The plasma concentration of VEGF, HE4 and CA125 as a new biomarkers panel in different stages and sub-types of epithelial ovarian tumors
VEGF may play a role in the pathogenesis of cancer disease, for example in cell growth, proliferation and angiogenesis. In this study, we investigated plasma levels of this cytokine in comparison to plasma levels of a new biomarker - HE4 and the established tumor marker CA125 in ovarian cancer patients (100) as compared to control groups: patients with a benign ovarian tumor (80) and healthy subjects (50).
Plasma levels of VEGF were determined by ELISA, HE4 and CA125 by CMIA method.
The results showed that levels of VEGF, CA125 and HE4 were significantly higher in ovarian cancer (OC) patients as compared to the both control groups. VEGF has demonstrated as high as comparative markers values of the diagnostic sensitivity (SE), specificity (SP), the predictive values of positive and negative test results (PV-PR, PV-NR), and the area under the ROC curve (AUC) in early stages of cancer tested groups. The combined use of parameters studied resulted in the increase in the diagnostic criteria values and the AUC.
These findings suggest the usefulness of VEGF in the early diagnostics of ovarian cancer, especially in combination with CA125 and HE4, as a new biomarkers panel. Additionally, VEGF is the most useful tool in the diagnostics of locally advanced ovarian cancer without metastases. Investigated cytokine presented similar to HE4 usefulness in differentiation of OC according to its histopathlogical sub-type, and could be used especially in the diagnostics of endometrioid epithelial OC.
- Siegel R, Ward E, Brawley O, Jemal A: Cancer statistics, 2011: the impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA Cancer J Clin 2011, 61:212–236. CrossRef
- Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D: Global cancer statistics. CA Cancer J Clin 2011, 61:69–90. CrossRef
- Bast RC Jr, Hennessy B, Mills GB: The biology of ovarian cancer: new opportunities for translation. Nat Rev Cancer 2009, 9:415–442. CrossRef
- Chetrit A, Hirsh-Yechezkel G, Ben-David Y, Lubin F, Friedman E, Sadetzki S: Effect of BRCA1/2 mutations on long term survival of patients with invasive ovarian cancer: the national Israeli study of ovarian cancer. J Clin Oncol 2008, 26:20–25. CrossRef
- Moore RG, Brown AK, Miller MC, Skates S, Allard WJ, Verch T, Steinhoff M, Messerlian G, DiSilwestro P, Granai CO, Bast RC: The use of multiple novel tumor biomarkers for the detection of ovarian carcinoma in patients with a pelvic mass. Gynecol Oncol 2008, 108:402–408. CrossRef
- Zhang Y, Guo B, Bi R: Ovarian cancer: biomarker proteomic diagnosis in progress. Appl Biochem Biotechnol 2012, 168:910–916. CrossRef
- Gadducci A, Cosio S, Carpi A, Nicolini A, Genazzani AR: Serum tumor markers in the management of ovarian, endometrial and cervical cancer. Biomed Pharmacother 2004, 58:24–38. CrossRef
- Haaften-Day C, Yu S, Fengji X, Yinhua Y, Berchuck A, Havrilesky LJ, de Bruijn HWA, van der Zee GJ, Bast RC Jr, Hacker NF: OVX1, macrophage-colony stimulating factor, and CA-125-II as tumor markers for epithelial ovarian carcinoma. Cancer 2001, 92:2837–2844. CrossRef
- Shah SA, Lowe KA, Paley P, Wallace E, Anderson GL, McIntosh MW, Andersen MR, Scholler N, Bergan LA, Thorpe JD, Urban N, Drescher CW: Influence of ovarian cancer risk status on the diagnostic performance of the serum biomarkers mesothelin, HE4 and CA 125. Cancer Epidemiol Biomarkers Prev 2009, 18:1365–1372. CrossRef
- Andersen MR, Goff BA, Lowe KA, Scholler N, Bergan L, Drescher CW, Paley P, Urban N: Use of a symptom index, CA 125, and HE-4 to predict ovarian cancer. Gynecol Oncol 2010, 116:378–383. CrossRef
- Ławicki S, Czygier M, Gacuta-Szumarska E, Knapp P, Szmitkowski M: The plasma levels and diagnostic utility of granulocyte-colony stimulating factor (G-CSF) and macrophage-colony stimulating factor (M-CSF) in ovarian cancer patients. Pol Merkur Lek 2006, 21:465–468.
- Skates S, Horick N, Yu Y, Xu FJ, Berchuck A, Havrilesky LJ, de Bruijn HW, van der Zee AG, Woolas RP, Jacobs IJ, Zhang Z, Bast RC: Preoperative sensitivity and specificity for early-stage ovarian cancer when combining cancer antigen CA 125 II, CA 15–3, CA 72–4, and macrophage colony-stimulating factor using mixtures of multivariate normal distributions. J Clin Oncol 2005, 22:4059–4066. CrossRef
- Ławicki S, Czygier M, Gacuta-Szumarska E, Knapp P, Szmitkowski M: The plasma levels and diagnostics utility of granulocyte-colony stimulating factor (G-CSF) and macrophage-colony stimulating factor (M-CSF) in ovarian cancer patients. Pol Merkur Lek 2006, 125:465–468.
- Jermaine IG, Coward , Hagen Kulbe : The role of interleukin-6 in gynaecological malignancies. Cytokine Growth Factor Rev 2012, 23:333–342. CrossRef
- Schummer M, Drescher C, Forrest R, Gough S, Thorpe J, Hellstrom I, Hellsttom KE, Urban N: Evaluation of ovarian cancer remission markers HE4, MMP7 and mesothelin by comparison to the established marker CA125. Gynecol Oncol 2012, 125:65–69. CrossRef
- Gersthein ES, Kushlinsky DN, Levkina NV, Tereshkina IV, Nosov VB, Laktionov KP, Adamyan LV: Relationship between the expression of VEGF signal components and matrix metalloproteinases in ovarian tumors. Bull Exp Biol Med 2011, 151:431–435.
- Kamińska J, Kowalska M: Clinical significance of serum tumor markers measurements in patients with ovarian cancer. Voice 2008, 2:16–21.
- Folkman J: Angiogenesis in cancer, vascular, rheumatoid, and other disease. Nat Med 1995, 1:27–31. CrossRef
- Carmeliet P: VEGF as a key mediator of angiogenesis in cancer. Oncology 2005,69(Suppl 3):4–10. CrossRef
- Kaplan RN, Riba RD, Zacharoulis S, Bramley AH, Vinent L, Costa C, MacDonald DD, Jin DK, Shido K, Kerns SA, Zhu Z, Hicklin D, Wu Y, Port JL, Altorki N, Port ER, Ruggero D, Shmelkov SV, Jensen KK, Rafii S, Lyden D: VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 2005, 438:820–827. CrossRef
- Lichtenberger BM, Tan PK, Niederleithner H, Ferrara N, Petzelbauer P, Sibilia M: Autocrine VEGF signaling synergizes with EGFR in tumor cells to promote epithelial cancer development. Cell 2010, 140:268–279. CrossRef
- Schoppmann SF, Horvat R, Birner P: Lymphatic vessels and lymphagiogenesis in female cancer: mechanisms, clinical impact and possible implications for anti-lymphangiogenic therapies (Review). Oncol Rep 2002, 9:455–460.
- Berezov TT, Ovchinnikova LK, Kuznetsova OM, Karabekova ZK, Vorotnikov IK, Tuleuova AA, Katunina AI, Dvorova EK: Vascular endothelial growth factor in the serum of breast cancer patients. Bull Exp Biol Med 2009, 148:419–424. CrossRef
- Dobrzycka B, Terlikowski SJ, Kowalczuk O, Kulikowski M, Niklinski J: Serum levels of VEGF and VEGF-C in patients with endometrial cancer. Eur Cytokine Netw 2011, 22:45–51.
- Piastowska-Ciesielska AW, Płuciennik E, Wójcik-Krowiranda K, Bieńkiewicz A, Bednarek A, Ochędalski T: Analysis of the expression of angiotensin II type 1 receptor and VEGF in endometrial adenocarcinoma with different clinicopathological characteristics. Tumour Biol 2012, 33:767–774. CrossRef
- Mazurek A, Pierzynski P, Kuc P, Kopinski P, Terlikowski S, Niklińska W, Trojan J, Laudański T: Evaluation of angiogenesis, p-53 tissue protein expression and serum VEGF in patients with endometrial cancer. Neoplasma 2004, 51:193–197.
- Hefler LA, Zeillinger R, Grimm C, Sood AK, Cheng WF, Gadducci A, Tempfer CB, Reinthaller A: Properative serum vascular endothelial growth factor as a prognostic parameter in ovarian cancer. Gynecol Oncol 2006, 103:512–517. CrossRef
- Sadłecki P, Walentowicz-Sadłecka M, Szymański W, Grabiec M: Comparison of VEGF, IL-8 and beta-FGF concentrations in the serum and ascites of patients with ovarian cancer. Ginekol Pol 2011, 82:498–502.
- Carrillo-de Santa Pau E, Carrillo Arias F, Caso Pelaez E, Muguruza Trueba I, Sanchez Hernandez I, Munoz Molina GM, Moreno Balsalobre R, Sacristan Lopez S, Gomez-Pinillos A, Toledo Lobo Mdel V: Vascular endothelial growth factor (VEGF) serum levels are associated with survival in early stages of lung cancer patients. Cancer Invest 2010, 28:393–398.
- Bunger S, Haug U, Kelly FM, Klempt-Giessing K, Cartwright A, Posorski N, Dibbelt L, Fitzgerald SP, Bruch HP, Roblick UJ, von Eggeling F, Brenner H, Habermann JK: Toward standardized high-through serum diagnostics: multiplex-protein array identifies IL-8 and VEGF as serum markers for colon cancer. J Biomol Screen 2011, 16:1018–1026. CrossRef
- Halmaciu I, Gurzu S, Dobreanu M, Suciu BA, Brinzaniuc K: Preliminary results regarding vascular endothelial growth factor (VEGF-A) levels in the serum of gastric cancer patients. Rev Med Chir Soc Med Nat Iasi 2012, 116:446–451.
- Clarke-Pearson DL: Clinical practice. Screening for ovarian cancer. N Engl J Med 2009, 361:170–177. CrossRef
- Jacobs I, Bast RC Jr: The CA 125 tumour-associated antigen: a review of the literature. Hum Reprod 1989, 4:1–12. CrossRef
- Li J, Dowdy S, Tipton T, Podratz K, Lu WG, Xie X, Jiang SW: HE4 as a biomarker for ovarian and endometrial cancer management. Expert Rev Mol Diagn 2009, 9:555–566. CrossRef
- Urban A, Miszczyk L: Ovarian cancer – diagnostical and therapeutical dilema in oncological gynecology. Wspol Onkol 2003, 7:294–300.
- Yurkowetsky Z, Skates S, Lomakin A, Nolen B, Pulsipher T, Modugno F, Marks J, Godwin A, Gorelik E, Jacobs I, Menon U, Lu K, Badgwell D, Bast RC Jr, Lokshin AE: Development of a multimarker assay for early detection of ovarian cancer. J Clin Oncol 2010, 28:2159–2166. CrossRef
- Park Y, Lee J-H, Hong DJ, Lee EY, Kim H-S: Diagnostic performances of HE4 and CA 125 for the detection of ovarian cancer from patients with various gynecologic and non-gynecologic diseases. Clin Biochem 2011, 44:884–888. CrossRef
- Ruggeri G, Bandiera E, Zanotti L, Belloni S, Ravaggi A, Romani C, Bignotti E, Tassi RA, Tognon G, Galli C, Caimi L, Pecorelli S: HE4 and epithelial ovarian cancer: comparison and clinical evaluation of two immunoassays and a combination algorithm. Clin Chim Acta 2011, 412:1447–1453. CrossRef
- Li L, Wang L, Zhang W, Tang B, Zhang J, Song H, Yao D, Tang Y, Chen X, Yang Z, Wang G, Li X, Zhao J, Ding H, Reed D, Li Q: Correlation of serum VEGF levels with clinical stage, therapy efficacy, tumor metastasis and patient survival in ovarian cancer. Anticancer Res 2004, 24:1973–1979.
- Sledakova I, Tosner J, Kopecky O, Vroblova V, Rezac A, Skapinec P, Andrys C: Vascular endothelial growth factor in ovarian cancer patients. Ceska Gynekol 2012, 77:415–420.
- Ivoino F, Ferraraccio F, Orditura M, Antoniol G, Morgillo F, Cascone T, Diadema MR, Aurilio G, Santabarbara G, Ruggiero R, Belli C, Irlandese E, Fasano M, Ciardiello F, Procaccini E, Lo Schiavo F, Catalano G, De Vita F: Serum vascular endothelial growth factor (VEGF) levels correlate with tumor VEGF and p53 overexpression in endocrine positive primary breast cancer. Cancer Invest 2008, 26:250–255. CrossRef
- Cheng D, Liang B, Li Y: Serum vascular endothelial growth factor (VEGF-C) as a diagnostic and prognostic marker in patients with ovarian cancer. PLoS One 2013, 8:e55309. CrossRef
- Candido dos Reis FJ, Moreira de Andrade J, Bighetti S: CA 125 and vascular endothelial growth factor in the differential diagnosis of epithelial ovarian tumors. Gynecol Obstet Invest 2002, 54:132–136. CrossRef
- Molina R, Escudero JM, Auge JM, Filella X, Foj L, Torne A, Lejarceguli J, Pahisa J: HE4 a novel tumour marker for ovarian cancer: comparison with CA 125 and ROMA algorithm in patients with gynaecological diseases. Tumor Biol 2011, 32:1087–1095. CrossRef
- Hamed EO, Ahmed H, Sedeek OB, Mohammed AM, Abd-Alla AA, Abdel Ghaffar HM: Significance of HE4 estimation in comparison with CA 125 in diagnosis of ovarian cancer and assessment of treatment response. Diagn Pathol 2013, 8:s11. CrossRef
- Macuks R, Baidekalna I, Donina S: An ovarian cancer malignancy risk index composed of HE4, CA 125, ultrasonographic score, and menopausal status: use in differentiation of ovarian cancers and benign lesions. Tumor Biol 2012, 33:1811–1817. CrossRef
- Sandri MT, Bottari F, Franchi D, Boveri S, Candiani M, Ronzoni S, Peiretti M, Radice D, Passerini R, Sideri M: Comparison of HE4, Ca 125 and ROMA algorithm in women with a pelvic mass: correlation with pathological out come. Gynecol Oncol 2013, 128:233–238. CrossRef
- Czekierdowski A, Czekierdowska S: The assessment of angiogenic factors VEGF, VEGER-2 and VCAM-1 in the serum of women with malignant ovarian tumours before and after the menopause. Przegląd Menopauzalny 2007, 3:128–133.
- Mattern J, Stammler G, Koomagi R, Wallwiener D, Kaufmann M, Volm M: Association of vascular endothelial growth factor expression with tumor cell proliferation in ovarian carcinoma. Anticancer Res 1997, 17:621–624.
- Naora H, Montell DJ: Ovarian cancer metastasis: integrating insights from disparate model organisms. Nat Rev Cancer 2005, 5:355–366. CrossRef
- Ławicki S, Gacuta-Szumarska E, Będkowska GE, Szmitkowski M: Hematopoietic cytokines as tumor markers in gynecological malignancies. A multivariate analysis in epithelial ovarian cancer patients. Growth Factors 2012, 30:357–366. CrossRef
- Moore RG, Miller MC, Steinhoff MM, Skates SJ, Lu KH, Lambert-Messerlian G, Bast RC Jr: Serum HE4 levels are less frequently elevated than CA 125 in women with benign gynecologic disorders. Am J Obstet Gynecol 2012, 206:351.e1–8.
- Tan XJ, Lang JH, Shen K, Wang L, Wu M, Xu XY: Correlartion of preoperative serum vascular endothelial growth factor level with CA 125 level in patients with epithelial ovarian cancer and its prognostic value. Zhonghua Fu Chan Ke Za Zhi 2008, 43:9–12.
- Mahner S, Woelber L, Eulenburg C, Schwarz J, Carney W, Jaenicke F, Milde-Langosh K, Mueller V: TIMP-1 and VEGF-165 serum concentration during first-line therapy of ovarian cancer patients. BMC Cancer 2010, 10:139–149. CrossRef
- Azzam AZ, Hashad DI, Kamel NA: Evaluation of HE4 as an extrabiomarker to CA 125 to improve detection of ovarian carcinoma: is it time for a step forward? Arch Gynecol Obstet 2013. Jan 30 [Epub ahead of print]
- Kraft A, Weindel K, Ochs A, Marth C, Zmija J, Schumacher P, Unger C, Marmé D, Gastl G: Vascular endothelial growth factor in the sera and effusions of patients with malignant and nonmalignant disease. Cancer 1999, 85:178–187. CrossRef
- Ławicki S, Będkowska GE, Gacuta-Szumarska E, Szmitkowski M: Hematopoietic cytokines as tumor markers in gynecological malignancies: A multivariate analysis with ROC curve in endometrial cancer patients. Growth Factors 2012, 30:29–36. CrossRef
- Ławicki S, Będkowska GE, Gacuta-Szumarska E, Knapp P, Szmitkowski M: Pretreatment plasma levels and diagnostic utility of hematopoietic cytokines in cervical cancer or cervical intraepithelial neoplasia patients. Folia Histochem Cytobiol 2012, 50:213–219.
- Broll R, Erdmann H, Duchrow M, Oevermann E, Schwandner O, Market U, Bruch HP, Windhovel U: Vascular endothelial growth factor (VEGF)-a valuable serum tumour marker in patients with colorectal cancer? Eur J Surg Oncol 2001, 27:37–42. CrossRef
- Chan KKL, Chen CA, Nam JH, Ochiai K, Wilailak S, Choon AT, Sabaratnam S, Hebbar S, Sickan J, Schodin BA, Sumpaico WW: The use of HE4 in the prediction of ovarian cancer in Asian women with a pelvic mass. Gynecol Oncol 2013, 128:239–244. CrossRef
- Holcomb K, Vucetic Z, Miller MC, Knapp RC: Human epididymis protein 4 offers superior specificity in the differentiation of benign and malignant adnexal masses in premenopausal women. Am J Obstet Gynecol 2011, 205:358.e1–6. CrossRef
- Zheng H, Gao Y: Serum HE4 as a useful biomarker in discriminating ovarian cancer from benign pelvic disease. Int J Gynecol Cancer 2012, 22:1000–1005. CrossRef
- The plasma concentration of VEGF, HE4 and CA125 as a new biomarkers panel in different stages and sub-types of epithelial ovarian tumors
- Open Access
- Available under Open Access This content is freely available online to anyone, anywhere at any time.
Journal of Ovarian Research
- Online Date
- July 2013
- Online ISSN
- BioMed Central
- Additional Links
- Author Affiliations
- 1. Department of Biochemical Diagnostics, Medical University Białystok, Waszyngtona 15A, Białystok, 15-269, Poland
- 2. Department of Gynecology, Medical University, Białystok, Poland