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Contribution of tumor endothelial cells to drug resistance: anti-angiogenic tyrosine kinase inhibitors act as p-glycoprotein antagonists

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An Erratum to this article was published on 09 May 2017

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Abstract

Tumor endothelial cells (TEC) differ from the normal counterpart, in both gene expression and functionality. TEC may acquire drug resistance, a characteristic that is maintained in vitro. There is evidence that TEC are more resistant to chemotherapeutic drugs, substrates of ATP-binding cassette (ABC) transporters. TEC express p-glycoprotein (encoded by ABCB1), while no difference in other ABC transporters was revealed compared to normal endothelia. A class of tyrosine kinase inhibitors (TKI), used as angiostatic compounds, interferes with the ATPase activity of p-glycoprotein, thus impairing its functionality. The exposure of ovarian adenocarcinoma TEC to the TKIs sunitinib or sorafenib was found to abrogate resistance (proliferation and motility) to doxorubicin and paclitaxel in vitro, increasing intracellular drug accumulation. A similar effect has been reported by the p-glycoprotein inhibitor verapamil. No beneficial effect was observed in combination with cytotoxic drugs that are not p-glycoprotein substrates. The current paper reviews the mechanisms of TEC chemoresistance and shows the role of p-glycoprotein in mediating such resistance. Inhibition of p-glycoprotein by anti-angiogenic TKI might contribute to the beneficial effect of these small molecules, when combined with chemotherapy, in counteracting acquired drug resistance.

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  • 09 May 2017

    An erratum to this article has been published.

References

  1. McMillin DW, Negri JM, Mitsiades CS (2013) The role of tumour–stromal interactions in modifying drug response: challenges and opportunities. Nat Rev Drug Discov 12:217–228. doi:10.1038/nrd3870

    Article  CAS  PubMed  Google Scholar 

  2. van Beijnum JR, Nowak-Sliwinska P, Huijbers EJM et al (2015) The great escape; the hallmarks of resistance to antiangiogenic therapy. Pharmacol Rev 67:441–461. doi:10.1124/pr.114.010215

    Article  PubMed  Google Scholar 

  3. Huijbers EJM, van Beijnum JR, Thijssen VL et al (2016) Role of the tumor stroma in resistance to anti-angiogenic therapy. Drug Resist Updat Rev Comment Antimicrob Anticancer Chemother 25:26–37. doi:10.1016/j.drup.2016.02.002

    Google Scholar 

  4. Nagy JA, Chang S-H, Shih S-C et al (2010) Heterogeneity of the tumor vasculature. Semin Thromb Hemost 36:321–331. doi:10.1055/s-0030-1253454

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Heldin C-H, Rubin K, Pietras K, Ostman A (2004) High interstitial fluid pressure—an obstacle in cancer therapy. Nat Rev Cancer 4:806–813. doi:10.1038/nrc1456

    Article  CAS  PubMed  Google Scholar 

  6. Hida K, Akiyama K, Ohga N et al (2013) Tumour endothelial cells acquire drug resistance in a tumour microenvironment. J Biochem (Tokyo) 153:243–249. doi:10.1093/jb/mvs152

    Article  CAS  Google Scholar 

  7. Alessandri G, Chirivi RG, Fiorentini S et al (1999) Phenotypic and functional characteristics of tumour-derived microvascular endothelial cells. Clin Exp Metastas 17:655–662

    Article  CAS  Google Scholar 

  8. Bussolati B, Deregibus MC, Camussi G (2010) Characterization of molecular and functional alterations of tumor endothelial cells to design anti-angiogenic strategies. Curr Vasc Pharmacol 8:220–232

    Article  CAS  PubMed  Google Scholar 

  9. Silini A, Ghilardi C, Figini S et al (2012) Regulator of G-protein signaling 5 (RGS5) protein: a novel marker of cancer vasculature elicited and sustained by the tumor’s proangiogenic microenvironment. Cell Mol Life Sci CMLS 69:1167–1178. doi:10.1007/s00018-011-0862-8

    Article  CAS  PubMed  Google Scholar 

  10. Ghilardi C, Silini A, Figini S et al (2015) Trypsinogen 4 boosts tumor endothelial cells migration through proteolysis of tissue factor pathway inhibitor-2. Oncotarget 6:28389–28400. doi:10.18632/oncotarget.4949

    Article  PubMed  PubMed Central  Google Scholar 

  11. Hida K, Maishi N, Torii C, Hida Y (2016) Tumor angiogenesis—characteristics of tumor endothelial cells. Int J Clin Oncol 21:206–212. doi:10.1007/s10147-016-0957-1

    Article  CAS  PubMed  Google Scholar 

  12. St Croix B, Rago C, Velculescu V et al (2000) Genes expressed in human tumor endothelium. Science 289:1197–1202

    Article  CAS  PubMed  Google Scholar 

  13. Lu C, Bonome T, Li Y et al (2007) Gene alterations identified by expression profiling in tumor-associated endothelial cells from invasive ovarian carcinoma. Cancer Res 67:1757–1768. doi:10.1158/0008-5472.CAN-06-3700

    Article  CAS  PubMed  Google Scholar 

  14. Seaman S, Stevens J, Yang MY et al (2007) Genes that distinguish physiological and pathological angiogenesis. Cancer Cell 11:539–554. doi:10.1016/j.ccr.2007.04.017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Ghilardi C, Chiorino G, Dossi R et al (2008) Identification of novel vascular markers through gene expression profiling of tumor-derived endothelium. BMC Genom 9:201. doi:10.1186/1471-2164-9-201

    Article  Google Scholar 

  16. Bussolati B, Deambrosis I, Russo S et al (2003) Altered angiogenesis and survival in human tumor-derived endothelial cells. FASEB J Off Publ Fed Am Soc Exp Biol 17:1159–1161. doi:10.1096/fj.02-0557fje

    CAS  Google Scholar 

  17. Grange C, Bussolati B, Bruno S et al (2006) Isolation and characterization of human breast tumor-derived endothelial cells. Oncol Rep 15:381–386

    CAS  PubMed  Google Scholar 

  18. Xiong Y-Q, Sun H-C, Zhang W et al (2009) Human hepatocellular carcinoma tumor-derived endothelial cells manifest increased angiogenesis capability and drug resistance compared with normal endothelial cells. Clin Cancer Res Off J Am Assoc Cancer Res 15:4838–4846. doi:10.1158/1078-0432.CCR-08-2780

    Article  CAS  Google Scholar 

  19. Holohan C, Van Schaeybroeck S, Longley DB, Johnston PG (2013) Cancer drug resistance: an evolving paradigm. Nat Rev Cancer 13:714–726. doi:10.1038/nrc3599

    Article  CAS  PubMed  Google Scholar 

  20. Camassei FD, Arancia G, Cianfriglia M et al (2002) Nephroblastoma: multidrug-resistance p-glycoprotein expression in tumor cells and intratumoral capillary endothelial cells. Am J Clin Pathol 117:484–490. doi:10.1309/L44X-L5DN-1VHV-X30N

    Article  PubMed  Google Scholar 

  21. Fattori S, Becherini F, Cianfriglia M et al (2007) Human brain tumors: multidrug-resistance p-glycoprotein expression in tumor cells and intratumoral capillary endothelial cells. Virchows Arch Int J Pathol 451:81–87. doi:10.1007/s00428-007-0401-z

    Article  CAS  Google Scholar 

  22. Ginguené C, Champier J, Maallem S et al (2010) P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) localize in the microvessels forming the blood-tumor barrier in ependymomas. Brain Pathol Zur Switz 20:926–935. doi:10.1111/j.1750-3639.2010.00389.x

    Google Scholar 

  23. Akiyama K, Ohga N, Hida Y et al (2012) Tumor endothelial cells acquire drug resistance by MDR1 up-regulation via VEGF signaling in tumor microenvironment. Am J Pathol 180:1283–1293. doi:10.1016/j.ajpath.2011.11.029

    Article  CAS  PubMed  Google Scholar 

  24. Ambudkar SV, Dey S, Hrycyna CA et al (1999) Biochemical, cellular, and pharmacological aspects of the multidrug transporter. Annu Rev Pharmacol Toxicol 39:361–398. doi:10.1146/annurev.pharmtox.39.1.361

    Article  CAS  PubMed  Google Scholar 

  25. Amin ML (2013) P-glycoprotein inhibition for optimal drug delivery. Drug Target Insights 7:27–34. doi:10.4137/DTI.S12519

    Article  PubMed  PubMed Central  Google Scholar 

  26. Gotink KJ, Verheul HMW (2010) Anti-angiogenic tyrosine kinase inhibitors: what is their mechanism of action? Angiogenesis 13:1–14. doi:10.1007/s10456-009-9160-6

    Article  CAS  PubMed  Google Scholar 

  27. Zhang Y, Wang Q (2013) Sunitinib reverse multidrug resistance in gastric cancer cells by modulating Stat3 and inhibiting P-gp function. Cell Biochem Biophys 67:575–581. doi:10.1007/s12013-013-9544-5

    Article  CAS  PubMed  Google Scholar 

  28. Tao L-Y, Liang Y-J, Wang F et al (2009) Cediranib (recentin, AZD2171) reverses ABCB1- and ABCC1-mediated multidrug resistance by inhibition of their transport function. Cancer Chemother Pharmacol 64:961–969. doi:10.1007/s00280-009-0949-1

    Article  CAS  PubMed  Google Scholar 

  29. Mi Y, Lou L (2007) ZD6474 reverses multidrug resistance by directly inhibiting the function of p-glycoprotein. Br J Cancer 97:934–940. doi:10.1038/sj.bjc.6603985

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Jovelet C, Bénard J, Forestier F et al (2012) Inhibition of p-glycoprotein functionality by vandetanib may reverse cancer cell resistance to doxorubicin. Eur J Pharm Sci Off J Eur Fed Pharm Sci 46:484–491. doi:10.1016/j.ejps.2012.03.012

    CAS  Google Scholar 

  31. Cesca M, Frapolli R, Berndt A et al (2009) The effects of vandetanib on paclitaxel tumor distribution and antitumor activity in a xenograft model of human ovarian carcinoma. Neoplasia N Y N 11:1155–1164

    Article  CAS  Google Scholar 

  32. Akiyama K, Maishi N, Ohga N et al (2015) Inhibition of multidrug transporter in tumor endothelial cells enhances antiangiogenic effects of low-dose metronomic paclitaxel. Am J Pathol 185:572–580. doi:10.1016/j.ajpath.2014.10.017

    Article  CAS  PubMed  Google Scholar 

  33. Alessandri G, Chirivi RG, Castellani P et al (1998) Isolation and characterization of human tumor-derived capillary endothelial cells: role of oncofetal fibronectin. Lab Investig J Tech Methods Pathol 78:127–128

    CAS  Google Scholar 

  34. van Beijnum JR, Rousch M, Castermans K et al (2008) Isolation of endothelial cells from fresh tissues. Nat Protoc 3:1085–1091

    Article  PubMed  Google Scholar 

  35. Jaffe EA, Nachman RL, Becker CG, Minick CR (1973) Culture of human endothelial cells derived from umbilical veins. Identification by morphologic and immunologic criteria. J Clin Invest 52:2745–2756. doi:10.1172/JCI107470

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Bonezzi K, Belotti D, North BJ et al (2012) Inhibition of SIRT2 potentiates the anti-motility activity of taxanes: implications for antineoplastic combination therapies. Neoplasia N Y N 14:846–854

    Article  CAS  Google Scholar 

  37. Workman P, Aboagye EO, Balkwill F et al (2010) Guidelines for the welfare and use of animals in cancer research. Br J Cancer 102:1555–1577. doi:10.1038/sj.bjc.6605642

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We are grateful to Sara Figini for technical support and to Viviana Rossi for assistance in manuscript preparation.

Funding

This study was supported by a Grant from the Italian Association for Cancer Research (AIRC No. 12182 and IG No. 18853 to RG).

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Author notes

  1. Raffaella Giavazzi and Carmen Ghilardi have contributed equally.

Authors and Affiliations

  1. Laboratory of Biology and Treatment of Metastasis, IRCCS-Mario Negri Institute for Pharmacological Research, via G. La Masa 19, 20156, Milan, Italy

    MariaRosa Bani, Alessandra Decio, Raffaella Giavazzi & Carmen Ghilardi

Authors
  1. MariaRosa Bani
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  2. Alessandra Decio
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  3. Raffaella Giavazzi
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  4. Carmen Ghilardi
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Corresponding author

Correspondence to Raffaella Giavazzi.

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The authors declare no conflict of interest.

Ethical approval

All applicable international, national and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with ethical standards of the institution or practice at which the studies were conducted.

Additional information

An erratum to this article is available at https://doi.org/10.1007/s10456-017-9558-5.

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Bani, M., Decio, A., Giavazzi, R. et al. Contribution of tumor endothelial cells to drug resistance: anti-angiogenic tyrosine kinase inhibitors act as p-glycoprotein antagonists. Angiogenesis 20, 233–241 (2017). https://doi.org/10.1007/s10456-017-9549-6

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