Association between the expression of CXCL12/CXCR4 and pancreatic cancer: a meta-analysis_Chinese Journal of Evidence-Based Medicine

Authors：

CAO Wei ¹ , CHENG Mengqiu ¹ ,  CHEN Bo ²

1. First School of Clinical Medicine, Anhui Medical University, Hefei 230000, P.R.China;
2. Department of General Surgery, the First Affiliated Hospital of Anhui Medical University, Hefei 230000, P.R.China;

Corresponding author：

CHEN Bo, Email: chenbo831116@163.com

Keywords：

Pancreatic cancer; Chemokine CXCL12; Chemokine receptor CXCR4; Meta-analysis; Systematic review; Case-control study

DOI：

10.7507/1672-2531.202002093

Video：

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Objective To systematically review the relationship between the expression of CXCL12/CXCR4 and pancreatic cancer.Methods PubMed, EMbase, The Cochrane Library, Wiley Online Library, CNKI, VIP, WanFang Data and CBM databases were electronically searched to collect case-control studies on CXCL12/CXCR4 expression in pancreatic cancer from inception to February 1^st 2020. Two reviewers independently screened literature, extracted data and assessed the risk of bias of included studies; then, meta-analysis was performed by using RevMan 5.3 software.Results A total of 21 case-control studies involving 1 677 cases and 1 690 controls were included. The results of meta-analysis showed that the expression of CXCR4 in pancreatic cancer tissue was higher than normal tissue (OR=21.40, 95%CI 5.70 to 80.31, P<0.01), in carcinoma of head of pancreas been higher than carcinoma of pancreatic body and tail, (OR=1.58, 95%CI 1.02 to 2.44, P=0.04), in pancreatic cancer with lymph node metastasis been higher than without lymph node metastasis (OR=3.14, 95%CI 1.98 to 4.99, P<0.01), in pancreatic cancer with high TNM stages (Ⅲ, Ⅳ) been higher than low TNM stages (Ⅰ, Ⅱ) (OR=3.67, 95%CI 1.98 to 6.81, P<0.01), in pancreatic cancer with distant metastasis been higher than without distant metastasis (OR=3.56, 95%CI 1.71 to 7.39, P<0.01), and in pancreatic cancer with vascular invasion was higher than without vascular invasion (OR=3.22, 95%CI 1.70 to 6.09, P<0.01). The expression of CXCR4 was not statistically correlated with age, gender, pancreatic cancer tissue and paracancerous tissue, pancreatic cancer tissue and paracancerous lymph nodes, differentiation degree. There was no statistical correlation between the expression of CXCL12 and the differentiation degree, and lymph node metastasis.Conclusions In pancreatic cancer, the high expression of CXCR4 is related to lymph node metastasis, high TNM stage, distant metastasis, vascular invasion indicate poor prognosis. Due to limited quality and quantity of the included studies, more high quality studies are required to verify above conclusions.

Citation： CAO Wei, CHENG Mengqiu, CHEN Bo. Association between the expression of CXCL12/CXCR4 and pancreatic cancer: a meta-analysis. Chinese Journal of Evidence-Based Medicine, 2021, 21(2): 179-185. doi: 10.7507/1672-2531.202002093 Copy

1.	吴万龙, 彭兵. 胰腺癌流行病学及危险因素. 中国普外基础与临床杂志, 2019, 26(12): 1500-1504.
2.	马少军, 屈振亮, 孔棣, 等. 胰腺癌流行病学及诊断研究进展. 中国中西医结合外科杂志, 2015, 21(1): 87-92.
3.	吕翼, 魏若征, 吴河水. 胰腺癌的早期诊断. 临床急诊杂志, 2018, 19(3): 149-151.
4.	刘梦奇, 吉顺荣, 徐晓武, 等. 2019年胰腺癌研究及诊疗新进展. 中国癌症杂志, 2020, 30(1): 1-10.
5.	张师容, 靳伟, 刘亮, 等. 2017年胰腺癌基础研究及诊疗新进展. 中国癌症杂志, 2018, 28(1): 1-10.
6.	潘博, 郭俊超, 廖泉, 等. 吉西他滨与胰腺癌化疗耐药. 中国普外基础与临床杂志, 2005, (5): 530-532.
7.	陈菊香, 周红轩, 马兰, 等. 吉西他滨联合奥沙利铂或替吉奥对比吉西他滨单药治疗晚期胰腺癌临床观察. 安徽医药, 2015, 19(2): 359-362.
8.	Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin, 2018, 68(1): 7-30.
9.	Righetti A, Giulietti M, Sabanovic B, et al. CXCL12 and its isoforms: different roles in pancreatic cancer? J Oncol, 2019, 2019 (8): 1-13.
10.	Lombardi L. Chemokine receptor CXCR4: What is its role in gastrointestinal cancer? J Clin Oncol, 2013, 31(15).
11.	Nazari A, Khorramdelazad H, Hassanshahi G. Biological/pathological functions of the CXCL12/CXCR4/CXCR7 axes in the pathogenesis of bladder cancer. Int J Clin Oncol, 2017, 22(6): 991-1000.
12.	Kajtazi Y, Kaemmerer D, Sänger J, et al. Somatostatin and chemokine CXCR4 receptor expression in pancreatic adenocarcinoma relative to pancreatic neuroendocrine tumours. J Cancer Res Clin Oncol, 2019, 145(10): 2481-2493.
13.	Zhou W, Guo S, Liu M, et al. Targeting CXCL12/CXCR4 axis in tumor immunotherapy. Curr Med Chem, 2019, 26(17): 3026-3041.
14.	Morimoto M, Matsuo Y, Koide S, et al. Enhancement of the CXCL12/CXCR4 axis due to acquisition of gemcitabine resistance in pancreatic cancer: effect of CXCR4 antagonists. BMC Cancer, 2016, 16(305).
15.	张红雨, 费立明, 王长亮, 等. 胰腺癌中CXCL12-CXCR4生物学轴与VEGF-C的表达及相关性研究. 中国现代普通外科进展, 2008, 11(4): 283-286.
16.	喻建, 曹军. VEGF-C, CXCR4在胰腺癌中的表达与意义. 医学新知杂志, 2008, 18(6): 342-343, 345.
17.	姚宝忠, 李良, 江鸣, 等. CD133和趋化因子受体4在胰腺癌中的表达及临床相关性. 中华普通外科学文献(电子版), 2017, 11(6): 375-379.
18.	许莹, 潘振国, 李倩君, 等. GSK3β, CXCR4, MMP-2与胰腺癌侵袭和转移的关系. 胃肠病学和肝病学杂志, 2016, 25(11): 1308-1311.
19.	徐锋. SDF-1/CXCR4和TECK/CCR9与胰腺癌预后不良相关性研究. 天津: 天津医科大学, 2013.
20.	王宝胜, 孟祥鹏, 刘臻, 等. 胰腺癌组织中SDF-1的表达与其临床病理特征的关系. 现代肿瘤医学, 2012, 20(3): 540-542.
21.	李玉军, 李霞, 孙玲玲, 等. 胰腺癌CXCR-4, MMP-2, VEGF的表达及其与肿瘤生物学行为的关系. 中华胰腺病杂志, 2009, 9(5): 334-336.
22.	李辉, 吕丽红, 张波, 等. CXCR-4在胰腺癌中的表达及临床意义. 山东医药, 2008, 48(6): 64-65.
23.	符亮, 吴冬冰, 万鸿兴. 胰腺癌组织转录中介因子1及趋化因子受体-4的表达特点及临床意义. 安徽医药, 2019, 23(9): 1842-1845.
24.	方德刚, 周光华. 人胰腺癌变组织中血管内皮生长因子微血管密度CXCR-4的表达及其意义. 山西医药杂志, 2011, 40(12): 1180-1181.
25.	Zhang J, Liu C, Mo X, et al. Mechanisms by which CXCR4/CXCL12 cause metastatic behavior in pancreatic cancer. Oncol Lett, 2018, 15(2): 1771-1776.
26.	Xu Q, Wang Z, Chen X, et al. Stromal-derived factor-1α/CXCL12-CXCR4 chemotactic pathway promotes perineural invasion in pancreatic cancer. Oncotarget, 2015, 6(7): 4717-4732.
27.	Wehler T, Wolfert F, Schimanski CC, et al. Strong expression of chemokine receptor CXCR4 by pancreatic cancer correlates with advanced disease. Oncol Rep, 2006, 16(6): 1159-1164.
28.	Wang Z, Ma Q, Li P, et al. Aberrant expression of CXCR4 and β-catenin in pancreatic cancer. Anticancer Res, 2013, 33(9): 4103-4110.
29.	Koshiba T, Hosotani R, Miyamoto Y, et al. Expression of stromal cell-derived factor 1 and CXCR4 ligand receptor system in pancreatic cancer: a possible role for tumor progression. Clin Cancer Res, 2000, 6(9): 3530-3535.
30.	Liang JJ, Zhu S, Bruggeman R, et al. High levels of expression of human stromal cell-derived factor-1 are associated with worse prognosis in patients with stage Ⅱ pancreatic ductal adenocarcinoma. Cancer Epidemiol Biomarkers Prev, 2010, 19(10): 2598-2604.
31.	Jiang YM, Li G, Sun BC, et al. Study on the relationship between CXCR4 expression and perineural invasion in pancreatic cancer. Asian Pac J Cancer Prev, 2014, 15(12): 4893-4896.
32.	Wu H, Zhu L, Zhang H, et al. Coexpression of EGFR and CXCR4 predicts poor prognosis in resected pancreatic ductal adenocarcinoma. PLoS One, 2015, 10(2): e116803.
33.	Liao W, Wang H, Huang H, et al. CXCR4 expression predicts early liver recurrence and poor survival after resection of pancreatic adenocarcinoma. Clin Transl Gastroenterol, 2012, 3(9): e22.
34.	Marechal R, Demetter P, Nagy N, et al. High expression of CXCR4 may predict poor survival in resected pancreatic adenocarcinoma. Br J Cancer, 2009, 100(9): 1444-1451.
35.	Gebauer F, Tachezy M, Effenberger K, et al. Prognostic impact of CXCR4 and CXCR7 expression in pancreatic adenocarcinoma. J Surg Oncol, 2011, 104(2): 140-145.
36.	彭松庆. 血清基质金属蛋白酶9和CC型趋化因子18对胰腺癌诊断性能评价. 中国卫生检验杂志, 2017, 27(23): 3417-3418.
37.	郭欣, 吕行, 谢娇贵, 等. 趋化因子配体18表达水平对胰腺癌患者的预后价值. 中华肝胆外科杂志, 2015, 21(7): 474-477.
38.	孙联康, 都大伟, 钱伟崐, 等. 趋化因子CXCL11激活NF-κB信号通路促进胰腺癌的侵袭转移及上皮间质转换. 西安交通大学学报(医学版), 2019, 40(4): 501-505.
39.	Zhang R, Liu Q, Peng J, et al. CXCL5 overexpression predicts a poor prognosis in pancreatic ductal adenocarcinoma and is correlated with immune cell infiltration. J Cancer, 2020, 11(9): 2371-2381.
40.	Fan H, Wang W, Yan J, et al. Prognostic significance of CXCR7 in cancer patients: a meta-analysis. Cancer Cell Int, 2018, 18: 212.
41.	Litman-Zawadzka A, Łukaszewicz-Zając M, Gryko M, et al. Serum chemokine CXCL8 as a better biomarker for diagnosis and prediction of pancreatic cancer than its specific receptor CXCR2, c-reactive protein, and classic tumor markers CA 19-9 and CEA. Pol Arch Intern Med, 2018, 128(9): 524-531.

1. 吴万龙, 彭兵. 胰腺癌流行病学及危险因素. 中国普外基础与临床杂志, 2019, 26(12): 1500-1504.
2. 马少军, 屈振亮, 孔棣, 等. 胰腺癌流行病学及诊断研究进展. 中国中西医结合外科杂志, 2015, 21(1): 87-92.
3. 吕翼, 魏若征, 吴河水. 胰腺癌的早期诊断. 临床急诊杂志, 2018, 19(3): 149-151.
4. 刘梦奇, 吉顺荣, 徐晓武, 等. 2019年胰腺癌研究及诊疗新进展. 中国癌症杂志, 2020, 30(1): 1-10.
5. 张师容, 靳伟, 刘亮, 等. 2017年胰腺癌基础研究及诊疗新进展. 中国癌症杂志, 2018, 28(1): 1-10.
6. 潘博, 郭俊超, 廖泉, 等. 吉西他滨与胰腺癌化疗耐药. 中国普外基础与临床杂志, 2005, (5): 530-532.
7. 陈菊香, 周红轩, 马兰, 等. 吉西他滨联合奥沙利铂或替吉奥对比吉西他滨单药治疗晚期胰腺癌临床观察. 安徽医药, 2015, 19(2): 359-362.
8. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin, 2018, 68(1): 7-30.
9. Righetti A, Giulietti M, Sabanovic B, et al. CXCL12 and its isoforms: different roles in pancreatic cancer? J Oncol, 2019, 2019 (8): 1-13.
10. Lombardi L. Chemokine receptor CXCR4: What is its role in gastrointestinal cancer? J Clin Oncol, 2013, 31(15).
11. Nazari A, Khorramdelazad H, Hassanshahi G. Biological/pathological functions of the CXCL12/CXCR4/CXCR7 axes in the pathogenesis of bladder cancer. Int J Clin Oncol, 2017, 22(6): 991-1000.
12. Kajtazi Y, Kaemmerer D, Sänger J, et al. Somatostatin and chemokine CXCR4 receptor expression in pancreatic adenocarcinoma relative to pancreatic neuroendocrine tumours. J Cancer Res Clin Oncol, 2019, 145(10): 2481-2493.
13. Zhou W, Guo S, Liu M, et al. Targeting CXCL12/CXCR4 axis in tumor immunotherapy. Curr Med Chem, 2019, 26(17): 3026-3041.
14. Morimoto M, Matsuo Y, Koide S, et al. Enhancement of the CXCL12/CXCR4 axis due to acquisition of gemcitabine resistance in pancreatic cancer: effect of CXCR4 antagonists. BMC Cancer, 2016, 16(305).
15. 张红雨, 费立明, 王长亮, 等. 胰腺癌中CXCL12-CXCR4生物学轴与VEGF-C的表达及相关性研究. 中国现代普通外科进展, 2008, 11(4): 283-286.
16. 喻建, 曹军. VEGF-C, CXCR4在胰腺癌中的表达与意义. 医学新知杂志, 2008, 18(6): 342-343, 345.
17. 姚宝忠, 李良, 江鸣, 等. CD133和趋化因子受体4在胰腺癌中的表达及临床相关性. 中华普通外科学文献(电子版), 2017, 11(6): 375-379.
18. 许莹, 潘振国, 李倩君, 等. GSK3β, CXCR4, MMP-2与胰腺癌侵袭和转移的关系. 胃肠病学和肝病学杂志, 2016, 25(11): 1308-1311.
19. 徐锋. SDF-1/CXCR4和TECK/CCR9与胰腺癌预后不良相关性研究. 天津: 天津医科大学, 2013.
20. 王宝胜, 孟祥鹏, 刘臻, 等. 胰腺癌组织中SDF-1的表达与其临床病理特征的关系. 现代肿瘤医学, 2012, 20(3): 540-542.
21. 李玉军, 李霞, 孙玲玲, 等. 胰腺癌CXCR-4, MMP-2, VEGF的表达及其与肿瘤生物学行为的关系. 中华胰腺病杂志, 2009, 9(5): 334-336.
22. 李辉, 吕丽红, 张波, 等. CXCR-4在胰腺癌中的表达及临床意义. 山东医药, 2008, 48(6): 64-65.
23. 符亮, 吴冬冰, 万鸿兴. 胰腺癌组织转录中介因子1及趋化因子受体-4的表达特点及临床意义. 安徽医药, 2019, 23(9): 1842-1845.
24. 方德刚, 周光华. 人胰腺癌变组织中血管内皮生长因子微血管密度CXCR-4的表达及其意义. 山西医药杂志, 2011, 40(12): 1180-1181.
25. Zhang J, Liu C, Mo X, et al. Mechanisms by which CXCR4/CXCL12 cause metastatic behavior in pancreatic cancer. Oncol Lett, 2018, 15(2): 1771-1776.
26. Xu Q, Wang Z, Chen X, et al. Stromal-derived factor-1α/CXCL12-CXCR4 chemotactic pathway promotes perineural invasion in pancreatic cancer. Oncotarget, 2015, 6(7): 4717-4732.
27. Wehler T, Wolfert F, Schimanski CC, et al. Strong expression of chemokine receptor CXCR4 by pancreatic cancer correlates with advanced disease. Oncol Rep, 2006, 16(6): 1159-1164.
28. Wang Z, Ma Q, Li P, et al. Aberrant expression of CXCR4 and β-catenin in pancreatic cancer. Anticancer Res, 2013, 33(9): 4103-4110.
29. Koshiba T, Hosotani R, Miyamoto Y, et al. Expression of stromal cell-derived factor 1 and CXCR4 ligand receptor system in pancreatic cancer: a possible role for tumor progression. Clin Cancer Res, 2000, 6(9): 3530-3535.
30. Liang JJ, Zhu S, Bruggeman R, et al. High levels of expression of human stromal cell-derived factor-1 are associated with worse prognosis in patients with stage Ⅱ pancreatic ductal adenocarcinoma. Cancer Epidemiol Biomarkers Prev, 2010, 19(10): 2598-2604.
31. Jiang YM, Li G, Sun BC, et al. Study on the relationship between CXCR4 expression and perineural invasion in pancreatic cancer. Asian Pac J Cancer Prev, 2014, 15(12): 4893-4896.
32. Wu H, Zhu L, Zhang H, et al. Coexpression of EGFR and CXCR4 predicts poor prognosis in resected pancreatic ductal adenocarcinoma. PLoS One, 2015, 10(2): e116803.
33. Liao W, Wang H, Huang H, et al. CXCR4 expression predicts early liver recurrence and poor survival after resection of pancreatic adenocarcinoma. Clin Transl Gastroenterol, 2012, 3(9): e22.
34. Marechal R, Demetter P, Nagy N, et al. High expression of CXCR4 may predict poor survival in resected pancreatic adenocarcinoma. Br J Cancer, 2009, 100(9): 1444-1451.
35. Gebauer F, Tachezy M, Effenberger K, et al. Prognostic impact of CXCR4 and CXCR7 expression in pancreatic adenocarcinoma. J Surg Oncol, 2011, 104(2): 140-145.
36. 彭松庆. 血清基质金属蛋白酶9和CC型趋化因子18对胰腺癌诊断性能评价. 中国卫生检验杂志, 2017, 27(23): 3417-3418.
37. 郭欣, 吕行, 谢娇贵, 等. 趋化因子配体18表达水平对胰腺癌患者的预后价值. 中华肝胆外科杂志, 2015, 21(7): 474-477.
38. 孙联康, 都大伟, 钱伟崐, 等. 趋化因子CXCL11激活NF-κB信号通路促进胰腺癌的侵袭转移及上皮间质转换. 西安交通大学学报(医学版), 2019, 40(4): 501-505.
39. Zhang R, Liu Q, Peng J, et al. CXCL5 overexpression predicts a poor prognosis in pancreatic ductal adenocarcinoma and is correlated with immune cell infiltration. J Cancer, 2020, 11(9): 2371-2381.
40. Fan H, Wang W, Yan J, et al. Prognostic significance of CXCR7 in cancer patients: a meta-analysis. Cancer Cell Int, 2018, 18: 212.
41. Litman-Zawadzka A, Łukaszewicz-Zając M, Gryko M, et al. Serum chemokine CXCL8 as a better biomarker for diagnosis and prediction of pancreatic cancer than its specific receptor CXCR2, c-reactive protein, and classic tumor markers CA 19-9 and CEA. Pol Arch Intern Med, 2018, 128(9): 524-531.

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Association between the expression of CXCL12/CXCR4 and pancreatic cancer: a meta-analysis

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