趋化因子受体（CXCR4/CCR7）与口腔鳞状细胞癌的关系研究
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摘要
研究背景和目的:口腔鳞状细胞癌(oral squamous cell carcinoma,OSCC)是发生于口腔黏膜的鳞状细胞癌,是口腔颌面部最常见的恶性肿瘤。在我国有逐年增高的趋势,且发现时多已达进展期,疗效欠佳。侵袭和转移是OSCC患者的主要死因,而颈部淋巴结转移是最常见的转移靶器官,但目前关于口腔鳞状细胞癌侵袭和淋巴结转移的分子机制还不清楚。趋化因子是一组具有趋化作用的细胞因子超家族,研究发现趋因子及其受体与肿瘤的侵袭和淋巴结转移密切相关。尤其是基质细胞衍生因子-1(stromal cell-derived factor-1,SDF-1)及其受体CXC类趋化因子受体4(chemokin CXC motif receptor 4,CXCR4)和CC类趋化因子受体7(chemokin CC motif receptor 7,CCR7)及其配体CC类趋化因子配体19(chemokin CC motif ligand 19,CCL19)和CC类趋化因子配体21(chemokim CC motif ligand 21,CCL21)在肿瘤相对器官特异性转移中的作用日益受到关注。已有研究表明,乳腺癌、黑色素瘤、胃癌、非小细胞肺癌、骨肉瘤、恶性胶质瘤、横纹肌瘤等恶性肿瘤中有CXCR4、CCR7高表达,而一些肿瘤特异性转移靶器官有其配体SDF-1、CCL19/CCL21高表达,从而“吸引”肿瘤细胞,引起癌转移,提示SDF-1/CXCR4、CCL19/CCR7和CCL21/CCR7受体配体系统在肿瘤细胞选择性转移中发挥关键作用。本研究旨在观察CXCR4、CCR7在正常口腔粘膜、口腔鳞癌原发灶、反应反应性增生淋巴结和淋巴结转移灶中的表达情况,分析其与口腔鳞癌临床病理特点及颈淋巴结转移的关系。并结合临床病理资料初步探讨其在OSCC颈淋巴结转移中的作用。
方法采用免疫组化链酶亲和素-生物素复合物(strept avidin-biotin complex,SABC)法和原位杂交法检测64例口腔鳞癌(其中包括39例颈淋巴结转移灶)、10例反应性增生淋巴结和10例正常口腔黏膜中CXCR4、CCR7蛋白的表达情况,并分析其与临床病理参数及颈淋巴结转移的关系。
结果1. CXCR4 mRNA和CXCR4蛋白在口腔鳞癌中呈阳性表达,CXCR4蛋白的阳性表达率为62.5%(40/64)。此外,CXCR4的表达与肿瘤的分化程度(P=0.0042)、侵袭模式(P<0.001)、淋巴浸润(P<0.001)和TNM分期(P=0.0012)密切相关,而与年龄、性别和肿瘤大小无关。
2. CCR7 mRNA和CCR7蛋白在口腔鳞癌中有阳性表达,且CCR7蛋白的阳性表达率为65.6%(42/64)。同时,CCR7的表达也与肿瘤的分化程度(P=0.027)、淋巴浸润(P<0.001)、侵袭模式(P<0.001)和临床分期(P<0.001)密切相关。但与年龄、性别和肿瘤大小无关。
3. CXCR4 mRNA和CXCR4在口腔鳞癌颈淋巴结转移灶中也有阳性表达,CXCR4蛋白的阳性表达率为74.4%(29/39)。并且CXCR4在伴有淋巴结转移病例中的表达显著高于无淋巴结转移者(P=0.0144)。逐步回归分析显示表达CXCR4是淋巴结转移最主要的因素
4 . CCR7 mRNA和CCR7在口腔鳞癌颈淋巴结转移灶中也有阳性表达,CCR7蛋白的阳性表达率为84.6%(33/39)。并且CCR7在伴有淋巴结转移病例中的表达显著高于无淋巴结转移者(P<0.001)。逐步回归分析显示表达CCR7是淋巴结转移最主要的因素。
结论CXCR4、CCR7在口腔鳞癌原发灶及淋巴结转移灶内肿瘤细胞中有阳性表达,其表达水平与口腔鳞癌的发生、发展和颈淋巴结转移有关。CXCR4、CCR7有可能成为口腔鳞癌治疗的新靶点。研究结果为进一步研究SDF-1/CXCR4及CCL19/CCR7和或CCL21/CCR7受体配体系统与OSCC侵袭和颈淋巴结转移分子机制奠定了基础。
Backgroud and object: Oral squamous cell carcinoma occur on the cutaneous surface of the face and mucous membrane of the mouth. It is a most common Oral and Maxillofacial malignancy, and the incidence rate of OSCC has a trend to elevation in china in recent years. Most of the patients who had a final diagnosis of were too late to accept radical prostatectomy, and the therapeutic efficacy was far from satisfication. Cancer invasion and metastasis is the major cause of deaths of OSCC, cervical lymph node is a most common target organ. Chemokines belong to the small molecule chemoattractive cytokine family. Recent studies showed that chemokines and their receptor are significantly associated with invasion and lymph node mtastasis of tumors. Stromal cell-derived factor-1(SDF-1) and its receptor CXCR4 (chemokine CXC motif receptor 4) and chemokine CC motif ligand 19 (CCL19) or chemokine CC motif ligand 21 (CCL21) and its receptor CCR7 (chemokine CC motif receptor 7) in tumor metastasis to special organ is being noticed. CXCR4 and CCR7 hightly overexpresses in breast cancer, melamna, gastric carcinoma, nonsmall cell lung cancer, osteosarcoma tumor, glioblastoma and rhabdomyosarcoma cells, SDF-1 and CCL19/CCL21 overespresses in several special organs Which "atract" tumor cells and lead to organ metastases eventually. These findings suggest that SDF-1/CXCR4 and CCL19/CCR7 or CCL21/CCR7 plays a critical role in tumor cells selective metastases. The aims of this study were to observe the expression of CXCR4 and CCR7 in primary tumor cells of Oral squamous cell carcinoma(OSCC )and the tumor cells of the regional metastasized lymph nodes and nomal mucous membrane of the mouth tissue, and to evaluate the possible correlation between the expression of CXCR4 and CCR7 and the clinicopathology factors, and cervical lymph node metastasis of OSCC and further to explore the role of CXCR4、CCR7 in cervical lymph nodes metastasis in OSCC.
Methods The expression of CXCR4 and CCR7 in 64 cases of OSCC(included 39 cases of lymph node metastasis of OSCC), 10 cases of reactive hyperplasia of lymph node of neck ,10 cases of nomal mucous membrane of the mouth tissue were detected by immunohistochemistryand in situ hybridization, and its relation to cliniopathological data and cervical lymph node metastasis of OSCC was also analyzed
Results 1. CXCR4 mRNA and CXCR4 was positively expressed in OSCC, and the positive expression rate of CXCR4 protein was 62.5%(40/64). In addition, expression of CXCR4 protein was also correlated with tumor histological type (P=0.0042), depth of invasion (P<0.001),lymphatic invasion (P<0.001), and TNM stage (P=0.0012), but not with age at surgery, gender and tumor size. Respectively.
2. CCR7 mRNA and CCR7 was positively expressed in OSCC, and the positive expression rate of CCR7 protein was 65.6%(42/64). Meanwhile,expression of CCR7 protein was also correlated with tumor histological type (P=0.027), depth of tumor invasion ( P<0.001 ) , lymphatic invasion (P<0.001), and TNM stage (P<0.001), but not with age at surgery, gender, tumor size.
3. CXCR4 mRNA and CXCR4 was positively expressed the tumor cells of the regional metastasized lymph nodes in OSCC, and the positive expression rate of CXCR4 protein was 74.4%(29/39). In addition, CXCR4 expression was significantly higher in the patients with lymph node metastasis than those without lymph node metastasis (P=0.0144). and stepwise regression analysis revealed that the most important factor related to lymph node metastasis was the expression of CXCR4.
4. CCR7 mRNA and CCR7 was positively expressed the tumor cells of the regional metastasized lymph nodes in OSCC, and the positive expression rate of CCR7 protein was 84.6%(33/39). Meanwhile, CCR7 expression was significantly higher in the patients with lymph node metastasis than those without lymph node metastasis (P<0.001), and stepwise regression analysis revealed that the most important factor related to lymph node metastasis was the expression of CCR7.
Conclusions CXCR4 and CCR7 is positive expressed in primary tumor cells of Oral squamous cell carcinoma(OSCC )and the tumor cells of the regional metastasized lymph nodes , and its expression was associated with the diverse progression of OSCC, including invasion and lymph node metastasis. CXCR4 and CCR7 as a potential therapeutic target in advanced cases of oral squamous cell carcinoma. Those data provide foundation for further study on the molecular mechanism of invasion and cervical lymph node metastasis of OSCC.
方法采用免疫组化链酶亲和素-生物素复合物(strept avidin-biotin complex,SABC)法和原位杂交法检测64例口腔鳞癌(其中包括39例颈淋巴结转移灶)、10例反应性增生淋巴结和10例正常口腔黏膜中CXCR4、CCR7蛋白的表达情况,并分析其与临床病理参数及颈淋巴结转移的关系。
结果1. CXCR4 mRNA和CXCR4蛋白在口腔鳞癌中呈阳性表达,CXCR4蛋白的阳性表达率为62.5%(40/64)。此外,CXCR4的表达与肿瘤的分化程度(P=0.0042)、侵袭模式(P<0.001)、淋巴浸润(P<0.001)和TNM分期(P=0.0012)密切相关,而与年龄、性别和肿瘤大小无关。
2. CCR7 mRNA和CCR7蛋白在口腔鳞癌中有阳性表达,且CCR7蛋白的阳性表达率为65.6%(42/64)。同时,CCR7的表达也与肿瘤的分化程度(P=0.027)、淋巴浸润(P<0.001)、侵袭模式(P<0.001)和临床分期(P<0.001)密切相关。但与年龄、性别和肿瘤大小无关。
3. CXCR4 mRNA和CXCR4在口腔鳞癌颈淋巴结转移灶中也有阳性表达,CXCR4蛋白的阳性表达率为74.4%(29/39)。并且CXCR4在伴有淋巴结转移病例中的表达显著高于无淋巴结转移者(P=0.0144)。逐步回归分析显示表达CXCR4是淋巴结转移最主要的因素
4 . CCR7 mRNA和CCR7在口腔鳞癌颈淋巴结转移灶中也有阳性表达,CCR7蛋白的阳性表达率为84.6%(33/39)。并且CCR7在伴有淋巴结转移病例中的表达显著高于无淋巴结转移者(P<0.001)。逐步回归分析显示表达CCR7是淋巴结转移最主要的因素。
结论CXCR4、CCR7在口腔鳞癌原发灶及淋巴结转移灶内肿瘤细胞中有阳性表达,其表达水平与口腔鳞癌的发生、发展和颈淋巴结转移有关。CXCR4、CCR7有可能成为口腔鳞癌治疗的新靶点。研究结果为进一步研究SDF-1/CXCR4及CCL19/CCR7和或CCL21/CCR7受体配体系统与OSCC侵袭和颈淋巴结转移分子机制奠定了基础。
Backgroud and object: Oral squamous cell carcinoma occur on the cutaneous surface of the face and mucous membrane of the mouth. It is a most common Oral and Maxillofacial malignancy, and the incidence rate of OSCC has a trend to elevation in china in recent years. Most of the patients who had a final diagnosis of were too late to accept radical prostatectomy, and the therapeutic efficacy was far from satisfication. Cancer invasion and metastasis is the major cause of deaths of OSCC, cervical lymph node is a most common target organ. Chemokines belong to the small molecule chemoattractive cytokine family. Recent studies showed that chemokines and their receptor are significantly associated with invasion and lymph node mtastasis of tumors. Stromal cell-derived factor-1(SDF-1) and its receptor CXCR4 (chemokine CXC motif receptor 4) and chemokine CC motif ligand 19 (CCL19) or chemokine CC motif ligand 21 (CCL21) and its receptor CCR7 (chemokine CC motif receptor 7) in tumor metastasis to special organ is being noticed. CXCR4 and CCR7 hightly overexpresses in breast cancer, melamna, gastric carcinoma, nonsmall cell lung cancer, osteosarcoma tumor, glioblastoma and rhabdomyosarcoma cells, SDF-1 and CCL19/CCL21 overespresses in several special organs Which "atract" tumor cells and lead to organ metastases eventually. These findings suggest that SDF-1/CXCR4 and CCL19/CCR7 or CCL21/CCR7 plays a critical role in tumor cells selective metastases. The aims of this study were to observe the expression of CXCR4 and CCR7 in primary tumor cells of Oral squamous cell carcinoma(OSCC )and the tumor cells of the regional metastasized lymph nodes and nomal mucous membrane of the mouth tissue, and to evaluate the possible correlation between the expression of CXCR4 and CCR7 and the clinicopathology factors, and cervical lymph node metastasis of OSCC and further to explore the role of CXCR4、CCR7 in cervical lymph nodes metastasis in OSCC.
Methods The expression of CXCR4 and CCR7 in 64 cases of OSCC(included 39 cases of lymph node metastasis of OSCC), 10 cases of reactive hyperplasia of lymph node of neck ,10 cases of nomal mucous membrane of the mouth tissue were detected by immunohistochemistryand in situ hybridization, and its relation to cliniopathological data and cervical lymph node metastasis of OSCC was also analyzed
Results 1. CXCR4 mRNA and CXCR4 was positively expressed in OSCC, and the positive expression rate of CXCR4 protein was 62.5%(40/64). In addition, expression of CXCR4 protein was also correlated with tumor histological type (P=0.0042), depth of invasion (P<0.001),lymphatic invasion (P<0.001), and TNM stage (P=0.0012), but not with age at surgery, gender and tumor size. Respectively.
2. CCR7 mRNA and CCR7 was positively expressed in OSCC, and the positive expression rate of CCR7 protein was 65.6%(42/64). Meanwhile,expression of CCR7 protein was also correlated with tumor histological type (P=0.027), depth of tumor invasion ( P<0.001 ) , lymphatic invasion (P<0.001), and TNM stage (P<0.001), but not with age at surgery, gender, tumor size.
3. CXCR4 mRNA and CXCR4 was positively expressed the tumor cells of the regional metastasized lymph nodes in OSCC, and the positive expression rate of CXCR4 protein was 74.4%(29/39). In addition, CXCR4 expression was significantly higher in the patients with lymph node metastasis than those without lymph node metastasis (P=0.0144). and stepwise regression analysis revealed that the most important factor related to lymph node metastasis was the expression of CXCR4.
4. CCR7 mRNA and CCR7 was positively expressed the tumor cells of the regional metastasized lymph nodes in OSCC, and the positive expression rate of CCR7 protein was 84.6%(33/39). Meanwhile, CCR7 expression was significantly higher in the patients with lymph node metastasis than those without lymph node metastasis (P<0.001), and stepwise regression analysis revealed that the most important factor related to lymph node metastasis was the expression of CCR7.
Conclusions CXCR4 and CCR7 is positive expressed in primary tumor cells of Oral squamous cell carcinoma(OSCC )and the tumor cells of the regional metastasized lymph nodes , and its expression was associated with the diverse progression of OSCC, including invasion and lymph node metastasis. CXCR4 and CCR7 as a potential therapeutic target in advanced cases of oral squamous cell carcinoma. Those data provide foundation for further study on the molecular mechanism of invasion and cervical lymph node metastasis of OSCC.
引文
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[1] Kim CH.The greater chemotactic network for lymphocytetrafficking:Chemokine and beyond[J].Lippincott Williams & Wikins,2005,12(4):298-304.
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[3] Balkwill F.Cancer and the chemokine network[J].Nat RevCancer,2004,4(7):49-55.
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[5] Koto M,Kitayama J,Kazama S,et al.Expression pattern of CXCR4 is corre -lated with lymph node metastasis in human invasive dutal carcinoma [J].Bteast Cancer Res,2003,5(5):R144-150.
[6] Tamamura H,Hori A,Kanzaki N,et al.T140 anaiogs as CXCR4 antagonists identified as anti-metastatic agents in the treatment of breast cancer [J].FEBS Lett,2003,550(1-3):79-83.
[7] Chen Y,Stamatoyannopoulos G,Song CZ. Down-regulation of CXCR4 by inducibe small inter-fering RNA inhibits breast cancer cell invasion in vitro [J].Cancer Res,2003,63(16):4801-4804.
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[1] Kim CH.The greater chemotactic network for lymphocytetrafficking:Chemokine and beyond[J].Lippincott Williams & Wikins,2005,12(4):298-304.
[2] Balkwill F.Chemokine biology in cancer[J].Semin Immunol,2003,15(1):49-55.
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[5] Koto M,Kitayama J,Kazama S,et al.Expression pattern of CXCR4 is corre -lated with lymph node metastasis in human invasive dutal carcinoma [J].Bteast Cancer Res,2003,5(5):R144-150.
[6] Tamamura H,Hori A,Kanzaki N,et al.T140 anaiogs as CXCR4 antagonists identified as anti-metastatic agents in the treatment of breast cancer [J].FEBS Lett,2003,550(1-3):79-83.
[7] Chen Y,Stamatoyannopoulos G,Song CZ. Down-regulation of CXCR4 by inducibe small inter-fering RNA inhibits breast cancer cell invasion in vitro [J].Cancer Res,2003,63(16):4801-4804.
[8] Scotton CJ,Wilson JL,Scott K,et al. Multiple actions of the chemokine CXCL12 on epithelial tumor cells in human ovarin cancer[J]. Cancer Res,2002,62(20): 5930-5938.
[9] Phillips RT,Burdick MD,Lutz M,et al. The stromal derived factor-1/ CXCL12-CXC chemokine receptor 4 biological axis in non-small cell lung cancer metastases[J]. AM J Respir Crit care Med,2003,167(12):1676-1686.
[10] 苏丽萍,张进平,徐焕宾,等.趋化因子受体 CXCR4 在肺癌高转移细胞株的表达和意义[J].中国免疫学杂志,2004,20(9):603-606.
[11] Mori T,Doi R,Koizumi M,et al.CXCR4 antagonist inhibits stromal cell- derived factor 1-induced migration and invasion of human pancreatic cancer[J].Mol Cancer Ther,2004,3(1):29-27.
[12] LI Fang,ZHU Huaishi,HAN Zhiqiang,et al.Effects of chemokine receptor and its ligand on migration of ovarian cancer cells[J].Chinese Journal of Cancer, 2005,24(1):23-27.
[13] Perissinotto E,Cavalloni G,Leone F,et al.Invonlvement of chemokine receptor4/ SDF-1 system during osteosarcoma tumor progression[J].Clin Cancer Res,2005,11(2):490-497.
[14] Mashino K,Sadanaga N,YamaguchiH,et al. Expression of chemokine receptor CCR7 is associated with lymph node metastasis of gastric carcinoma[J]. Cancer Res,2002,62(10):2937.
[15] Kido S,Kitadai Y,Hattari N,et al. Interleukin 8 and vascular endothelial growth factor-prognostic factors in human gastric carcinomas Eur[J]. Cancer 2001, 37(12):1482.
[16] Inoue K,Slaton JW,Eve BY,et al. Interleukin 8 expression regulates tumorigenicity and metastases in androgen-independent prostate cancer [J]. Clin Cancer Res,2006,6(5):2104-2119.
[17] Dias,Choy M,Rafii S,et al.The role of CXC chemokine in the regualation of tumor angiogenesis[J].Cancer Invest,2001,19(7):732-738.
[18] Helbig G,Chritopherson KW 2nd,Bhat-Nakshatri P,et al. NF-kappaB promot -es breast cancer cell migration and metastasis by inducing the exp -ression of the chemokine receptor CXCR4[J]. J Biol Chem,2003,278(24): 21631-21638.
[19] Staller P,Sulitkova J,Lisztwan J,et al. Chemokin receptor CXCR4 down -regulated by von Hippel-Lindau tumour suppressor Pvhl[J]. Nature, 2003,425(6955):307-311.
[20] Jortoe GM,Petersen lc,Albrektsen T,et al. Tissue factor-factor V2a- specific up-regulation of IL-8 expression in MDA-MB-231 cells is mediated by PAR-2 and results in increased ceii migration[J]. Blood, 2004,103(8):3029-3037.
[21] Lin Y,Huang R,Chen L,et al. Identification of interleukin-8 as estrogen receptor-regulated factor involved in breast cancer invasion and angiogenesis by protein arrays[J]. Int J Cancer,2004,109(4):507-515.
[22] Hall JM,Korach KS. Stromal cell-derived factor 1,a novel target of estrogen receptor action,mediates the mitogenic effects of estradiol in ovarian and breast cancer cells[J] .Mol Endocrinol,2003,17(5):792 803.
[23] Uchida D,Begum NM,Almofti A,et al. Possible role of stromal-cell- derived factor-1/CXCR4 signaling on lymph node metastasis of oral squamous cell carcinoma[J]. Exp Cell Res,2003,290(2):289-302.
[24] Katayama A,Ogino T,Bandon N,et al.Expression of CXCR4 and its down-re –gulation by IFN-gamma in head and neck squamous cell carcinoma[J]. Clin Cancer Res,2005,11(8):2937-2946.
[25] Almofti A,Uchida D,Begum NM,et al.The clinicopathological significance ofCXCR4 protein in oral squamous cell carcinoma[J]. Int J Oncol, 2004,25(1):65-71.
[26] XU Yong,ZHANG Suzhen,HUANG Peichun,et al. Expression of chemokine receptor CXCR4 in nasopharyngeal carcinoma cells[J]. Chinese Journal of Cancer,2004,23(2):136-140.
[27] Delibasi CB,Okura M,Iida S,et al.Investigation of CXCR4 in squamous cell carcinoma of the tonque[J]. Oral Oncol,2004,40(2):154-157.
[28] Ding Y,Shimada Y,Maeda M,et al. Association of CC chemokine receptor 7 with lymph node metastasis of esophageal squamous cell carcinoma[J]. Clin Cancer Res,2003,9(8):3406-3412
[29] Wang J,Xi L,Hunt JL,et al.Expression pattern of chemokine receptor 6(CCR6) and CCR7 in squamous cell carcinoma of the head and neck identifies a novel metastatic phenotype[J].Cancer Res,2004,64(27): 1861-1866.