Correlation between Vascular Endothelial Growth Factor Expression and Prognosis of Esophageal Cancer: A Meta-Analysis_Chinese Journal of Evidence-Based Medicine

Authors：

WANG Que , ZHOU Rubai , TIAN Lixing ,  LU You

West China Hospital, Sichuan University, Chengdu 610041, China;

Corresponding author：

LU You, Email: radyoulu@hotmail.com

Keywords：

Esophageal cancer; Vascular endothelial growth factor; Prognosis; Survival rate; Meta-analysis; Cohort study

DOI：

10.7507/1672-2531.20130098

Video：

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Abstract Full text Figures/Tables Video References Cited by

Objective 　To assess the value of vascular endothelial growth factor (VEGF) expression in the prognosis of esophageal cancer.
Methods 　PubMed and EMbase were searched for collecting retrospective cohort studies on the correlation between VEGF expression and prognosis of esophageal cancer, and relevant articles were also retrieved from inception to June, 2012. Two reviewers independently screened the literature, extracted the data, and evaluated the quality. Then the meta-analysis was performed by using RevMan5.0 software, and the publication bias of literature was evaluated by means of Begg’s funnel plot and Egger’s method.
Results 　Finally 10 cohort studies involving 811 patients were included. The meta-analysis showed that, patients with high level of VEGF had poor overall survival (HR=1.55, 95%CI 1.25 to 1.91). The results of subgroup analyses including VEGF subtype, critical value of VEGF and source of patient showed that: a) there was no correlation between patient’s prognosis and high level of VEGF-C; b) The high level of VEGF subtype in cancer tissue indicated a higher risk of death when the critical value was 10%, while it was not related to the prognosis when the critical value was 30%; and c) The high level of VEGF in cancer tissue was more valuable to predict the prognosis of esophageal cancer for Chinese patients rather than non-Chinese patients.
Conclusion 　The level of VEGF’s expression in cancer tissue is valuable to predict the prognosis of esophageal cancer.

Citation： WANG Que,ZHOU Rubai,TIAN Lixing,LU You. Correlation between Vascular Endothelial Growth Factor Expression and Prognosis of Esophageal Cancer: A Meta-Analysis. Chinese Journal of Evidence-Based Medicine, 2013, 13(5): 553-559. doi: 10.7507/1672-2531.20130098 Copy

1.	Bradbury PA, Zhai R, Ma C, et al. Vascular endothelial growth factor polymorphisms and esophageal cancer prognosis. Clin Cancer Res, 2009, 15(14): 4680-4685.
2.	Crew KD, Neugut A. Epidemiology of upper gastrointestinal malignancies. Semin Oncol, 2004, 31(4): 450-464.
3.	蔡燕, 陈先卓, 彭乙华, 等. 食管癌组织中存活蛋白的异常表达. 重庆医学, 2012, 41(5): 432-434.
4.	Jemal A, Bray F, Center MM, et al. Global cancer statistics. CA Cancer J Clin, 2011, 61(2): 134.
5.	Yoko O, Satoshi Y, Kunihiro Y, et al. Angiogenesis-Related Factors are Molecular Targets for Diagnosis and Treatment of Patients with Esophageal Carcinoma. Ann Thorac CardiovascSurg, 2010, 16(6): 389-393.
6.	Vallböhmer D, Lenz HJ. Predictive and prognostic molecular markers in outcome of esophageal cancer. Diseases of the Esophagus, 2006, 19(6): 425-432.
7.	Ferrara N, Davis-Smyth T. The biology of vascular endothelial growth factor. Endocr Rev, 1997, 18(1): 4-25.
8.	Toi M, Matsumoto T, Bando H, et al. Vascular endothelial growth factor: its prognostic, predictive, and therapeutic implications. Lancet Oncol, 2001, 2(11): 667-673.
9.	Shih CH, Ozawa S, Ando N, et al. Vascular endothelial growth factor expression predicts outcome and lymph node metastasis in squamous cell carcinoma of the esophagus. Clin Cancer Res, 2000, 6(3): 1161-1168.
10.	Kitadai Y, Haruma K, Tokutomi T, et al. Significance of vessel count and vascular endothelial growth factor in human esophageal carcinomas. Clin Cancer Res, 1998, 4(9): 2195-2200.
11.	Inoue K, Ozeki Y, Suganuma T, et al. Vascular endothelial growth factor expression in primary esophageal squamous cell carcinoma. Association with angiogenesis and tumor progression. Cancer, 1997, 79(2): 206-213.
12.	Kleespies A, Guba M, Jauch KW, et al. Vascular endothelial growth factor in esophageal cancer. J SurgOncol, 2004, 87(2): 95-104.
13.	William PT, David PK, David HI, et al. Targeted Therapies for Esophageal Cancer. The Oncologist, 2005, 10(8): 590-601.
14.	李宝江, 贾王生, 臧长运. 食管癌组织VEGF的表达与肿瘤血管生成的关系. 实用癌症杂志, 2000, 15(6): 583-584.
15.	Poon RTP, Fan ST, Wong J, et al. Clinical significance of angiogenesis in gastrointestinal cancers – a target of novel prognostic and therapeutic approaches. Ann Surg, 2003, 238(1): 9-28.
16.	Nicosia R. What is the role of vascular endothelial growth factorrelated molecules in tumor angiogenesis. Am J Pathol, 1998, 153(1): 11-16.
17.	Miroslaw K, Oksana K, Robert M, et al. Serum vascular endothelial growth factors C and D in patients with oesophageal cancer. Eur J Cardio-thoracic Surg, 2010, 38(3): 260-267.
18.	Cavazzola LT, Rosa AR, Schirmer CC, et al. Immunohistochemical evaluation for P53 and VEGF (Vascular Endothelial Growth Factor) is not prognostic for long term survival in end stage esophageal adenocarcinoma. Rev Col Bras Cir, 2009, 36(1): 24-34.
19.	Koide N, Nishio A, Hiraguri M, et al. Coexpression of vascular endothelial growth factor and p53 protein in squamous cell carcinoma of the esophagus. Am J Gastroenterol, 2001, 96(6): 1733-1740.
20.	Shih CH, Ozawa S, Ando N, et al. Vascular endothelial growth factor expression predicts outcome and lymph node metastasis in squamous cell carcinoma of the esophagus. Clin Cancer Res, 2000, 6(3): 1161-1168.
21.	Rosa AR, Schirmer CC, Gurki RR, et al. Prognostic value of p53 protein expression and vascular endothelial growth factor expression in resected squamous cell carcinoma of theesophagus. Dis Esophagus, 2003, 16(2): 112-118.
22.	Shimada H, Takeda A, Nabeya Y, et al. Clinical significance of serum vascular endothelial growth factor in esophageal squamous cell carcinoma. Cancer, 2001, 92(3): 663-669.
23.	季卫忠, 顾汝军. 食管癌患者手术治疗前后血清IGF-I、VEGF和TSGF检测的临床意义. 放射免疫学杂志, 2011, 24(5): 496-497.
24.	Kimura H, Kato H, Tanaka N, et al. Preoperative serum vascular endothelial growth factor-C (VEGF-C) levels predict recurrence in patients with esophageal cancer. Anticancer Res, 2008, 28(1A): 165-169.
25.	Krzystek-Korpacka M, Matusiewicz M, Diakowska D, et al. Up-regulation of VEGF-C secreted by cancer cells and not VEGF-A correlates with clinical evaluation of lymph node metastasis in esophageal squamous cell carcinoma (ESCC). Cancer Lett, 2007, 249(2): 171-177.
26.	Naumnik W, Izycki T, Swidzin´ska E, et al. Serumlevels of VEGF-C, VEGF-D, and sVEGF-R2 in patients with lung cancer during chemotherapy. Oncol Res, 2007, 16(9): 445-451.
27.	Moundhri MS, Shukaili A, Nabhani M, et al. Measurement of circulating levels of VEGF-A, -C, and -D and their receptors, VEGFR-1 and -2 in gastric adenocarcinoma. World J Gastroenterol, 2008, 14(24): 3879-3883.
28.	Des GG, Uzzan B, Nicolas P, et al. Microvessel density and VEGF expression are prognostic factors in colorectal cancer: Meta-analysis of the literature. Br J Cancer, 2006, 94(12): 1823-1832.
29.	Li C, Zang J, Li XS, et al. Prognostic role of vascular endothelial growth factor in oral carcinoma: a meta analysis. West China Journal of Stomatology, 2011, 29(1): 39-43.
30.	Chen J, Li T, Wu Y, et al. Prognostic significance of vascular endothelial growth factor expression in gastric carcinoma: a meta-analysis. J Cancer Res ClinOncol, 2011, 137(12): 1799-1812.
31.	Schoenleber SJ, Kurtz DM, Talwalkar JA, et al. Prognostic role of vascular endothelial growth factor in hepatocellular carcinoma: Systematic review and meta-analysis. Br J Cancer, 2009, 100(9): 1385-1392.
32.	Veikkola T, Alitalo K. VEGFS, receptors and angiogenesis. Semin Cancer Bio, 1999, 9(3): 211-220.
33.	Jeltsch M, Kaipainen A, Joukov V, et al. Hyperplasia of lymphatic vessels in VEGF-Ctransgenicmice. Science, 1997, 277(5325): 463.
34.	Chen M, Cai E, Huang J, et al. Prognostic Value of Vascular Endothelial Growth Factor Expression in Patients with Esophageal Cancer: ASystematic Review and Meta-analysis. Cancer Epidemiol Biomarkers Prev, 2012, 21(7): 1126-1134.
35.	Akemi I, Hiromitsu M, Natsuya K, et al. Intratumorallymphangiogenesis of esophageal squamouscell carcinoma and relationship with regulatory factorsand prognosis. Pathology International, 2008, 58(10): 611-619.
36.	Ching T, Shih CL, Ho J, et al. Expression of hypoxia-inducible factor(HIF)-1α and vascular endothelial growthfactor (VEGF)-D as outcome predictors inresected esophageal squamous cell carcinoma. Disease Markers, 2008, 25(3): 141-148.
37.	Shimada H, Hoshino T, Okazumi S, et al. Expression of angiogenic factors predicts response tochemoradiotherapy and prognosis of oesophageal squamous cellcarcinoma. Br J Cancer, 2002, 86(4): 552-557.
38.	Joon YC, Kee-Taek J, Young MS, et al. Prognostic Significance of Vascular Endothelial GrowthFactor Expression and Microvessel Density in EsophagealSquamous Cell Carcinoma: Comparison With PositronEmission Tomography. Annals of Surgical Oncology, 2006, 13(8): 1054-1062.
39.	Myung J, Se-Jin J, Yong W, et al. Clinical Prognostic Values of Vascular Endothelial Growth Factor,Microvessel Density, and p53 Expression in Esophageal Carcinomas. J Korean Med Sci, 2002, 17(2): 201-207.
40.	Liu P, Chen W, Zhu H, et al. Expression of VEGF-C Correlates with a Poor Prognosis Basedon Analysis of Prognostic Factors in 73 Patients with EsophagealSquamous Cell Carcinomas. Jpn J ClinOncol, 2009, 39(10): 644-650.
41.	Tatsuya T, Hideyuki I, Yoshiyuki K, et al. Vascular endothelial growth factor C and D expression correlates with lymph node metastasis and poor prognosis in patients with resected esophageal cancer. J Experimental Clin Cancer Research, 2010, 29: 83.
42.	Okazawa T, Yoshida T, Shirai Y, et al. Expression of Vascular EndothelialGrowth Factor C is a Prognostic Indicatorin Esophageal Cancer. Hepato-Gastroenterology, 2008, 55(86-87): 1503-1508.
43.	Sun ZG, Wang Z, Liu XY, et al. Mucin 1 and Vascular Endothelial Growth Factor C ExpressionCorrelates with Lymph Node Metastatic Recurrence in Patientswith N0 Esophageal Cancer After Ivor-Lewis Esophagectomy. World J Surg, 2011, 35(1): 70-77.
44.	Kozlowski M, Naumnik W, Niklinski J, et al. Vascular endothelial growth factor C and D expression correlates with lymph node metastasis and poor prognosis in patients with resected esophageal cancer. Neoplasma, 2011, 58(4): 311-319.
45.	Reigetsu Y, Yoshinori F, Kenji K, et al. Cyclooxygenase-2 expression after preoperative chemoradiotherapy correlates with more frequent esophageal cancer recurrence. World J Gastroenterol, 2007, 13(16): 2283-2288.
46.	Lisa MM, Douglas GA, Willi S, et al. Reporting recommendations for tumor MARKer prognostic studies (REMARK). Nature, 2005, 2(8): 416-422.

1. Bradbury PA, Zhai R, Ma C, et al. Vascular endothelial growth factor polymorphisms and esophageal cancer prognosis. Clin Cancer Res, 2009, 15(14): 4680-4685.
2. Crew KD, Neugut A. Epidemiology of upper gastrointestinal malignancies. Semin Oncol, 2004, 31(4): 450-464.
3. 蔡燕, 陈先卓, 彭乙华, 等. 食管癌组织中存活蛋白的异常表达. 重庆医学, 2012, 41(5): 432-434.
4. Jemal A, Bray F, Center MM, et al. Global cancer statistics. CA Cancer J Clin, 2011, 61(2): 134.
5. Yoko O, Satoshi Y, Kunihiro Y, et al. Angiogenesis-Related Factors are Molecular Targets for Diagnosis and Treatment of Patients with Esophageal Carcinoma. Ann Thorac CardiovascSurg, 2010, 16(6): 389-393.
6. Vallböhmer D, Lenz HJ. Predictive and prognostic molecular markers in outcome of esophageal cancer. Diseases of the Esophagus, 2006, 19(6): 425-432.
7. Ferrara N, Davis-Smyth T. The biology of vascular endothelial growth factor. Endocr Rev, 1997, 18(1): 4-25.
8. Toi M, Matsumoto T, Bando H, et al. Vascular endothelial growth factor: its prognostic, predictive, and therapeutic implications. Lancet Oncol, 2001, 2(11): 667-673.
9. Shih CH, Ozawa S, Ando N, et al. Vascular endothelial growth factor expression predicts outcome and lymph node metastasis in squamous cell carcinoma of the esophagus. Clin Cancer Res, 2000, 6(3): 1161-1168.
10. Kitadai Y, Haruma K, Tokutomi T, et al. Significance of vessel count and vascular endothelial growth factor in human esophageal carcinomas. Clin Cancer Res, 1998, 4(9): 2195-2200.
11. Inoue K, Ozeki Y, Suganuma T, et al. Vascular endothelial growth factor expression in primary esophageal squamous cell carcinoma. Association with angiogenesis and tumor progression. Cancer, 1997, 79(2): 206-213.
12. Kleespies A, Guba M, Jauch KW, et al. Vascular endothelial growth factor in esophageal cancer. J SurgOncol, 2004, 87(2): 95-104.
13. William PT, David PK, David HI, et al. Targeted Therapies for Esophageal Cancer. The Oncologist, 2005, 10(8): 590-601.
14. 李宝江, 贾王生, 臧长运. 食管癌组织VEGF的表达与肿瘤血管生成的关系. 实用癌症杂志, 2000, 15(6): 583-584.
15. Poon RTP, Fan ST, Wong J, et al. Clinical significance of angiogenesis in gastrointestinal cancers – a target of novel prognostic and therapeutic approaches. Ann Surg, 2003, 238(1): 9-28.
16. Nicosia R. What is the role of vascular endothelial growth factorrelated molecules in tumor angiogenesis. Am J Pathol, 1998, 153(1): 11-16.
17. Miroslaw K, Oksana K, Robert M, et al. Serum vascular endothelial growth factors C and D in patients with oesophageal cancer. Eur J Cardio-thoracic Surg, 2010, 38(3): 260-267.
18. Cavazzola LT, Rosa AR, Schirmer CC, et al. Immunohistochemical evaluation for P53 and VEGF (Vascular Endothelial Growth Factor) is not prognostic for long term survival in end stage esophageal adenocarcinoma. Rev Col Bras Cir, 2009, 36(1): 24-34.
19. Koide N, Nishio A, Hiraguri M, et al. Coexpression of vascular endothelial growth factor and p53 protein in squamous cell carcinoma of the esophagus. Am J Gastroenterol, 2001, 96(6): 1733-1740.
20. Shih CH, Ozawa S, Ando N, et al. Vascular endothelial growth factor expression predicts outcome and lymph node metastasis in squamous cell carcinoma of the esophagus. Clin Cancer Res, 2000, 6(3): 1161-1168.
21. Rosa AR, Schirmer CC, Gurki RR, et al. Prognostic value of p53 protein expression and vascular endothelial growth factor expression in resected squamous cell carcinoma of theesophagus. Dis Esophagus, 2003, 16(2): 112-118.
22. Shimada H, Takeda A, Nabeya Y, et al. Clinical significance of serum vascular endothelial growth factor in esophageal squamous cell carcinoma. Cancer, 2001, 92(3): 663-669.
23. 季卫忠, 顾汝军. 食管癌患者手术治疗前后血清IGF-I、VEGF和TSGF检测的临床意义. 放射免疫学杂志, 2011, 24(5): 496-497.
24. Kimura H, Kato H, Tanaka N, et al. Preoperative serum vascular endothelial growth factor-C (VEGF-C) levels predict recurrence in patients with esophageal cancer. Anticancer Res, 2008, 28(1A): 165-169.
25. Krzystek-Korpacka M, Matusiewicz M, Diakowska D, et al. Up-regulation of VEGF-C secreted by cancer cells and not VEGF-A correlates with clinical evaluation of lymph node metastasis in esophageal squamous cell carcinoma (ESCC). Cancer Lett, 2007, 249(2): 171-177.
26. Naumnik W, Izycki T, Swidzin´ska E, et al. Serumlevels of VEGF-C, VEGF-D, and sVEGF-R2 in patients with lung cancer during chemotherapy. Oncol Res, 2007, 16(9): 445-451.
27. Moundhri MS, Shukaili A, Nabhani M, et al. Measurement of circulating levels of VEGF-A, -C, and -D and their receptors, VEGFR-1 and -2 in gastric adenocarcinoma. World J Gastroenterol, 2008, 14(24): 3879-3883.
28. Des GG, Uzzan B, Nicolas P, et al. Microvessel density and VEGF expression are prognostic factors in colorectal cancer: Meta-analysis of the literature. Br J Cancer, 2006, 94(12): 1823-1832.
29. Li C, Zang J, Li XS, et al. Prognostic role of vascular endothelial growth factor in oral carcinoma: a meta analysis. West China Journal of Stomatology, 2011, 29(1): 39-43.
30. Chen J, Li T, Wu Y, et al. Prognostic significance of vascular endothelial growth factor expression in gastric carcinoma: a meta-analysis. J Cancer Res ClinOncol, 2011, 137(12): 1799-1812.
31. Schoenleber SJ, Kurtz DM, Talwalkar JA, et al. Prognostic role of vascular endothelial growth factor in hepatocellular carcinoma: Systematic review and meta-analysis. Br J Cancer, 2009, 100(9): 1385-1392.
32. Veikkola T, Alitalo K. VEGFS, receptors and angiogenesis. Semin Cancer Bio, 1999, 9(3): 211-220.
33. Jeltsch M, Kaipainen A, Joukov V, et al. Hyperplasia of lymphatic vessels in VEGF-Ctransgenicmice. Science, 1997, 277(5325): 463.
34. Chen M, Cai E, Huang J, et al. Prognostic Value of Vascular Endothelial Growth Factor Expression in Patients with Esophageal Cancer: ASystematic Review and Meta-analysis. Cancer Epidemiol Biomarkers Prev, 2012, 21(7): 1126-1134.
35. Akemi I, Hiromitsu M, Natsuya K, et al. Intratumorallymphangiogenesis of esophageal squamouscell carcinoma and relationship with regulatory factorsand prognosis. Pathology International, 2008, 58(10): 611-619.
36. Ching T, Shih CL, Ho J, et al. Expression of hypoxia-inducible factor(HIF)-1α and vascular endothelial growthfactor (VEGF)-D as outcome predictors inresected esophageal squamous cell carcinoma. Disease Markers, 2008, 25(3): 141-148.
37. Shimada H, Hoshino T, Okazumi S, et al. Expression of angiogenic factors predicts response tochemoradiotherapy and prognosis of oesophageal squamous cellcarcinoma. Br J Cancer, 2002, 86(4): 552-557.
38. Joon YC, Kee-Taek J, Young MS, et al. Prognostic Significance of Vascular Endothelial GrowthFactor Expression and Microvessel Density in EsophagealSquamous Cell Carcinoma: Comparison With PositronEmission Tomography. Annals of Surgical Oncology, 2006, 13(8): 1054-1062.
39. Myung J, Se-Jin J, Yong W, et al. Clinical Prognostic Values of Vascular Endothelial Growth Factor,Microvessel Density, and p53 Expression in Esophageal Carcinomas. J Korean Med Sci, 2002, 17(2): 201-207.
40. Liu P, Chen W, Zhu H, et al. Expression of VEGF-C Correlates with a Poor Prognosis Basedon Analysis of Prognostic Factors in 73 Patients with EsophagealSquamous Cell Carcinomas. Jpn J ClinOncol, 2009, 39(10): 644-650.
41. Tatsuya T, Hideyuki I, Yoshiyuki K, et al. Vascular endothelial growth factor C and D expression correlates with lymph node metastasis and poor prognosis in patients with resected esophageal cancer. J Experimental Clin Cancer Research, 2010, 29: 83.
42. Okazawa T, Yoshida T, Shirai Y, et al. Expression of Vascular EndothelialGrowth Factor C is a Prognostic Indicatorin Esophageal Cancer. Hepato-Gastroenterology, 2008, 55(86-87): 1503-1508.
43. Sun ZG, Wang Z, Liu XY, et al. Mucin 1 and Vascular Endothelial Growth Factor C ExpressionCorrelates with Lymph Node Metastatic Recurrence in Patientswith N0 Esophageal Cancer After Ivor-Lewis Esophagectomy. World J Surg, 2011, 35(1): 70-77.
44. Kozlowski M, Naumnik W, Niklinski J, et al. Vascular endothelial growth factor C and D expression correlates with lymph node metastasis and poor prognosis in patients with resected esophageal cancer. Neoplasma, 2011, 58(4): 311-319.
45. Reigetsu Y, Yoshinori F, Kenji K, et al. Cyclooxygenase-2 expression after preoperative chemoradiotherapy correlates with more frequent esophageal cancer recurrence. World J Gastroenterol, 2007, 13(16): 2283-2288.
46. Lisa MM, Douglas GA, Willi S, et al. Reporting recommendations for tumor MARKer prognostic studies (REMARK). Nature, 2005, 2(8): 416-422.

Chinese Journal of Evidence-Based Medicine

Correlation between Vascular Endothelial Growth Factor Expression and Prognosis of Esophageal Cancer: A Meta-Analysis

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