FGF23 is elevated in multiple myeloma and increases heparanase expression by tumor cells

Attaya Suvannasankha, Douglas R. Tompkins, Daniel F. Edwards, Katarina V. Petyaykina, Colin D. Crean, Pierrick G. Fournier, Jamie M. Parker, George E. Sandusky, Shoji Ichikawa, Erik A. Imel, John M. Chirgwin

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

Multiply myeloma (MM) grows in and destroys bone, where osteocytes secrete FGF23, a hormone which affects phosphate homeostasis and aging. We report that multiple myeloma (MM) cells express receptors for and respond to FGF23. FGF23 increased mRNA for EGR1 and its target heparanase, a pro-osteolytic factor in MM. FGF23 signals through a complex of klotho and a classical FGF receptor (FGFR); both were expressed by MM cell lines and patient samples. Bone marrow plasma cells from 42 MM patients stained positively for klotho, while plasma cells from 8 patients with monoclonal gammopathy of undetermined significance (MGUS) and 6 controls were negative. Intact, active FGF23 was increased 2.9X in sera of MM patients compared to controls. FGF23 was not expressed by human MM cells, but co-culture with mouse bone increased its mRNA. The FGFR inhibitor NVP-BGJ398 blocked the heparanase response to FGF23. NVP-BGJ398 did not inhibit 8226 growth in vitro but significantly suppressed growth in bone and induction of the osteoclast regulator RANK ligand, while decreasing heparanase mRNA. The bone microenvironment provides resistance to some anti-tumor drugs but increased the activity of NVP-BGJ398 against 8226 cells. The FGF23/klotho/heparanase signaling axis may offer targets for treatment of MM in bone.

Original languageEnglish (US)
Pages (from-to)19647-19660
Number of pages14
JournalOncotarget
Volume6
Issue number23
DOIs
StatePublished - Jan 1 2015

Keywords

  • FGF receptor
  • FGF23
  • Klotho
  • Multiple myeloma
  • Osteocytes

ASJC Scopus subject areas

  • Oncology

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    Suvannasankha, A., Tompkins, D. R., Edwards, D. F., Petyaykina, K. V., Crean, C. D., Fournier, P. G., Parker, J. M., Sandusky, G. E., Ichikawa, S., Imel, E. A., & Chirgwin, J. M. (2015). FGF23 is elevated in multiple myeloma and increases heparanase expression by tumor cells. Oncotarget, 6(23), 19647-19660. https://doi.org/10.18632/oncotarget.3794