Advances in Clinical and Experimental Medicine

Title abbreviation: Adv Clin Exp Med
JCR Impact Factor (IF) – 1.736
5-Year Impact Factor – 2.135
Index Copernicus  – 168.52
MEiN – 70 pts

ISSN 1899–5276 (print)
ISSN 2451-2680 (online)
Periodicity – monthly

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Advances in Clinical and Experimental Medicine

2018, vol. 27, nr 2, February, p. 153–158

doi: 10.17219/acem/68271

Publication type: original article

Language: English

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Blocking MET receptor signaling in multiple myeloma cells in vitro and in vivo

Artur Jurczyszyn1,A,B,C,D,E,F, Anna Zebzda2,A,B,C,D,E,F, Joanna Gdula-Argasińska3,D,F, Jacek Czepiel4,E,F, David H. Vesole5,6,E,F, William Perucki7,D, Marcin Majka2,A,B,C,D,E,F

1 Department of Hematology, Faculty of Medicine, Jagiellonian University Medical College, Kraków, Poland

2 Department of Transplantology, Faculty of Medicine, Jagiellonian University Medical College, Kraków, Poland

3 Radioligand Department, Faculty of Pharmacy, Jagiellonian University Medical College, Kraków, Poland

4 Department of Infectious Diseases, Faculty of Medicine, Jagiellonian University Medical College, Kraków, Poland

5 John Theurer Cancer Center, Hackensack University Medical Center, USA

6 School of Medicine, Georgetown University, USA

7 John Dempsey Hospital, Department of Medicine, University of Connecticut, Farmington, USA

Abstract

Background. Numerous studies have shown a role of the hepatocyte growth factor (HGF) as a ligand for the MET receptor in promoting aggressiveness in myeloma cells.
Objectives. The aim of this study was to confirm the presence of the MET receptor in myeloma cell lines, to establish a stable lentiviral construct directed against MET receptor mRNA and then to evaluate the effect of blocking MET receptor expression both in vitro and in vivo.
Material and Methods. The U266 and INA6 cells were transduced using a lentiviral vector carrying siRNA to achieve the reduction of MET receptor expression. The ocular sinus of NOD/SCID mice was injected with wt-U266, shMET-U266 and shLacZ-U266 cells.
Results. MET receptor expression was demonstrated in all tested myeloma cell lines. Blocking the HGF/MET axis did not affect the growth of transduced U266 and INA6 cell lines. The inoculation of NOD/SCID mice with myeloma cells with reduced expression of MET led to increased survival of the animals.
Conclusion. MET receptor expression was constituently expressed in all tested myeloma cell lines. A lentiviral construct can effectively reduce the expression of the MET receptor in myeloma cells. Further studies are necessary to evaluate the effect of the reduction of MET receptor expression in multiple myeloma, focusing on animal models with a larger test group size.

Key words

hepatocyte growth factor, transduction, U266, INA6

References (38)

  1. Ludwig H, Sonneveld P, Davies F, et al. European perspective on multiple myeloma treatment strategies in 2014. Oncologist. 2014;19;829–844.
  2. Warren JL, Harlan LC, Stevens J, Little RF, Abel GA. Multiple myeloma treatment transformed: A population-based study of changes in initial management approaches in the United States. J Clin Oncol. 2013;31:1984–1989.
  3. Kumar SK, Dispenzieri A, Lacy MQ, Gertz MA, Buadi FK. Continued improvement in survival in multiple myeloma: Changes in early mortality and outcomes in older patients. Leukemia. 2014;28:1122–1128.
  4. Gambella M, Palumbo A, Rocci A. MET/HGF pathway in multiple myeloma: From diagnosis to targeted therapy? Expert Rev Mol Diagn. 2015;15(7):881–893.
  5. Kato T, Oka K, Nakamura T, Ito A. Decreased expression of MET during differentiation in rat lung. Eur J Histochem. 2016;60:2575. doi:10.4081/ejh.2016.2575.
  6. Jia Y, Dai G, Wang J, et al. c-MET inhibition enhances the response of the colorectal cancer cells to irradiation in vitro and in vivo. Oncol Lett. 2016;11:2879–2885.
  7. Ferrucci A, Moschetta M, Frassanito MA, et al. A HGF/cMET autocrine loop is operative in multiple myeloma bone marrow endothelial cells and may represent a novel therapeutic target. Clin Cancer Res. 2014:20:5796–5807.
  8. Jakob C, Sterz J, Zavrski I, et al. Angiogenesis in multiple myeloma. Eur J Cancer. 2006;42:1581–1590.
  9. Boissinot M, Vilaine M, Hermouet S. The hepatocyte growth factor (HGF)/Met axis: A neglected target in the treatment of chronic myeloproliferative neoplasms? Cancers (Basel). 2014;6(3):1631–1669.
  10. Wader KF, Fagerli UM, Holt RU, Børset M, Sundan A, Waage A. Soluble c-Met in serum of patients with multiple myeloma: Correlation with clinical parameters. Eur J Haematol. 2011; 87:394–399.
  11. Mahtouk K, Tjin EP, Spaargaren M, Pals ST. The HGF/MET pathway as target for the treatment of multiple myeloma and B-cell lymphomas. Biochim Biophys Acta. 2010;1806:208–219.
  12. Kristensen IB, Christensen JH, Lyng MB, et al. Hepatocyte growth factor pathway upregulation in the bone marrow microenvironment in multiple myeloma is associated with lytic bone disease. Br J Haematol. 2013;161(3):373–382.
  13. Petrini I. Biology of MET: A double life between normal tissue repair and tumor progression. Ann Transl Med. 2015;3:82.
  14. Sakai K, Aoki S, Matsumoto K. Hepatocyte growth factor and MET in drug discovery. J Biochem. 2015;157(5):271–284.
  15. Watanabe K, Hirata M, Tominari T, et al. The MET/VEGFR-targeted tyrosine kinase inhibitor attenuates FMS-dependent osteoclast differentiation and bone destruction induced by prostate cancer. J Biol Chem. 2016. doi:jbc.M116.727875
  16. Robinson KW, Sandler AB. The role of MET receptor tyrosine kinase in non-small cell lung cancer and clinical development of targeted anti-MET agents. Oncologist. 2013;18(2):115–122.
  17. Brockmann MA, Papadimitriou A, Brandt M, Fillbrandt R, Westphal M, Lamszus K. Inhibition of intracerebral glioblastoma growth by local treatment with the scatter factor/hepatocyte growth factor-antagonist NK4. Clin Cancer Res. 2003;9(12):4578–4585.
  18. Nakamura T, Sakai K, Nakamura T, Matsumoto K. Anti-cancer approach with NK4: Bivalent action and mechanisms. Anticancer Agents Med Chem. 2010;10(1):36–46.
  19. Du W, Hattori Y, Yamada T, et al. NK4, an antagonist of hepatocyte growth factor (HGF), inhibits growth of multiple myeloma cells: Molecular targeting of angiogenic growth factor. Blood. 2007;109:3042–3049.
  20. Martens T, Schmidt NO, Eckerich C, et al. A novel one-armed anti-c-Met antibody inhibits glioblastoma growth in vivo. Clin Cancer Res. 2006;12:6144–6152.
  21. Vigna E, Pacchiana G, Mazzone M, et al. “Active” cancer immunotherapy by anti-Met antibody gene transfer. Cancer Res. 2008;68:9176–9183.
  22. Kawas LH, Yamamoto BJ, Wright JW, Harding JW. Mimics of the dimerization domain of hepatocyte growth factor exhibit anti-Met and anticancer activity. J Pharmacol Exp Ther. 2011;339(2):509–518.
  23. Kong-Beltran M, Stamos J, Wickramasinghe D. The Sema domain of MET is necessary for receptor dimerization and activation. Cancer Cell. 2004;6:75–84.
  24. Hov H, Holt RU, Rø TB, et al. A selective c-Met inhibitor blocks an autocrine hepatocyte growth factor growth loop in ANBL-6 cells and prevents migration and adhesion of myeloma cells. Clin Cancer Res. 2004;10:6686–6694.
  25. Christensen JG, Burrows J, Salgia R. c-Met as a target for human cancer and characterization of inhibitors for therapeutic intervention. Cancer Letters. 2005;225:1–26.
  26. Christensen JG, Schreck R, Burrows J, et al. A selective small molecule inhibitor of c-Met kinase inhibits c-Met-dependent phenotypes in vitro and exhibits cytoreductive antitumor activity in vivo. Cancer Res. 2003;63:7345–7355.
  27. Stabile LP, Lyker JS, Huang L, Siegfried JM. Inhibition of human non-small cell lung tumors by a c-Met antisense/U6 expression plasmid strategy. Gene Ther. 2004;11:325–335.
  28. Abounader R, Lal B, Luddy C, et al. In vivo targeting of SF/HGF and c-met expression via U1snRNA/ribozymes inhibits glioma growth and angiogenesis and promotes apoptosis. FASEB J. 2002;16:108–110.
  29. Que W, Chen J, Chuang M, Jiang D. Knockdown of c-Met enhances sensitivity to bortezomib in human multiple myeloma U266 cells via inhibiting Akt ⁄mTOR activity. APMIS. 2012;120:195–203.
  30. Que W, Chen J. Knockdown of c-Met inhibits cell proliferation and invasion and increases chemosensitivity to doxorubicin in human multiple myeloma U266 cells in vitro. Mol Med Rep. 2011;4:343–349.
  31. Shen A, Wang L, Huang M, et al. c-Myc alterations confer therapeutic response and acquired resistance to c-Met inhibitors in MET-addicted cancers. Cancer Res. 2015;75(21):4548–4559.
  32. Phan LM, Fuentes-Mattei E, Wu W, et al. Hepatocyte growth factor/cMET pathway activation enhances cancer hallmarks in adrenocortical carcinoma. Cancer Res. 2015;75(19):4131–4142.
  33. Elbashir SM, Harborth J, Weber K, Tuschl T. Analysis of gene function in somatic mammalian cells using small interfering RNAs. Methods. 2002;26:199–213.
  34. Yi Y, Kim HJ, Mi P, et al. Targeted systemic delivery of siRNA to cervical cancer model using cyclic RGD-installed unimer polyion complex-assembled gold nanoparticles. J Control Release. 2016;28;244(Part B):247–256. doi: 10.1016/j.jconrel.2016.08.041
  35. Liu J, Xue H, Zhang J, et al. MicroRNA-144 inhibits the metastasis of gastric cancer by targeting MET expression. J Exp Clin Cancer Res. 2015;17:34–35.
  36. Taulli R, Scuoppo C, Bersani F, et al. Validation of MET as a therapeutic target in alveolar and embryonal rhabdomyosarcoma. Cancer Res. 2006;66:4742–4749.
  37. Jankowski K, Kucia M, Wysoczynski M, et al. Both hepatocyte growth factor (HGF) and stromal-derived factor-1 regulate the metastatic behavior of human rhabdomyosarcoma cells, but only HGF enhances their resistance to radiochemotherapy. Cancer Res. 2003;63:7926–7935.
  38. Teoh HK, Chong PP, Abdullah M, et al. Small interfering RNA silencing of interleukin-6 in mesenchymal stromal cells inhibits multiple myeloma cell growth. Leuk Res. 2016;40:44–53.