19):7022-7029.
27 Oosterling SJ, van derBij GJ, Meijer GA, et al. Macrophages direct tumour histology and clinical outcome in a colon cancermodel.[J] Pathol.2005;207 (2):147-155.
28 Ben-Barnch A. Inflammation-associated immune suppression in cancer:the roles played by cytokines, chemokines and additional mediators.[J] Semin Cancer Biol.2006;16 (1):38-52.
29 Maruyama K, Ii M, Cursiefen C, et al. Inflammation-induced lymphangiogenesis in the cornea arises from CD1 lb-positive macrophages.[J] Clin Invest.2005;115 (9):2363-2372.
30 Kerjaschki D. The crucial role of macrophages in lymphangiogenesis.[J] Clin Invest.2005;115 (9):2316-2319.
31 Schoppmann SF, Birner P, Stockl J, et al. Tumor-associated macrophages express lymphatic endothelial growth factors and are related to peritumoral lymphangiogenesis. [J] Am J Pathol. 2002; 161 (3):947-956.
32 Bjorndahl MA, Cao R Burton JB, et al. Vascular endothelial growth factor-a promotes pefitumoml lymphangiogenesis and lymphaticmetastasis[J].Cancer Res.2005;65(20): 9261-9268.
33 SkobeM, Hamberg LM, Hawighorst T, et al. Concurrent induction of lymphangiogenesis, angiogenesis, and macrophage recruitment by vascular endothelial growth factor-C in melanoma.[J] Am J Pathol.2001;159 (3):893-903.
34冯红超,宋宇峰,温玉明.口腔癌组织中血管内皮生长皮生长因子2C在肿瘤相关巨噬细胞内的表达及与淋巴结转移的关系.[J]癌症,2004；23(3)：278-281.
35 ColomboMP, MantovaniA. Targetingmyelomonocytic cells to revert inflmtion-dependent cancer promotion.[J] Cancer Re.2005; 65 (20):9113-9116.
36 Guiducci C, Vicari AP, Sangaletti S, et al. Redirecting in vivo elicited tumor infiltrating macrophages and dendritic cells towards tumor rejection. [J] Cancer Res.2005; 65 (8):3437-3446.
1 Jonson JD et al. Association and phosphorylation-dependent dissociation of proteins in the insulin receptor complex. [J] Proc Natl Acad Sci USA.1993;90(23):11317-21.
2 Lai C et al. Structure and expression of the Tyro 10 receptor tyrosine kinase.[J]Oncogene.1994; 9:877
3 G. Agarwal, L. Kovac, C. Radziejewski et al. Binding of discoidin domain receptor 2 to collagen I:an atomic force microscopy investigation. [J]Biochemistry.2002;41(37):11091.
4 B. Leitinger, A. Steplewski, A. Fertala. The D2 period of collagen II contains a specific binding site for the human discoidin domain receptor, DDR2. [J]Mol Biol.2004; 344(4):993-1003.
5 W. Vogel, C. Brakebusch, R. Fassler et al. Discoidin domain receptor 1 is activated independently of beta(l) integrin. [J] Biol Chem.2000;275(8):5779-84.
6 D.L. Simpson, S.D. Rosen, S.H. Barondes. Discoidin, a developmentally regulated carbohydrate-binding protein from Dictyostelium discoideum. Purification and characterization. [J]Biochemistry.1974;13(17):3487-93.
7 Alves F, Vogel W, Mossie K et al. Distinct structural characteristics of discoidin I subfamily receptor tyrosine kinases and complementary expression in human cancer. [J]Oncogene.1995; 10 (3):609-18.
8 Leitinger B. Molecular analysis of collagen binding by the human discoidin domain receptors, DDR1 and DDR2. Identification of collagen binding sites in DDR2. [J]Biol. Chem.2003;278 (19):16761-9.
9 R. Abdulhussein, C. McFadden, P. Fuentes-Prior et al. [J]Biol. Chem.2004;279 (30):31462.
10 Vogel WF. Ligand-induced shedding of discoidin domain receptor 1. [J]FEBS Lett.2002;514 (2-3):175-80.
11 Wybenga-Groot LE, Baskin B, Ong SH, et al. Structural basis for autoinhibition of the Ephb2 receptor tyrosine kinase by the unphosphorylated juxtamembrane region. [J] Cell.2006; 106 (6): 745-57.
12 Alves F, Saupe S, Ledwon M et al.Identification of two novel, kinase-deficient variants of discoidin domain receptor 1:differential expression in human colon cancer cell lines. FASEB J. 2001;15 (7):1321-3.
13 Perez JL, Shen X, Finkernagel S et al. Identification and chromosomal mapping of a receptor tyrosine kinase with a putative phospholipid binding sequence in its ectodomain. [J]Oncogene.1994; 9 (1):211-9
14 Sakuma S, Saya H, Tada M et al. Receptor protein tyrosine kinase DDR is up-regulated by p53 protein. [J] FEBS Lett 1996;398 (2-3):165-9.
15 Foehr ED, Tatavos A, Tanabe E et al. Discoidin domain receptor 1 (DDR1) signaling in PC 12 cells:activation of juxtamembrane domains in PDGFR/DDR/TrkA chimeric receptors. [J]FASEB.2000;14 (7):973-81.
16 Wang CZ, Hsu YM, Tang MJ.Function of discoidin domain receptor I in HGF-induced branching tubulogenesis of MDCK cells in collagen gel. [J]Cell. Physiol.2005;203 (1): 295-304.
17 Barker KT et al. Expression patterns of the novel receptor-like tyrosine kinase, DDR, in human breast tumours. [J]Oncogene.1995; 10(3):569-75..
18 Matsuyama W, Watanabe M, Shirahama Y et al. Activation of discoidin domain receptor 1 on CD14-positive bronchoalveolar lavage fluid cells induces chemokine production in idiopathic pulmonary fibrosis. [J]Immunol.2005;174 (10):6490-8.
19 Matsuyama W, Kamohara H, Galligan C et al. Interaction of discoidin domain receptor 1 isoform b (DDRlb) with collagen activates p38 mitogen-activated protein kinase and promotes differentiation of macrophages. FASEB J.2003; 17 (10):1286-8.
20 Matsuyama W, Faure M, Yoshimura T.Activation of discoidin domain receptor 1 facilitates the maturation of human monocyte-derived dendritic cells through the TNF receptor associated factor 6/TGF-beta-activated protein kinase 1 binding protein 1 beta/p38 alpha mitogen-activated protein kinase signaling cascade. [J]Immunol.2003;171 (7):3520-32.
21 Matsuyama W, Wang L, Farrar WL et al. Activation of discoidin domain receptor 1 isoform b with collagen up-regulates chemokine production in human macrophages:role of p38 mitogen-activated protein kinase and NF-kappa B. [J]Immuno.2004;172 (4):2332-40.
22 Vogel W, Lammers R, Huang J et al. Activation of a phosphotyrosine phosphatase by tyrosine phosphorylation. [J]Science.1999;259(5101):1611-4
23 L'hote CG, Thomas PH, Ganesan TS.Functional analysis of discoidin domain receptor 1:effect of adhesion on DDR1 phosphorylation. FASEB J.2002;16 (2):234-6
24 Faraci-Orf E, McFadden C, Vogel WF.DDR1 signaling is essential to sustain Stat5 function during lactogenesis. [J]Cell Biochem.2006;97 (1):109-21.
25 Dejmek J, Leandersson K, Manjer J et al. Expression and signaling activity of Wnt-5a/discoidin domain receptor-1 and Syk plays distinct but decisive roles in breast cancer patient survival. [J]Clin. Cancer Res.2005;11(2 Pt 1):520-8.
26 Dejmek J, Dib K, Jonsson M et al. Wnt-5a and G-protein signaling are required for collagen-induced DDR1 receptor activation and normal mammary cell adhesion. Int. J. Cancer.2003;103 (3):344-51.
27 Ikeda K, Wang LH, Torres R et al.Discoidin domain receptor 2 interacts with Src and Shc following its activation by type I collagen. [J]Biol.Chem.2002;277 (21):19206-12.
28 Yang K, Kim JH, Kim HJ et al. Tyrosine 740 phosphorylation of discoidin domain receptor 2 by Src stimulates intramolecular autophosphorylation and Shc signaling complex formation. [J] Biol. Chem.2005;280 (47):39058-66.
29 Faraci E, Eck M, Gerstmayer B et al. An extracellular matrix-specific microarray allowed the identification of target genes downstream of discoidin domain receptors.[J]Matrix Biol.2003;22(4):373-81.
30 Zerlin M, Julius MA, Goldfarb M.NEP:a novel receptor-like tyrosine kinase expressed in proliferating neuroepithelia. [J]Oncogene.1993;8 (10):2731-9.
31 Lai C, Lemke G Structure and expression of the Tyro 10 receptor tyrosine kinase. [J]Oncogene.1994;9 (3):877-83
32 Bhatt RS, Tomoda T, Fang Y et al. Discoidin domain receptor 1 functions in axon extension of cerebellar granule neurons. [J]Genes Dev.2000;14 (17):2216-18.
33 Sakamoto O, Suga M, Suda T et al.Expression of discoidin domain receptor 1 tyrosine kinase on the human bronchial epithelium. [J]Eur. Respir.2001;17 (5):969-74.
34 Labrador JP, Azcoitia V, Tuckermann J et al. The collagen receptor DDR2 regulates proliferation and its elimination leads to dwarfism. [J]EMBO Rep.2001;2 (5):446-52.
35 Ferri N, Carragher NO, Raines EW.Role of discoidin domain receptors 1 and 2 in human smooth muscle cell-mediated collagen remodeling:potential implications in atherosclerosis and lymphangioleiomyomatosis. Am. J. Pathol.2004;164 (5):1575-85.
36 Hou G, Vogel W, Bendeck MP.The discoidin domain receptor tyrosine kinase DDR1 in arterial wound repair. [J]Clin. Invest.2001;107 (6):727-35.
37 Hou G, Vogel WF, Bendeck MP.Tyrosine kinase activity of discoidin domain receptor 1 is necessary for smooth muscle cell migration and matrix metalloproteinase expression. [J]Circ Res.2002;90(11):1147-9.
38 Shyu KG, Chao YM, Wang BW et al. Regulation of discoidin domain receptor 2 by cyclic mechanical stretch in cultured rat vascular smooth muscle cells. [J]Hypertension.2005;46 (3): 614-21.
39 Mao TK, Kimura Y, Kenny TP et al. Elevated expression of tyrosine kinase DDR2 in primary biliary cirrhosis. [J]Autoimmunity.2002;35 (8):521-9
40 Chin GS, Lee S, Hsu M et al. Discoidin domain receptors and their ligand, collagen, are temporally regulated in fetal rat fibroblasts in vitro. [J] Reconstr. Surg.2001;107 (3):769-76.
41 Johnson JD, Edman JC, Rutter WJ.A receptor tyrosine kinase found in breast carcinoma cells has an extracellular discoidin I-like domain. [J]Proc. Natl. Acad. Sci.1993;90(12):5677-81.
42 Barker KT, Martindale JE, Mitchell PJ et al. Expression patterns of the novel receptor-like tyrosine kinase, DDR, in human breast tumours. [J]Oncogene.1995; 10 (3):569-75.
43 Ongusaha PP, Kim JI, Fang L, et al. p53 induction and activation of DDR1 kinase counteract p53-mediated apoptosis and influence p53 regulation through a positive feedback loop. Lee, EMBO J.2003;22 (6):1289-301.
44 Balduino A, Hurtado SP, Frazao P et al. Bone marrow subendosteal microenvironment harbours functionally distinct haemosupportive stromal cell populations. [J]Cell Tissue Res. 2005;319 (2):255-66.
© 2004-2018 中国地质图书馆版权所有 京ICP备05064691号 京公网安备11010802017129号 地址：北京市海淀区学院路29号 邮编：100083 电话：办公室：(+86 10)66554848；文献借阅、咨询服务、科技查新：66554700 |