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Expression of a novel endothelial marker, C-type lectin 14A, in epithelial ovarian cancer and its prognostic significance

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Abstract

Objective

The purpose of this study was to evaluate microvessel density (MVD) as assessed by C-type lectin 14A (CLEC14A), which is a new marker for endothelial cells, and compare its expression to CD31 and CD105 in epithelial ovarian cancer (EOC).

Methods

MVD was evaluated in tumors (n = 50) from patients with EOC who underwent primary surgery and in patients with EOC who received preoperative chemotherapy (n = 49) using immunohistochemistry with antibodies to CLEC14A, CD31 and CD105. The median duration of follow-up was 24.5 months (range 1−101 months). The effect of prognostic factors on event-free survival (EFS) and overall survival (OS) was assessed using the Cox regression model.

Results

The amount of residual disease was found to be an independent prognostic factor in multivariate analysis with respect to EFS (P = 0.009) and OS (P < 0.001). The mean MVD of CLEC14A (MVD = 6), in tumors from patients who underwent primary surgery, was significantly lower than that of CD31 (MVD = 25, P < 0.0001) and CD105 (MVD = 11, P = 0.018). However, there was no significant correlation between MVD as detected by these markers and clinical outcome. There was no expression of CLEC14A in tumors from patients who received preoperative chemotherapy and the MVD of CD31 and CD105 was significantly reduced (P = 0.001 and 0.006, respectively) in this set of patients.

Conclusion

This study demonstrates MVD as detected by CLEC14A in EOC. Treatment with chemotherapy reduces tumor blood vessels significantly. We suggest that CLEC14A may be a more specific endothelial marker to assess tumor angiogenesis.

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References

  1. Folkman J (1971) Tumour angiogenesis: therapeutic implications. N Engl J Med 285:1182–1186

    Article  CAS  PubMed  Google Scholar 

  2. Brekken RA, Li C, Kumar S (2002) Strategies for vascular targeting in tumours. Int J Cancer 100:123–130

    Article  CAS  PubMed  Google Scholar 

  3. Krishna Priya S, Nagare RP, Sneha VS et al (2016) Tumour angiogenesis−origin of blood vessels. Int J Cancer 139:729–735

    Article  CAS  PubMed  Google Scholar 

  4. Fox SB, Harris AL (2004) Histological quantitation of tumour angiogenesis. APMIS 112:413–430

    Article  PubMed  Google Scholar 

  5. Weidner N (1993) Tumour angiogenesis: review of current applications in tumour prognostication. Semin Diagn Pathol 10:302–313

    CAS  PubMed  Google Scholar 

  6. He L, Wang Q, Zhao X (2015) Microvessel density as a prognostic factor in ovarian cancer: a systematic review and meta-analysis. Asian Pac J Cancer Prev 16:869–874

    Article  PubMed  Google Scholar 

  7. Mura M, Swain RK, Zhuang X et al (2012) Identification and angiogenic role of the novel tumour endothelial marker CLEC14A. Oncogene 31:293–305

    Article  CAS  PubMed  Google Scholar 

  8. Rho S-S, Choi H-J, Min J-K et al (2011) CLEC14A is specifically expressed in endothelial cells and mediates cell to cell adhesion. Biochem Biophys Res Commun 404:103–108

    Article  CAS  PubMed  Google Scholar 

  9. Zhuang X, Cross D, Heath VL, Bicknell R (2011) Shear stress, tip cells and regulators of endothelial migration. Biochem Soc Trans 39:1571–1575

    Article  CAS  PubMed  Google Scholar 

  10. Ki MK, Jeoung MH, Choi JR et al (2013) Human antibodies targeting the C-type lectin-like domain of the tumour endothelial cell marker CLEC14A regulate angiogenic properties in vitro. Oncogene 32:5449–5457

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Zanivan S, Maione F, Hein MY et al (2013) SILAC-based proteomics of human primary endothelial cell morphogenesis unveils tumour angiogenic markers. Mol Cell Proteomics 12:3599–3611

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Noy PJ, Lodhia P, Khan K et al (2015) Blocking CLEC14A-MMRN2 binding inhibits sprouting angiogenesis and tumour growth. Oncogene. 34(47):5821–5831

    Article  CAS  PubMed  Google Scholar 

  13. Horak ER, Leek R, Klenk N et al (1992) Angiogenesis, assessed by platelet/endothelial cell adhesion molecule antibodies, as indicator of node metastases and survival in breast cancer. Lancet 340:1120–1124

    Article  CAS  PubMed  Google Scholar 

  14. Parums DV, Cordell JL, Micklem K et al (1990) JC70: a new monoclonal antibody that detects vascular endothelium associated antigen on routinely processed tissue sections. J Clin Pathol 43:752–757

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Haruta Y, Seon BK (1986) Distinct human leukemia-associated cell surface glycoprotein GP160 defined by monoclonal antibody SN6. Proc Natl Acad Sci USA 83:7898–7902

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Nassiri F, Cusimano MD, Scheithauer BW et al (2011) Endoglin (CD105): a review of its role in angiogenesis and tumour diagnosis, progression and therapy. Anticancer Res 31:2283–2290

    CAS  PubMed  Google Scholar 

  17. Li DY, Sorensen LK, Brooke BS et al (1999) Defective angiogenesis in mice lacking endoglin. Science 284:1534–1537

    Article  CAS  PubMed  Google Scholar 

  18. Rosen LS, Hurwitz HI, Wong MK et al (2012) A phase I first-in-human study of TRC105 (anti-endoglin antibody) in patients with advanced cancer. Clin Cancer Res 18:4820–4829

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Karzai FH, Apolo AB, Cao L et al (2014) A phase I study of TRC105 anti-CD105 (endoglin) antibody in metastatic castration-resistant prostate cancer. BJU Int 116(4):546–555

    Article  Google Scholar 

  20. Gordon MS, Robert F, Matei D et al (2014) An open-label phase Ib dose-escalation study of trc105 (anti-endoglin antibody) with bevacizumab in patients with advanced cancer. Clin Cancer Res 20:5918–5926

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Costello B, Li C, Duff S et al (2004) Perfusion of 99Tcm-labeled CD105 Mab into kidneys from patients with renal carcinoma suggests that CD105 is a promising vascular target. Int J Cancer 109:436–441

    Article  CAS  PubMed  Google Scholar 

  22. Steg AD, Bevis KS, Katre AA et al (2012) Stem cell pathways contribute to clinical chemoresistance in ovarian cancer. Clin Cancer Res 18:869–881

    Article  CAS  PubMed  Google Scholar 

  23. Cox DR, Oakes D (1984) Analysis of Survival Data. Chapman and Hall, New York

    Google Scholar 

  24. Kaplan EL, Meier P (1958) Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457

    Article  Google Scholar 

  25. Taskiran C, Erdem O, Onan A et al (2006) The prognostic value of endoglin (CD105) expression in ovarian carcinoma. Int J Gynecol Cancer 16:1789–1793

    Article  CAS  PubMed  Google Scholar 

  26. Rubatt JM, Darcy KM, Hutson A et al (2009) Independent prognostic relevance of microvessel density in advanced epithelial ovarian cancer and associations between CD31, CD105, p53 status, and angiogenic marker expression: a Gynecologic Oncology Group study. Gynecol Oncol 112:469–474

    Article  CAS  PubMed  Google Scholar 

  27. Saad RS, Liu YL, Nathan G et al (2004) Endoglin (CD105) and vascular endothelial growth factor as prognostic markers in colorectal cancer. Mod Pathol 17:197–203

    Article  CAS  PubMed  Google Scholar 

  28. El-Gohary YM, Silverman JF, Olson PR et al (2007) Endoglin (CD105) and vascular endothelial growth factor as prognostic markers in prostatic adenocarcinoma. Am J Clin Pathol 127:572–579

    Article  CAS  PubMed  Google Scholar 

  29. Miyata Y, Sagara Y, Watanabe S et al (2013) CD105 is a more appropriate marker for evaluating angiogenesis in urothelial cancer of the upper urinary tract than CD31 or CD34. Virchows Arch Int J Pathol 463:673–679

    Article  CAS  Google Scholar 

  30. Dales J-P, Garcia S, Bonnier P et al (2003) CD105 expression is a marker of high metastatic risk and poor outcome in breast carcinomas. Correlations between immunohistochemical analysis and long-term follow-up in a series of 929 patients. Am J Clin Pathol 119:374–380

    Article  PubMed  Google Scholar 

  31. Rau K-M, Huang C-C, Chiu T-J et al (2012) Neovascularization evaluated by CD105 correlates well with prognostic factors in breast cancers. Exp Ther Med 4:231–236

    PubMed  PubMed Central  Google Scholar 

  32. Sundar SS, Zhang H, Brown P et al (2006) Role of lymphangiogenesis in epithelial ovarian cancer. Br J Cancer 94:1650–1657

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Cwiklnska A, Sobstyl M, Kwasniewski W, Bednarek W (2013) Microtissue density prognostic factor evaluation based on antigens CD34 and CD 105 in ovarian cancer patients. Ann Agric Environ Med 20:838–842

    PubMed  Google Scholar 

  34. Bock AJ, Tuft Stavnes H, Kærn J et al (2011) Endoglin (CD105) expression in ovarian serous carcinoma effusions is related to chemotherapy status. Tumour Biol 32:589–596

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Orre M, Lotfi-Miri M, Mamers P, Rogers PA (1998) Increased microvessel density in mucinous compared with malignant serous and benign tumours of the ovary. Br J Cancer 77:2204–2209

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Cerami E, Gao J, Dogrusoz U et al (2012) The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov 2:401–404

    Article  PubMed  Google Scholar 

  37. Gao J, Aksoy BA, Dogrusoz U et al (2013) Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal 6:pl1

    Article  PubMed  PubMed Central  Google Scholar 

  38. Beresford MJ, Harris AL, Ah-See M et al (2006) The relationship of the neo-angiogenic marker, endoglin, with response to neoadjuvant chemotherapy in breast cancer. Br J Cancer 95:1683–1688

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Hollingsworth HC, Kohn EC, Steinberg SM et al (1995) Tumour angiogenesis in advanced stage ovarian carcinoma. Am J Pathol 147:33–41

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Alvarez AA, Krigman HR, Whitaker RS et al (1999) The prognostic significance of angiogenesis in epithelial ovarian carcinoma. Clin Cancer Res 5:587–591

    CAS  PubMed  Google Scholar 

  41. Abulafia O, Ruiz JE, Holcomb K et al (2000) Angiogenesis in early-invasive and low-malignant-potential epithelial ovarian carcinoma. Obstet Gynecol 95:548–552

    CAS  PubMed  Google Scholar 

  42. Huynh H, Teo CCM, Soo KC (2007) Bevacizumab and rapamycin inhibit tumour growth in peritoneal model of human ovarian cancer. Mol Cancer Ther 6:2959–2966

    Article  CAS  PubMed  Google Scholar 

  43. Perren TJ, Swart AM, Pfisterer J et al (2011) A phase 3 trial of bevacizumab in ovarian cancer. N Engl J Med 365:2484–2496

    Article  CAS  PubMed  Google Scholar 

  44. Burger RA, Brady MF, Bookman MA et al (2011) Incorporation of bevacizumab in the primary treatment of ovarian cancer. N Engl J Med 365:2473–2483

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We thank the Board of Research in Nuclear Sciences (BRNS) and the Department of Biotechnology, Government of India for the funding. We are grateful to the faculty and technical staff in the department of histopathology, Amrita Institute of Medical Sciences (AIMS) for their help. We thank Dr. S. Shirley and Dr. Kanchan Murhekar, Cancer Institute (WIA) for their timely suggestions. We acknowledge the assistance of Dr. K. R. Sundaram and Ms. Amrutha Jose, Department of Biostatistics, AIMS, Cochin and Dr. Swaminathan and Dr. Rama, Tumour Registry, Cancer Institute (WIA), Chennai for statistical analysis.

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Authors and Affiliations

  1. Laboratory for Cancer Biology, Medical Oncology and Clinical Research, Cancer Institute (WIA), 38, Sardar Patel Road, Guindy, Chennai, Tamil Nadu, 600036, India

    S. Krishna Priya, Rohit. P. Nagare & T. S. Ganesan

  2. Medical Oncology, Command Hospital (CC), Lucknow Cantt., Lucknow, UP, 226002, India

    Kishore Kumar

  3. Department of Histopathology, Amrita Institute of Medical Sciences and Research Centre, Cochin, Kerala, 682041, India

    K. R. Hiran & M. R. Bindhu

  4. Department of Surgical Oncology, Amrita Institute of Medical Sciences and Research Centre, Cochin, Kerala, 682041, India

    D. K. Vijaykumar

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  1. S. Krishna Priya
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  2. Kishore Kumar
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  3. K. R. Hiran
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  4. M. R. Bindhu
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  5. Rohit. P. Nagare
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Corresponding author

Correspondence to T. S. Ganesan.

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The authors declare that they have no conflict of interest.

Funding

This study was funded by the Board of Research in Nuclear Sciences and Department of Biotechnology, Government of India. Ms.S.Krishna Priya and Mr.Rohit P Nagare are recipients of a Senior Research Fellowship from the Indian Council for Medical Research (ICMR), Government of India.

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Krishna Priya, S., Kumar, K., Hiran, K.R. et al. Expression of a novel endothelial marker, C-type lectin 14A, in epithelial ovarian cancer and its prognostic significance. Int J Clin Oncol 22, 107–117 (2017). https://doi.org/10.1007/s10147-016-1033-6

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  • DOI: https://doi.org/10.1007/s10147-016-1033-6

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