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BMC Cancer

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Open Access 01-12-2017 | Research article

Immunohistochemical evaluation of epithelial ovarian carcinomas identifies three different expression patterns of the MX35 antigen, NaPi2b

Authors: Kristina Levan, Matin Mehryar, Constantina Mateoiu, Per Albertsson, Tom Bäck, Karin Sundfeldt

Published in: BMC Cancer | Issue 1/2017

Abstract

Background

To characterize the expression of the membrane transporter NaPi2b and antigen targeted by the MX35 antibody in ovarian tumor samples. The current interest to develop monoclonal antibody based therapy of ovarian cancer by targeting NaPi2b emphasizes the need for detailed knowledge and characterization of the expression pattern of this protein. For the majority of patients with ovarian carcinoma the risk of being diagnosed in late stages with extensive loco-regional spread disease is substantial, which stresses the need to develop improved therapeutic agents.

Methods

The gene and protein expression of SLC34A2/NaPi2b were analyzed in ovarian carcinoma tissues by QPCR (n = 73) and immunohistochemistry (n = 136). The expression levels and antigen localization were established and compared to the tumor characteristics and clinical data.

Results

Positive staining for the target protein, NaPi2b was detected for 93% of the malignant samples, and we identified three separate distribution patterns of the antigen within the tumors, based on the localization of NaPi2b. There were differences in the staining intensity as well as the distribution pattern when comparing the tumor grade and histology, the mucinous tumors presented a significantly lower expression of both the targeted protein and its related gene.

Conclusion

Our study identified differences regarding the level of the antigen expression between tumor grade and histology. We have identified differences in the antigen localization between borderline tumors, type 1 and type 2 tumors, and suggest that a pathological evaluation of NaPi2b in the tumors would be helpful in order to know which patients that would benefit from this targeted therapy.

Murer H, Forster I, Biber J. The sodium phosphate cotransporter family SLC34. Pflugers Arch. 2004;447(5):763–7.CrossRefPubMed

Xu H, Bai L, Collins JF, Ghishan FK. Molecular cloning, functional characterization, tissue distribution, and chromosomal localization of a human, small intestinal sodium-phosphate (Na+−pi) transporter (SLC34A2). Genomics. 1999;62(2):281–4.CrossRefPubMed

Yin BW, Kiyamova R, Chua R, Caballero OL, Gout I, Gryshkova V, Bhaskaran N, Souchelnytskyi S, Hellman U, Filonenko V, et al. Monoclonal antibody MX35 detects the membrane transporter NaPi2b (SLC34A2) in human carcinomas. Cancer Immun. 2008;8:3.PubMedPubMedCentral

Rubin SC, Kostakoglu L, Divgi C, Federici MG, Finstad CL, Lloyd KO, Larson SM, Hoskins WJ. Biodistribution and intraoperative evaluation of radiolabeled monoclonal antibody MX35 in patients with epithelial ovarian cancer. Gynecol Oncol. 1993;51(1):61–6.CrossRefPubMed

Gryshkova V, Goncharuk I, Gurtovyy V, Khozhayenko Y, Nespryadko S, Vorobjova L, Usenko V, Gout I, Filonenko V, Kiyamova R. The study of phosphate transporter NAPI2B expression in different histological types of epithelial ovarian cancer. Exp Oncol. 2009;31(1):37–42.PubMed

Kiyamova R, Shyian M, Lyzogubov VV, Usenko VS, Gout T, Filonenko V. Immunohistochemical analysis of NaPi2b protein (MX35 antigen) expression and subcellular localization in human normal and cancer tissues. Exp Oncol. 2011;33(3):157–61.PubMed

Soares IC, Simoes K, de Souza JE, Okamoto OK, Wakamatsu A, Tuma M, Ritter G, Alves VA. In silico analysis and immunohistochemical characterization of NaPi2b protein expression in ovarian carcinoma with monoclonal antibody Mx35. Appl Immunohistochem Mol Morphol. 2012;20(2):165–72.CrossRefPubMed

Uhlen M, Fagerberg L, Hallstrom BM, Lindskog C, Oksvold P, Mardinoglu A, Sivertsson A, Kampf C, Sjostedt E, Asplund A, et al. Proteomics. Tissue-based map of the human proteome. Science. 2015;347(6220):1260419.CrossRefPubMed

Mattes MJ, Look K, Furukawa K, Pierce VK, Old LJ, Lewis JL Jr, Lloyd KO. Mouse monoclonal antibodies to human epithelial differentiation antigens expressed on the surface of ovarian carcinoma ascites cells. Cancer Res. 1987;47(24 Pt 1):6741–50.PubMed

10.

Lopes dos Santos M, Yeda FP, Tsuruta LR, Horta BB, Pimenta AA Jr, Degaki TL, Soares IC, Tuma MC, Okamoto OK, Alves VA, et al. Rebmab200, a humanized monoclonal antibody targeting the sodium phosphate transporter NaPi2b displays strong immune mediated cytotoxicity against cancer: a novel reagent for targeted antibody therapy of cancer. PLoS One. 2013;8(7):e70332.CrossRefPubMed

11.

Prat J. Ovarian carcinomas: five distinct diseases with different origins, genetic alterations, and clinicopathological features. Virchows Arch. 2012;460(3):237–49.CrossRefPubMed

12.

Andersson H, Cederkrantz E, Back T, Divgi C, Elgqvist J, Himmelman J, Horvath G, Jacobsson L, Jensen H, Lindegren S, et al. Intraperitoneal alpha-particle radioimmunotherapy of ovarian cancer patients: pharmacokinetics and dosimetry of (211)at-MX35 F(ab')2--a phase I study. J Nucl Med. 2009;50(7):1153–60.CrossRefPubMed

13.

Cederkrantz E, Andersson H, Bernhardt P, Back T, Hultborn R, Jacobsson L, Jensen H, Lindegren S, Ljungberg M, Magnander T, et al. Absorbed doses and risk estimates of (211)at-MX35 F(ab')2 in Intraperitoneal therapy of ovarian cancer patients. Int J Radiat Oncol Biol Phys. 2015;93(3):569–76.CrossRefPubMed

14.

Elgqvist J, Frost S, Pouget JP, Albertsson P. The potential and hurdles of targeted alpha therapy - clinical trials and beyond. Front Oncol. 2014;3:324.CrossRefPubMedPubMedCentral

15.

Lin K, Rubinfeld B, Zhang C, Firestein R, Harstad E, Roth L, Tsai SP, Schutten M, Xu K, Hristopoulos M, et al. Preclinical development of an anti-NaPi2b (SLC34A2) antibody-drug conjugate as a therapeutic for non-small cell lung and ovarian cancers. Clin Cancer Res. 2015;21(22):5139–50.CrossRefPubMed

16.

Meredith RF, Torgue J, Azure MT, Shen S, Saddekni S, Banaga E, Carlise R, Bunch P, Yoder D, Alvarez R. Pharmacokinetics and imaging of 212Pb-TCMC-trastuzumab after intraperitoneal administration in ovarian cancer patients. Cancer Biother Radiopharm. 2014;29(1):12–7.CrossRefPubMedPubMedCentral

17.

Finstad CL, Lloyd KO, Federici MG, Divgi C, Venkatraman E, Barakat RR, Finn RD, Larson SM, Hoskins WJ, Humm JL. Distribution of radiolabeled monoclonal antibody MX35 F(ab')2 in tissue samples by storage phosphor screen image analysis: evaluation of antibody localization to micrometastatic disease in epithelial ovarian cancer. Clin Cancer Res. 1997;3(8):1433–42.PubMed

18.

Chouin N, Lindegren S, Frost SH, Jensen H, Albertsson P, Hultborn R, Palm S, Jacobsson L, Back T. Ex vivo activity quantification in micrometastases at the cellular scale using the alpha-camera technique. J Nucl Med. 2013;54(8):1347–53.CrossRefPubMed

19.

Chouin N, Lindegren S, Jensen H, Albertsson P, Back T. Quantification of activity by alpha-camera imaging and small-scale dosimetry within ovarian carcinoma micrometastases treated with targeted alpha therapy. Q J Nucl Med Mol Imaging. 2012;56(6):487–95.PubMed

20.

Palm S, Back T, Haraldsson B, Jacobsson L, Lindegren S, Albertsson P. Biokinetic modeling and Dosimetry for optimizing Intraperitoneal Radioimmunotherapy of ovarian cancer Microtumors. J Nucl Med. 2016;57(4):594–600.CrossRefPubMed

21.

Shyian M, Gryshkova V, Kostianets O, Gorshkov V, Gogolev Y, Goncharuk I, Nespryadko S, Vorobjova L, Filonenko V, Kiyamova R. Quantitative analysis of SLC34A2 expression in different types of ovarian tumors. Exp Oncol. 2011;33(2):94–8.PubMed

22.

Kristjansdottir B, Levan K, Partheen K, Sundfeldt K. Diagnostic performance of the biomarkers HE4 and CA125 in type I and type II epithelial ovarian cancer. Gynecol Oncol. 2013;131(1):52–8.CrossRefPubMed

23.

Tavassoli FA, Devilee P. Pathology and Genetics of Tumours of the Breast and Female Genital Organs, vol. Chapter 2. Lyon: IARC Publications; 2003.

24.

Shih Ie M, Kurman RJ. Ovarian tumorigenesis: a proposed model based on morphological and molecular genetic analysis. Am J Pathol. 2004;164(5):1511–8.CrossRefPubMed

25.

Kurman RJ, Shih Ie M. Molecular pathogenesis and extraovarian origin of epithelial ovarian cancer--shifting the paradigm. Hum Pathol. 2011;42(7):918–31.CrossRefPubMedPubMedCentral

26.

Rangel LB, Sherman-Baust CA, Wernyj RP, Schwartz DR, Cho KR, Morin PJ. Characterization of novel human ovarian cancer-specific transcripts (HOSTs) identified by serial analysis of gene expression. Oncogene. 2003;22(46):7225–32.CrossRefPubMed

27.

Nishimura M, Naito S. Tissue-specific mRNA expression profiles of human solute carrier transporter superfamilies. Drug Metab Pharmacokinet. 2008;23(1):22–44.CrossRefPubMed

28.

Lindegren S, Andrade LN, Back T, Machado CM, Horta BB, Buchpiguel C, Moro AM, Okamoto OK, Jacobsson L, Cederkrantz E, et al. Binding affinity, specificity and comparative Biodistribution of the parental Murine monoclonal antibody MX35 (anti-NaPi2b) and its humanized version Rebmab200. PLoS One. 2015;10(5):e0126298.CrossRefPubMedPubMedCentral

29.

Tomic TT, Gustavsson H, Wang W, Jennbacken K, Welen K, Damber JE. Castration resistant prostate cancer is associated with increased blood vessel stabilization and elevated levels of VEGF and Ang-2. Prostate. 2012;72(7):705–12.CrossRefPubMed

30.

Uhlén M, Fagerberg L, Hallström BM, Lindskog C, Oksvold P, Mardinoglu A, Sivertsson Å, Kampf C, Sjöstedt E, Asplund A, Olsson I, Edlund K, Lundberg E, Navani S, Szigyarto CA, Odeberg J, Djureinovic D, Takanen JO, Hober S, Alm T, Edqvist PH, Berling H, Tegel H, Mulder J, Rockberg J, Nilsson P, Schwenk JM, Hamsten M, von Feilitzen K, Forsberg M, Persson L, Johansson F, Zwahlen M, von Heijne G, Nielsen J, Pontén F. Tissue-based map of the human proteome. Science. 2015;347(6220):1260419.

31.

Elgqvist J, Andersson H, Back T, Claesson I, Hultborn R, Jensen H, Johansson BR, Lindegren S, Olsson M, Palm S, et al. Alpha-radioimmunotherapy of intraperitoneally growing OVCAR-3 tumors of variable dimensions: outcome related to measured tumor size and mean absorbed dose. J Nucl Med. 2006;47(8):1342–50.PubMed

32.

Elgqvist J, Andersson H, Back T, Hultborn R, Jensen H, Karlsson B, Lindegren S, Palm S, Warnhammar E, Jacobsson L. Therapeutic efficacy and tumor dose estimations in radioimmunotherapy of intraperitoneally growing OVCAR-3 cells in nude mice with (211)at-labeled monoclonal antibody MX35. J Nucl Med. 2005;46(11):1907–15.PubMed

33.

Mulford DA, Scheinberg DA, Jurcic JG. The promise of targeted {alpha}-particle therapy. J Nucl Med. 2005;46(Suppl 1):199S–204S.PubMed

34.

Frost SH, Back T, Chouin N, Hultborn R, Jacobsson L, Elgqvist J, Jensen H, Albertsson P, Lindegren S. Comparison of 211At-PRIT and 211At-RIT of ovarian microtumors in a nude mouse model. Cancer Biother Radiopharm. 2013;28(2):108–14.CrossRefPubMed

35.

Mullard A. Maturing antibody-drug conjugate pipeline hits 30. Nat Rev Drug Discov. 2013;12(5):329–32.CrossRefPubMed

36.

Burris HA, Gordon MS, Gerber DE, Spigel DR, Mendelson DS, Schiller JH, Wang Y, Choi Y, Wood K, Maslyar DJ, et al. A phase I study of DNIB0600A, an antibody-drug conjugate (ADC) targeting NaPi2b, in patients (pts) with non-small cell lung cancer (NSCLC) or platinum-resistant ovarian cancer (OC). In: 2014 ASCO annual meeting. J Clin Oncol. 2014;32:5s.

37.

Meredith R, Torgue J, Shen S, Fisher DR, Banaga E, Bunch P, Morgan D, Fan J, Straughn JM Jr. Dose escalation and Dosimetry of first-in-human alpha Radioimmunotherapy with 212Pb-TCMC-Trastuzumab. J Nucl Med. 2014;55(10):1636–642.

Title: Immunohistochemical evaluation of epithelial ovarian carcinomas identifies three different expression patterns of the MX35 antigen, NaPi2b
Authors: Kristina Levan
Matin Mehryar
Constantina Mateoiu
Per Albertsson
Tom Bäck
Karin Sundfeldt
Publication date: 01-12-2017
Publisher: BioMed Central
Published in: BMC Cancer / Issue 1/2017
Electronic ISSN: 1471-2407
DOI: https://doi.org/10.1186/s12885-017-3289-2

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