趋化因子受体CXCR4和CCR7在Barrett's食管、食管腺癌和食管鳞状细胞癌中的表达及其临床意义
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摘要
目的：探讨Barrett's食管(BE)、食管腺癌(EADC)和食管鳞癌(ESCC)中趋化因子受体4(CXCR4)和趋化因子受体7(CCR7)表达的临床意义。
方法：应用免疫组织化学SP法对56例正常食管黏膜、80例BE(含22例BE伴多灶性非典型增生)、25例EADC和48例ESCC中的CXCR4和CCR7的表达进行检测,运用免疫组织化学图像分析加以定量,然后进行统计学分析。
结果CXCR4和CCR7在BE、EADC和ESCC中的表达均显著高于正常食管黏膜组织(CXCR4：78.75%,68.00%,83.33%vs39.29%;CCR7：60.00%,60.00%,58.33%vs30.36%：均P<0.01);CXCR4和CCR7的表达在BE、EADC和ESCC这3类食管病理类型中的表达无差异：CXCR4的表达在BE和ESCC中均显著高于CCR7(P<0.05,P<0.01)。并且CXCR4和CCR7的表达差异与临床病理特征有一定关系：CXCR4和CCR7在BE、EADC和ESCC的表达与性别、年龄、病变发生位置均无关：CXCR4和CCR7的表达在BE无非典型增牛和BE伴多灶性非典型增生这两类组织样本中无差异：CXCR4和CCR7在中-低分化EADC中的表达较高分化,以及有淋巴结转移较无淋巴结转移均显著升高(P<0.05);CXCR4和CCR7在ESCC中的表达水平在肿瘤TNM分期的Ⅲ-Ⅳ级较Ⅰ-Ⅱ级以及有淋巴结转移较无淋巴结转移均显著升高(P<0.05),中-低分化较高分化则极显著升高(P<0.01)。BE无非典型增生、BE伴多灶性非典型增生和EADC组织中CXCR4的表达与CCR7的表达呈明显的正相关(r=0.456,r=0.652.r=0.490),而在ESCC中CXCR4的表达与CCR7的表达无相关性(r=0.076)。
结论：联合检测CXCR4和CCR7有助于更准确诊断BE、EADC和ESCC:CXCR4和CCR7高表达是EADC和ESCC具有较强浸润和转移潜能的重要标志;CXCR4和CCR7可能共同参与了丛BE到EADC的发展过程。
OBJECTIVE:To detect the expression of CXC chemokine receptor4(CXCR4) and CC chemokine receptor7(CCR7) in normal esophageal mucosa, Barrett's esophagus(BE). esophageal adenocarcinoma(EADC), and esophageal squamous cell carci-noma(ESCC).and to investigate their clinical significance.
METHODS:The expression of CXCR4and CCR7in56normal esophageal mucosal specimens,80BE specimens(including22cases of BE with multifocal atypical hyperplasia).25EADC specimens, and48ESCC specimens was examined by immunohistochemistry. The expression levels of CXCR4and CCR7were then quantified and analyzed statistically.
RESULTS:The positive expression rates of CXCR4and CCR7in BE. EADC and ESCC were significantly higher than those in normal esophageal mucosa(CXCR4:78.75%,68.00%,83.33%vs39.29%; CCR7:60.00%,60.00%,58.33%vs30.36%:all P<0.01). However, there were no significant differences in the positive expression rates of CXCR4and CCR7among BE, EADC and ESCC. The positive expression rates of CXCR4were significantly higher than those of CCR7in both BE and ESCC(P<0.05and0.01). CXCR4and CCR7expression was not associated with gender, age. and lesion site in BE, EADC and ESCC. but correlated with tumor differentiation and lymph node metastasis in EADC(both P<0.05) and TNM stage, lymph node metastasis, and differentiation in ESCC(all P<0.05). A significant correlation was noted between CXCR4and CCR7expression in BE and EADC(r=0.262.0.490). but not in ESCC(r=0.076).
CONCLUSION:Combined detection of CXCR4and CCR7expression may contribute to more accurate diagnosis of BE. EADC and ESCC. High expression levels of CXCR4and CCR7can be used as important parameters for evaluating tumor invasion and metastasis in both EADC and ESCC.
方法：应用免疫组织化学SP法对56例正常食管黏膜、80例BE(含22例BE伴多灶性非典型增生)、25例EADC和48例ESCC中的CXCR4和CCR7的表达进行检测,运用免疫组织化学图像分析加以定量,然后进行统计学分析。
结果CXCR4和CCR7在BE、EADC和ESCC中的表达均显著高于正常食管黏膜组织(CXCR4：78.75%,68.00%,83.33%vs39.29%;CCR7：60.00%,60.00%,58.33%vs30.36%：均P<0.01);CXCR4和CCR7的表达在BE、EADC和ESCC这3类食管病理类型中的表达无差异：CXCR4的表达在BE和ESCC中均显著高于CCR7(P<0.05,P<0.01)。并且CXCR4和CCR7的表达差异与临床病理特征有一定关系：CXCR4和CCR7在BE、EADC和ESCC的表达与性别、年龄、病变发生位置均无关：CXCR4和CCR7的表达在BE无非典型增牛和BE伴多灶性非典型增生这两类组织样本中无差异：CXCR4和CCR7在中-低分化EADC中的表达较高分化,以及有淋巴结转移较无淋巴结转移均显著升高(P<0.05);CXCR4和CCR7在ESCC中的表达水平在肿瘤TNM分期的Ⅲ-Ⅳ级较Ⅰ-Ⅱ级以及有淋巴结转移较无淋巴结转移均显著升高(P<0.05),中-低分化较高分化则极显著升高(P<0.01)。BE无非典型增生、BE伴多灶性非典型增生和EADC组织中CXCR4的表达与CCR7的表达呈明显的正相关(r=0.456,r=0.652.r=0.490),而在ESCC中CXCR4的表达与CCR7的表达无相关性(r=0.076)。
结论：联合检测CXCR4和CCR7有助于更准确诊断BE、EADC和ESCC:CXCR4和CCR7高表达是EADC和ESCC具有较强浸润和转移潜能的重要标志;CXCR4和CCR7可能共同参与了丛BE到EADC的发展过程。
OBJECTIVE:To detect the expression of CXC chemokine receptor4(CXCR4) and CC chemokine receptor7(CCR7) in normal esophageal mucosa, Barrett's esophagus(BE). esophageal adenocarcinoma(EADC), and esophageal squamous cell carci-noma(ESCC).and to investigate their clinical significance.
METHODS:The expression of CXCR4and CCR7in56normal esophageal mucosal specimens,80BE specimens(including22cases of BE with multifocal atypical hyperplasia).25EADC specimens, and48ESCC specimens was examined by immunohistochemistry. The expression levels of CXCR4and CCR7were then quantified and analyzed statistically.
RESULTS:The positive expression rates of CXCR4and CCR7in BE. EADC and ESCC were significantly higher than those in normal esophageal mucosa(CXCR4:78.75%,68.00%,83.33%vs39.29%; CCR7:60.00%,60.00%,58.33%vs30.36%:all P<0.01). However, there were no significant differences in the positive expression rates of CXCR4and CCR7among BE, EADC and ESCC. The positive expression rates of CXCR4were significantly higher than those of CCR7in both BE and ESCC(P<0.05and0.01). CXCR4and CCR7expression was not associated with gender, age. and lesion site in BE, EADC and ESCC. but correlated with tumor differentiation and lymph node metastasis in EADC(both P<0.05) and TNM stage, lymph node metastasis, and differentiation in ESCC(all P<0.05). A significant correlation was noted between CXCR4and CCR7expression in BE and EADC(r=0.262.0.490). but not in ESCC(r=0.076).
CONCLUSION:Combined detection of CXCR4and CCR7expression may contribute to more accurate diagnosis of BE. EADC and ESCC. High expression levels of CXCR4and CCR7can be used as important parameters for evaluating tumor invasion and metastasis in both EADC and ESCC.
引文
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5. Kato M. Kitayama J. Kazama S. etal. Expression pattern of CXC chemokine receptor-4 is correlated with lymph node metastasis in human invasive ductal carcinoma [J]. Breast Cancer Res.2003.5(5):R144-150.
6. Kaifi JT. Yekebas EF, Schurr P. et al. Tumor-cell homing to lymph nodes and bone marrow and CXCR4 expression in esophageal cancer [J]. J Natl Cancer Inst.2005.97(24):1840-1847.
7. Kryczek I, Wei S, Keller E, et al. Stroma-derived factor(SDF-1/CXCL12) and human tumor pathogenesis [J].Am J Physiol Cell Physiol.2007.292(3):C987-995.
8. Welder T, Wolferr F, Schimanski CC,et al. Strong expression of chemokine receptor CXCR4 by pancreatic cancer correlates with advanced dim [J] Oncol Rep,2006.16(6):1159-1164.
9. Dcwun MZ, Ahmed S. lwasaki Y, et al. Stromal cell-derived factor-1 and CXCB4 receptor interaction in tumor growth and metastasis of breast cancer[J]. Biomed Pharmacother,2006. 60(6):273-276.
10. Zhang JP.Lu WG, Ye F, et al. Study on CXCR4/SDF-lalpha axis in lymph node metastasis of cervical sauamous cell carcinoma [J]. Int J Gynecol Cancer,2007.17(2):478-483.
11 Darash-Yahana M. Pikarsky E. Abramovitch R. et al. Role of high expression levels of CXCR4 in tumor growth, vascularization. and metastasis [J]. Fascb J.2004.18(11):1240-1242
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5. Muller A, Homey B. Soto H, et al. Involvement of chemokine receptors in breast cancer metastasis. Nature.2001,410:50-56. PMid:11242036
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7. 樊祥奎,严瑞华，王磊,等，趋化因子受体7在食管癌及转移淋巴结中的表达意义.中华临床医师杂志,2008，2(5)：556-512.
8. 张义侠,赵成海,张海鹏,趋化因子受体CCR7在结直肠癌中的异常表达.世界华人消化杂志.2008,16(16)：1828-1831.
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2. Forman D. Review article:oesophago-gastric adenocarcinoma-an epidemiological perspective. Aliment Pharmacol Ther 2004; 20 Suppl 5:55-60; discussion 61-62. PMid: 15456465
3. Shaheen N, Ransohoff DF. Gastroesophageal reflux, barrett esophagus, and esophageal cancer: scientific review. JAMA,2002.287:1972-1981. PMid:11960540
4. Balkwill F:The significance of cancer cell expression of the chemokine receptor CXCR4 [J].Semin Cancer Biol,2004,14(3):171-179.
5. Kato M. Kitayama J. Kazama S. etal. Expression pattern of CXC chemokine receptor-4 is correlated with lymph node metastasis in human invasive ductal carcinoma [J]. Breast Cancer Res.2003.5(5):R144-150.
6. Kaifi JT. Yekebas EF, Schurr P. et al. Tumor-cell homing to lymph nodes and bone marrow and CXCR4 expression in esophageal cancer [J]. J Natl Cancer Inst.2005.97(24):1840-1847.
7. Kryczek I, Wei S, Keller E, et al. Stroma-derived factor(SDF-1/CXCL12) and human tumor pathogenesis [J].Am J Physiol Cell Physiol.2007.292(3):C987-995.
8. Welder T, Wolferr F, Schimanski CC,et al. Strong expression of chemokine receptor CXCR4 by pancreatic cancer correlates with advanced dim [J] Oncol Rep,2006.16(6):1159-1164.
9. Dcwun MZ, Ahmed S. lwasaki Y, et al. Stromal cell-derived factor-1 and CXCB4 receptor interaction in tumor growth and metastasis of breast cancer[J]. Biomed Pharmacother,2006. 60(6):273-276.
10. Zhang JP.Lu WG, Ye F, et al. Study on CXCR4/SDF-lalpha axis in lymph node metastasis of cervical sauamous cell carcinoma [J]. Int J Gynecol Cancer,2007.17(2):478-483.
11 Darash-Yahana M. Pikarsky E. Abramovitch R. et al. Role of high expression levels of CXCR4 in tumor growth, vascularization. and metastasis [J]. Fascb J.2004.18(11):1240-1242
1. Yoshida R, Nagira M. Kitaura M. et al.Secondary lymphoid-tissue chemokine is a functional ligand for the CC chemokine receptor CCR7. J Biol Chem,1998.273: 7118-7122. PMid:9507024
2. Yanagihara S, Komura E. Nagafune J, et al. EBI1/CCR7 is a new member of dendritic cell chemokine receptor that is up-regulated upon maturation. J Immunol, 1998,161:3096-3102. PMid:9743376
3. Willimann K, Legler DF, Loetscher M, et al. The chemokine SLC is expressed in T-cell areas of lymph nodes and mucosal lymphoid tissues and attracts activated T cells via CCR7. Eur J Immunol 1998.28:2025-2034. PMid:9645384
4. Gunn MD, Tangemann K. Tam C, et al. A chemokine expressed in lymphoid high endothelial venules promotes the adhesion and chemotaxis of naive T lymphocytes. Proc Natl Acad Sci USA,1998.95:258-63. PMid:9419363
5. Muller A, Homey B. Soto H, et al. Involvement of chemokine receptors in breast cancer metastasis. Nature.2001,410:50-56. PMid:11242036
6.赵焕芬,何春年,翟金萍,等.趋化因子受体CCR7在不同类型肺癌组织中的表达及其临床意义.第四军医大学学.2007.28(23)：2126-2129.
7. 樊祥奎,严瑞华，王磊,等，趋化因子受体7在食管癌及转移淋巴结中的表达意义.中华临床医师杂志,2008，2(5)：556-512.
8. 张义侠,赵成海,张海鹏,趋化因子受体CCR7在结直肠癌中的异常表达.世界华人消化杂志.2008,16(16)：1828-1831.
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