Ann Surg Treat Res.  2019 Jul;97(1):15-20. 10.4174/astr.2019.97.1.15.

The correlation between serum vascular endothelial growth factor (VEGF) and tumor VEGF receptor 3 in colorectal cancer

• Goulart A
• Ferreira C
• Rodrigues
• Coimbra B
• Sousa N
• Leão P

• KMID: 2450985
• DOI: http://doi.org/10.4174/astr.2019.97.1.15

Abstract

PURPOSE
Despite plasma biomarkers offering a number of advantages over tissue-based markers, the relationship between serum vascular endothelial growth factor (VEGF) and VEGF receptor (VEGF-R) tumor expression in colorectal cancer (CRC) is still unclear. This study was designed to establish the relationship between the concentration of serum VEGF and tumor VEGF-R expression in patients with CRC.
METHODS
A prospective study of consecutive patients undergoing elective colorectal surgery during 1 year. Preoperative VEGF was determined by enzyme-linked immunosorbent assay and VEGF-R3 by immunochemistry.
RESULTS
The initial sample included 134 patients with CRC diagnosis. Results showed significant association of serum values of VEGF with VEGF-R3 expression (P < 0.001), even in the presence of confounders (sex, age, body mass index, tumor location, and surgical approach). The estimated effect size was high (η² = 0.35).
CONCLUSION
Serum VEGF has a significant correlation with tumoral VEGF-R3 expression in CRC.

Keyword

Colorectal neoplasms; Vascular endothelial growth factors; Enzyme-linked immunosorbent assay; Immunohistochemistry

MeSH Terms

Biomarkers
Body Mass Index
Colorectal Neoplasms*
Colorectal Surgery
Diagnosis
Enzyme-Linked Immunosorbent Assay
Humans
Immunochemistry
Immunohistochemistry
Plasma
Prospective Studies
Receptors, Vascular Endothelial Growth Factor*
Vascular Endothelial Growth Factor A*
Vascular Endothelial Growth Factors
Biomarkers
Receptors, Vascular Endothelial Growth Factor
Vascular Endothelial Growth Factor A
Vascular Endothelial Growth Factors

Figure

• 

  Fig. 1 Immunohistochemical staining for VEGF-R3 in malignant colorectal endothelium. (A) Absent expression of VEGF-R3 in CRC (×100). (B) Weak/very limited moderate staining of VEGF-R3 (×100). (C) Moderate widespread/strong localized staining of VEGF-R3 (×100). (D) Strong widespread staining of VEGF-R3 (×100). VEGF, vascular endothelial growth factor; VEGF-R3, VEGF receptor 3; CRC, colorectal cancer.

• 

  Fig. 2 Serum values of VEGF distribution by immunochemistry VEGF-R3 expression. VEGF, vascular endothelial growth factor; VEGF-R3, VEGF receptor 3; CRC, colorectal cancer.

Reference

1. Larijani LV, Ghasemi M, Charati JY, Mehrabian-Fard M, Saravi NS. Evaluation of VEGF immunohistochemical expression and correlation with clinicopathologic features in colorectal cancer. Govaresh. 2015; 20:199–204.

2. Al-Rawi MA, Mansel RE, Jiang WG. Molecular and cellular mechanisms of lymphangiogenesis. Eur J Surg Oncol. 2005; 31:117–121.

3. Jurgensmeier JM, Schmoll HJ, Robertson JD, Brooks L, Taboada M, Morgan SR, et al. Prognostic and predictive value of VEGF, sVEGFR-2 and CEA in mCRC studies comparing cediranib, bevacizumab and chemotherapy. Br J Cancer. 2013; 108:1316–1323.

4. Peng Y, Wang L, Du C, Gu J. Expression of vascular endothelial growth factor can predict distant metastasis and disease-free survival for clinical stage III rectal cancer following 30-Gy/10-f preoperative radiotherapy. Int J Colorectal Dis. 2012; 27:1555–1560.

5. Gupta VK, Jaskowiak NT, Beckett MA, Mauceri HJ, Grunstein J, Johnson RS, et al. Vascular endothelial growth factor enhances endothelial cell survival and tumor radioresistance. Cancer J. 2002; 8:47–54.

6. Benevento I, De Felice F, Musio D, Tombolini V. The addition of target therapy to neoadjuvant chemoradiotherapy in locally advanced rectal cancer: a review. Chemotherapy. 2017; 62:314–322.

7. Byrne AM, Bouchier-Hayes DJ, Harmey JH. Angiogenic and cell survival functions of vascular endothelial growth factor (VEGF). J Cell Mol Med. 2005; 9:777–794.

8. Bottomley MJ, Webb NJ, Watson CJ, Holt L, Bukhari M, Denton J, et al. Placenta growth factor (PlGF) induces vascular endothelial growth factor (VEGF) secretion from mononuclear cells and is co-expressed with VEGF in synovial fluid. Clin Exp Immunol. 2000; 119:182–188.

9. Jelkmann W. Pitfalls in the measurement of circulating vascular endothelial growth factor. Clin Chem. 2001; 47:617–623.

10. Martins SF, Reis RM, Rodrigues AM, Baltazar F, Filho AL. Role of endoglin and VEGF family expression in colorectal cancer prognosis and anti-angiogenic therapies. World J Clin Oncol. 2011; 2:272–280.

11. Cressey R, Wattananupong O, Lertprasertsuke N, Vinitketkumnuen U. Alteration of protein expression pattern of vascular endothelial growth factor (VEGF) from soluble to cell-associated isoform during tumourigenesis. BMC Cancer. 2005; 5:128.

12. White JD, Hewett PW, Kosuge D, McCulloch T, Enholm BC, Carmichael J, et al. Vascular endothelial growth factor-D expression is an independent prognostic marker for survival in colorectal carcinoma. Cancer Res. 2002; 62:1669–1675.

13. Zheng S, Han MY, Xiao ZX, Peng JP, Dong Q. Clinical significance of vascular endothelial growth factor expression and neovascularization in colorectal carcinoma. World J Gastroenterol. 2003; 9:1227–1230.

14. Martins SF, Garcia EA, Luz MA, Pardal F, Rodrigues M, Filho AL. Clinicopathological correlation and prognostic significance of VEGF-A, VEGF-C, VEGFR-2 and VEGFR-3 expression in colorectal cancer. Cancer Genomics Proteomics. 2013; 10:55–67.

15. Des Guetz G, Uzzan B, Nicolas P, Cucherat M, Morere JF, Benamouzig R, et al. Microvessel density and VEGF expression are prognostic factors in colorectal cancer. Meta-analysis of the literature. Br J Cancer. 2006; 94:1823–1832.

16. Tsai HL, Yang IP, Lin CH, Chai CY, Huang YH, Chen CF, et al. Predictive value of vascular endothelial growth factor overexpression in early relapse of colorectal cancer patients after curative resection. Int J Colorectal Dis. 2013; 28:415–424.

17. De Vita F, Orditura M, Lieto E, Infusino S, Morgillo F, Martinelli E, et al. Elevated perioperative serum vascular endothelial growth factor levels in patients with colon carcinoma. Cancer. 2004; 100:270–278.

18. Takahashi Y, Kitadai Y, Bucana CD, Cleary KR, Ellis LM. Expression of vascular endothelial growth factor and its receptor, KDR, correlates with vascularity, metastasis, and proliferation of human colon cancer. Cancer Res. 1995; 55:3964–3968.

19. Tokunaga T, Oshika Y, Abe Y, Ozeki Y, Sadahiro S, Kijima H, et al. Vascular endothelial growth factor (VEGF) mRNA isoform expression pattern is correlated with liver metastasis and poor prognosis in colon cancer. Br J Cancer. 1998; 77:998–1002.

20. Ishigami SI, Arii S, Furutani M, Niwano M, Harada T, Mizumoto M, et al. Predictive value of vascular endothelial growth factor (VEGF) in metastasis and prognosis of human colorectal cancer. Br J Cancer. 1998; 78:1379–1384.

21. Takahashi Y, Tucker SL, Kitadai Y, Koura AN, Bucana CD, Cleary KR, et al. Vessel counts and expression of vascular endothelial growth factor as prognostic factors in node-negative colon cancer. Arch Surg. 1997; 132:541–546.

22. Cascinu S, Staccioli MP, Gasparini G, Giordani P, Catalano V, Ghiselli R, et al. Expression of vascular endothelial growth factor can predict event-free survival in stage II colon cancer. Clin Cancer Res. 2000; 6:2803–2807.

23. Werther K, Christensen IJ, Brunner N, Nielsen HJ. Soluble vascular endothelial growth factor levels in patients with primary colorectal carcinoma. The Danish RANX05 Colorectal Cancer Study Group. Eur J Surg Oncol. 2000; 26:657–662.

24. Werther K, Christensen IJ, Nielsen HJ. Danish RANX05 Colorectal Cancer Study Group. The association between preoperative concentration of soluble vascular endothelial growth factor, perioperative blood transfusion, and survival in patients with primary colorectal cancer. Eur J Surg. 2001; 167:287–292.

25. Werther K, Christensen IJ, Nielsen HJ. Danish RANX05 Colorectal Cancer Study Group. Prognostic impact of matched preoperative plasma and serum VEGF in patients with primary colorectal carcinoma. Br J Cancer. 2002; 86:417–423.

26. Nakayama Y, Sako T, Shibao K, Okazaki K, Rempo N, Onitsuka K, et al. Prognostic value of plasma vascular endothelial growth factor in patients with colorectal cancer. Anticancer Res. 2002; 22:2437–2442.