Relationship of ovarian cancer tumour markers’ concentration between local fluid and serum: comparison of malignant to benign condition

Objective: The aim of the study was to evaluate the relationship of ovarian tumour markers osteopontin (sOPN) and splice variant 6 of sCD44 (sCD44-v6) between serum and local environment, represented by ascites or peritoneal fluid (PF) / peritoneal washing (PW), in patients with malignant and non-malignant conditions, respectively. Materials and Methods: The study included 33 women with advanced ovarian malignancy and 33 women with benign gynaecological conditions. Tumour markers concentrations were determined by flow cytometry. Results: Mean concentrations in ascites for both tumour markers were significantly higher than in PF or PW. Serum sOPN concentrations did not correlate with local fluid levels in either group and showed a tendency for retention in local fluid which was potentiated in malignant condition. Serum sCD44-v6 concentrations positively correlated with concentrations in ascites, PF, and PW. However, the magnitude of slope of the regression line was lower in malignant situation. Conclusion: Although concentrations of both potential biomarkers significantly increase in ascites produced by metastatic ovarian cancer, serum values are not a simple reflection of local environment changes.

Ovarian cancer; Tumour markers; sOPN; sCD44-v6; Serum; Peritoneal fluid.

[1] Siegel R., Naishadham D., Jemal A.: “Cancer Statistics, 2013”. CA Cancer J. Clin., 2013, 63, 11.

[2] Nguyen L., Cardenas-Goicoechea S.J., Gordon P., Curtin C., Momeni M., Chuang L., Fishman D.: “Biomarkers for early detection of ovarian cancer”. Women’s Health (Lond. Engl.), 2013, 9, 171.

[3] Mok S.C., Ye B., Cramer D.W.: “Methods of detecting ovarian cancer based on osteopontin. WO 2006009875 A1; 2006”. Available at: http://www.google.com.ar/patents/WO2006009875A1?cl=en

[4] Cramer D.W., Bast R.C. Jr., Berg C.D., Diamandis E.P., Godwin A.K., Hartge P., et al.: “Ovarian Cancer Biomarker Performance in Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial Specimens”. Cancer Prev. Res., 2011, 4, 365.

[5] Gao C., Guo H., Downey L., Marroquin C., Wei J., Kuo P.C.: “Osteopontin-dependent CD44v6 expression and cell adhesion in HepG2 cells”. Carcinogenesis, 2003, 24, 1871.

[6] Khan S.A., Cook A.C., Kappil M., Günthert U., Chambers A.F., Tuck A.B., Denhardt D.T.: “Enhanced cell surface CD44 variant (v6, v9) expression by osteopontin in breast cancer epithelial cells facilitates tumor cell migration: novel post-transcriptional, post-translational regulation”. Clin. Exp. Metastasis, 2005, 22, 663.

[7] Mohamaden W., Wang H., Guan H., Meng X., Li J.: “Immunohistochemical localization and mRNA quantification of osteopontin and Tamm-Horsfall protein in canine renal tissue after potassium oxalate injection”. BMC Vet. Res., 2014, 17, 10.

[8] Bhatt A.N., Mathur R., Farooque A., Verma A., Dwarakanath B.S.: “Cancer biomarkers - current perspectives”. Indian J. Med. Res., 2010, 132, 129.

[9] Lutz A.M., Willmann J.K., Cochran F.V., Ray P., Gambhir S.S.: “Cancer screening: a mathematical model relating secreted blood biomarker levels to tumor sizes”. PLoS Med., 2008, 5, e170.

[10] Amon L.M., Law W., Fitzgibbon M.P., Gross J.A., O’Briant K., Peterson A., et al.: “Integrative proteomic analysis of serum and peritoneal fluids helps identify proteins that are up-regulated in serum of women with ovarian cancer”. PLoS One, 2010, 5, e11137.

[11] Bissel D.: “Observations on the cyclical pelvic fluid in the female. A preliminary report”. Am. J. Obstet. Gynecol., 1932, 24, 271.

[12] Jakimovska M., Černe K., Verdenik I., Kobal B.: “Circulating serum sVCAM-1 concentration in advanced ovarian cancer patients: correlation with concentration in ascites”. Radiol. Oncol., 2014, 48, 307.

[13] Nakae M., Iwamoto I., Fujino T., Maehata Y., Togami S., Yoshinaga M., Douchi T.: “Preoperative plasma osteopontin level as a biomarker complementary to carbohydrate antigen 125 in predicting ovarian cancer”. J. Obstet.Gynaecol. Res., 2006, 32, 309.

[14] Prat J.: “Staging classification for cancer of the ovary, fallopian tube, and peritoneum”. Int. J. Gynaecol. Obstet., 2014, 124, 1.

[15] Galic Jerman K., Kobal B., Jakimovska M., Verdenik I., Cerne K.: “Control values of ovarian cancer tumor markers and standardisation of a protocol for sampling peritoneal fluid and performing washing during laparoscopy”. World J. Surg.Oncol., 2014, 12, 278.

[16] Maathuis J.B., Van Look P.F., Michie E.A.,: “Changes in volume, total protein and ovarian steroid concentrations of peritoneal fluid throughout the human menstrual cycle”. J. Endocrinol., 1978, 76, 123.

[17] Bouckaert P.X., Evers J.L., Doesburg W.H., Schellekens L.A., Brombacher P.H., Rolland R.: “Patterns of changes in proteins in the peritoneal fluid of women during the periovulatory phase of the menstrual cycle”. J. Reprod. Fertil., 1986, 77, 329.

[18] Brown L.F., Berse B., Van de Water L., Papadopoulos-Sergiou A., Perruzzi C.A., Manseau E.J., et al.: “Expression and distribution of osteopontin in human tissues: widespread association with luminal epithelial surfaces”. Mol. Biol. Cell., 1992, 3, 1169.

[19] Avilés M., Gutiérrez-Adán A., Coy P.: “Oviductal secretions: will they be key factors for the future ARTs?” Mol. Hum. Reprod., 2010, 16, 896.

[20] Apparao K.B., Murray M.J., Fritz M.A., Meyer W.R., Chambers A.F., Truong P.R., Lessey B.A.: “Osteopontin and its receptor alphavbeta(3) integrin are coexpressed in the human endometrium during the menstrual cycle but regulated differentially“. J. Clin. Endocrinol. Metab., 2001, 86, 4991.

[21] Rang H.P., Dale M.M., Ritter J.M., Flower R.J., Henderson G.: “Rang and Dale’s Pharmacology”. London: Elsevier, 2012.

[22] Mazzali M., Kipari T., Ophascharoensuk V., Wesson J.A., Johnson R., Hughes J.: “Osteopontin—a molecule for all seasons”. QJM., 2002, 95, 3.

[23] Noh S.M.: “Measurement of peritoneal fluid pH in patients with nonserosal invasive gastric cancer”. Yonsei Med. J., 2003, 44, 45.

[24] Ye B., Skates S., Mok S.C., Horick N.K., Rosenberg H.F., Vitonis A., et al.: “Proteomic-based discovery and characterization of glycosylated eosinophil-derived neurotoxin and COOH-terminal osteopontin fragments for ovarian cancer in urine”. Clin. Cancer Res., 2006, 12, 432.

[25] Kim J.H., Skates S.J., Uede T., Wong K.K., Schorge J.O., Feltmate C.M., et al.: “Osteopontin as a potential diagnostic biomarker for ovarian cancer“. JAMA, 2002, 287, 1671.

[26] Mor G., Visintin I., Lai Y., Zhao H., Schwartz P., Rutherford T., et al.: “Serum protein markers for early detection of ovarian cancer”. Proc. Natl. Acad. Sci. U S A, 2005, 102, 7677.

[27] Visintin I., Feng Z., Longton G., Ward D.C., Alvero A.B., Lai Y., et al.: “Diagnostic markers for early detection of ovarian cancer“. Clin. Cancer Res., 2008, 14, 1065.

[28] Wang Y.D., Chen H., Liu H.Q., Hao M.: “Correlation between ovarian neoplasm and serum levels of osteopontin: a meta-analysis“. Tumour Biol., 2014, 35, 11799.

[29] Song G., Cai Q.F., Mao Y.B., Ming Y.L., Bao S.D., Ouyang G.L.: “Osteopontin promotes ovarian cancer progression and cell survival and increases HIF-1alpha expression through the PI3-K/Akt pathway“. Cancer Sci., 2008, 99, 1901.

[30] Weber G.F.: “The cancer biomarker osteopontin: combination with other markers”. Cancer Genomics Proteomics, 2011, 8, 263.

[31] Sarapik A., Velthut A., Haller-Kikkatalo K., Faure G.C., Béné M.C., de Carvalho Bittencourt M., et al.: “Follicular proinflammatory cytokines and chemokines as markers of IVF success”. Clin. Dev. Immunol., 2012, 2012, 606459.

[32] Dong W.G., Sun X.M., Yu B.P., Luo H.S., Yu J.P.: “Role of VEGF and CD44v6 in differentiating benign from malignant ascites”. World J. Gastroenterol., 2003, 9, 2596.

[33] Sun Y., Shen Z., Ji X.: “Study on the relationship between CD44v6, p53 gene mutation and ovarian carcinoma metastasis”. Zhonghua Fu Chan Ke Za Zhi, 2000, 35, 225.

[34] Bar J.K., Grelewski P., Popiela A., Noga L., Rabczyñski J.: “Type IV collagen and CD44v6 expression in benign, malignant primary and metastatic ovarian tumors: correlation with Ki-67 and p53 immunoreactivity”. Gynecol. Oncol., 2004, 95, 23.

[35] Shi J., Zhou Z., Di W., Li N.: “Correlation of CD44v6 expression with ovarian cancer progression and recurrence”. BMC Cancer, 2013, 13, 182.

[36] Todaro M., Gaggianesi M., Catalano V., Benfante A., Iovino F., Biffoni M.: “CD44v6 is a marker of constitutive and reprogrammed cancer stem cells driving colon cancer metastasis”. Cell Stem Cell, 2014, 14, 342.

[37] Tjhay F., Motohara T., Tayama S., Narantuya D., Fujimoto K., Guo J., et al.: “CD44 variant 6 is correlated with peritoneal dissemination and poor prognosis in patients with advanced epithelial ovarian cancer”. Cancer Sci., 2015, 106, 1421.

[38] Stickeler E., Vogl F.D., Denkinger T., Mobus V.J., Kreienberg R., Runnebaum I.B.: “Soluble CD44 splice variants and pelvic lymph node metastasis in ovarian cancer patients”. Int. J. Mol. Med., 2000, 6, 595.

[39] Zhou D.X., Liu Y.X., Xue Y.H.: “Expression of CD44v6 and its association with prognosis in epithelial ovarian carcinomas“. Patholog. Res. Int., 2012, 2012, 908206.