title: Clinical significance of preoperative serum vascular endothelial growth factor, interleukin-6, and C-reactive protein level in colorectal cancer.
abstract: BACKGROUND
  Angiogenesis is a multistep process in which many growth factors and cytokines have an essential role. Vascular endothelial growth factor (VEGF) is a potent angiogenic agent that acts as a specific mitogen for vascular endothelial cells through specific cell surface receptors. The interleukin-6 (IL-6) pathway is another mechanism linking angiogenesis to malignancy. C-reactive protein (CRP), a representative marker for inflammation, is known for its association with disease progression in many cancer types. The aim of this study was to determine preoperative serum levels of VEGF, IL-6, and CRP in colorectal carcinoma, and to correlate them with disease status and prognosis.
  
  
  METHODS
  A 132 of 143 patients who underwent curative resection for colorectal cancer were enrolled in this study. 11 patients with resection margin positive were excluded. Factors considered in analysis of the relationship between VEGF, IL-6, and CRP and histological findings. Patient prognosis was investigated. Serum levels of VEGF and IL-6 were assessed using Enzyme-Linked Immuno-Sorbent Assay (ELISA), and CRP was measured using immunoturbidimetry.
  
  
  RESULTS
  Median follow-up duration was 18.53 months (range 0.73-43.17 months) and median age of the patients was 62 years (range, 26-83 years). Mean and median levels of VEGF and CRP in colorectal cancer were significantly higher than in the normal control group; 608 vs. 334 pg/mL and 528 (range 122-3242) vs. 312 (range 16-1121) (p < 0.001); 1.05 mg/dL vs. 0.43 mg/dL and 0.22 (range 0.00-18.40) vs. 0.07 (range 0.02-6.94) (p = 0.002), respectively. However mean and median level of IL-6 in patients were not significantly higher than in control; 14.33 pg/mL vs. 5.65 pg/mL and 6.00 (range 1.02-139.17) vs. 5.30 (4.50-13.78) (p = 0.327). Although IL-6 and CRP levels were not correlated with other pathological findings, VEGF level was significantly correlated with tumor size (p = 0.012) and CEA (p = 0.038). When we established the cutoff value for VEGF (825 pg/mL), IL-6 (8.09 pg/mL), and CRP (0.51 mg/dL) by Receiver Operating Characteristic (ROC) curve, we noted that high VEGF levels tended to reduce overall survival (p = 0.053), but not significantly. However, IL-6 and CRP demonstrated no significance with regard to disease free survival (p = 0.531, p = 0.701, respectively) and overall survival (p = 0.563, p = 0.572, respectively). Multivariate analysis showed that VEGF (p = 0.032), CEA (p = 0.012), lymph node metastasis (p = 0.002), and TNM stage (p = 0.025) were independently associated with overall survival.
  
  
  CONCLUSIONS
  Preoperative serum VEGF and CRP level increased in colorectal cancer patients. High VEGF level has been proposed as a poor prognostic factor for overall survival in patients with colorectal cancer.
authors.affiliation: Department of Internal Medicine, Dong-A university College of Medicine, Busan, Korea.
authors.forename: Kyung A
authors.initials: KA
authors.lastname: Kwon
authors.forename: Sung Hyun
authors.initials: SH
authors.lastname: Kim
authors.forename: Sung Yong
authors.initials: SY
authors.lastname: Oh
authors.forename: Suee
authors.initials: S
authors.lastname: Lee
authors.forename: Jin-Yeong
authors.initials: JY
authors.lastname: Han
authors.forename: Kyeong Hee
authors.initials: KH
authors.lastname: Kim
authors.forename: Ri Young
authors.initials: RY
authors.lastname: Goh
authors.forename: Hong Jo
authors.initials: HJ
authors.lastname: Choi
authors.forename: Ki Jae
authors.initials: KJ
authors.lastname: Park
authors.forename: Mee Sook
authors.initials: MS
authors.lastname: Roh
authors.forename: Hyo-Jin
authors.initials: HJ
authors.lastname: Kim
authors.forename: Hyuk-Chan
authors.initials: HC
authors.lastname: Kwon
authors.forename: Jong Hoon
authors.initials: JH
authors.lastname: Lee
mesh_terms: D000230:Adenocarcinoma / Q000097:blood* / Q000556:secondary / Q000601:surgery*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000097:blood*; D002097:C-Reactive Protein / Q000378:metabolism*; D002272:Carcinoembryonic Antigen / Q000097:blood; D016022:Case-Control Studies; D003082:Colectomy; D015179:Colorectal Neoplasms / Q000097:blood* / Q000473:pathology / Q000601:surgery*; D018572:Disease-Free Survival; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D015850:Interleukin-6 / Q000097:blood*; D053208:Kaplan-Meier Estimate; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009391:Nephelometry and Turbidimetry; D011237:Predictive Value of Tests; D057234:Preoperative Period; D016016:Proportional Hazards Models; D012372:ROC Curve; D012189:Retrospective Studies; D013997:Time Factors; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000097:blood*; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D002272:Carcinoembryonic Antigen; C508600:IL6 protein, human; D015850:Interleukin-6; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D002097:C-Reactive Protein
references.citation: Blood. 1996 May 1;87(9):4016-7
references.pmid: 8611738
references.citation: Clin Chem Lab Med. 2008;46(3):359-64
references.pmid: 18303990
references.citation: Am J Surg. 1998 Oct;176(4):335-8
references.pmid: 9817250
references.citation: Circulation. 2003 Jan 28;107(3):363-9
references.pmid: 12551853
references.citation: Cancer Res. 1995 Sep 15;55(18):3964-8
references.pmid: 7664263
references.citation: Science. 1988 Aug 19;241(4868):961-5
references.pmid: 2841761
references.citation: J Natl Cancer Inst. 1990 Jan 3;82(1):4-6
references.pmid: 1688381
references.citation: Br J Cancer. 1998 Mar;77(6):998-1002
references.pmid: 9528847
references.citation: Eur J Surg Oncol. 2000 Nov;26(7):657-62
references.pmid: 11078612
references.citation: Br J Cancer. 2002 Feb 1;86(3):417-23
references.pmid: 11875709
references.citation: Cytokine. 1992 Sep;4(5):361-8
references.pmid: 1420997
references.citation: Am J Pathol. 1995 May;146(5):1029-39
references.pmid: 7538264
references.citation: Cancer Metastasis Rev. 1995 Dec;14(4):263-77
references.pmid: 8821090
references.citation: Br J Cancer. 2006 Jun 5;94(11):1568-71
references.pmid: 16685271
references.citation: Eur J Surg. 2001 Apr;167(4):287-92
references.pmid: 11354321
references.citation: CA Cancer J Clin. 2004 Nov-Dec;54(6):295-308
references.pmid: 15537574
references.citation: Cancer Res Treat. 2009 Sep;41(3):122-31
references.pmid: 19809561
references.citation: Res Immunol. 1992 Sep;143(7):724-34
references.pmid: 1439145
references.citation: Am J Clin Oncol. 2000 Jun;23(3):263-6
references.pmid: 10857890
references.citation: Cancer. 2004 Jan 15;100(2):270-8
references.pmid: 14716760
references.citation: Arch Surg. 1997 May;132(5):541-6
references.pmid: 9161399
references.citation: Am J Surg. 1995 Oct;170(4):319-22
references.pmid: 7573721
references.citation: Clin Cancer Res. 2000 Jul;6(7):2803-7
references.pmid: 10914727
references.citation: Annu Rev Immunol. 1990;8:253-78
references.pmid: 2188664
references.citation: Ann Surg Oncol. 2000 Mar;7(2):133-8
references.pmid: 10761792
references.citation: Br J Cancer. 1998 Nov;78(10):1379-84
references.pmid: 9823983
references.citation: Am J Clin Oncol. 2006 Aug;29(4):408-17
references.pmid: 16891872
references.citation: EXS. 1997;79:233-69
references.pmid: 9002222
references.citation: J Mol Med (Berl). 1999 Jul;77(7):527-43
references.pmid: 10494799
references.citation: Clin Immunol. 2002 Feb;102(2):169-78
references.pmid: 11846459
references.citation: Cancer Epidemiol Biomarkers Prev. 2006 Feb;15(2):381-4
references.pmid: 16492932
references.citation: J Surg Res. 2008 Jun 1;147(1):99-107
references.pmid: 17655863
references.citation: N Engl J Med. 1988 Sep 1;319(9):525-32
references.pmid: 2841597
references.citation: J Natl Cancer Inst. 2007 Jun 6;99(11):890-4
references.pmid: 17551149
references.citation: J Biol Chem. 1996 Jan 12;271(2):736-41
references.pmid: 8557680
references.citation: World J Gastroenterol. 2006 Jul 28;12(28):4473-7
references.pmid: 16874857
references.citation: World J Gastroenterol. 2005 Mar 21;11(11):1639-43
references.pmid: 15786541
references.citation: Blood. 1993 Jul 15;82(2):513-20
references.pmid: 8329706
references.citation: FEBS Lett. 1988 May 23;232(2):347-50
references.pmid: 2454206
references.citation: Microsc Res Tech. 2003 Feb 1;60(2):199-207
references.pmid: 12539174