HIF-1α inhibition blocks the cross talk between multiple myeloma plasma cells and tumor microenvironment

Enrica Borsi, Giulia Perrone, Carolina Terragna, Marina Martello, Elena Zamagni, Paola Tacchetti, Lucia Pantani, Annamaria Brioli, Angela Flores Dico, Beatrice Anna Zannetti, Serena Rocchi, Michele Cavo

Research output: Contribution to journalArticle

Abstract

Multiple myeloma (MM) is a malignant disorder of post-germinal center B cells, characterized by the clonal proliferation of malignant plasma cells (PCs) within the bone marrow (BM). The reciprocal and complex interactions that take place between the different compartments of BM and the MM cells result in tumor growth, angiogenesis, bone disease, and drug resistance. Given the importance of the BM microenvironment in MM pathogenesis, we investigated the possible involvement of Hypoxia-Inducible transcription Factor-1 alpha (HIF-1α) in the PCs-bone marrow stromal cells interplay. To test this hypothesis, we used EZN-2968, a 3rd generation antisense oligonucleotide against HIF-1α, to inhibit HIF-1α functions. Herein, we provide evidence that the interaction between MM cells and BM stromal cells is drastically reduced upon HIF-1α down-modulation. Notably, we showed that upon exposure to HIF-1α inhibitor, neither the incubation with IL-6 nor the co-culture with BM stromal cells were able to revert the anti-proliferative effect induced by EZN-2968. Moreover, we observed a down-modulation of cytokine-induced signaling cascades and a reduction of MM cells adhesion capability to the extracellular matrix proteins in EZN-2968-treated samples. Taken together, these results strongly support the concept that HIF-1α plays a critical role in the interactions between bone BM cells and PCs in Multiple Myeloma.

Original languageEnglish
Pages (from-to)444-455
Number of pages12
JournalExperimental Cell Research
Volume328
Issue number2
DOIs
Publication statusPublished - Nov 1 2014

Keywords

  • Cell adhesion
  • HIF-1α
  • MAPKs
  • Multiple myeloma
  • Tumor microenvironment

ASJC Scopus subject areas

  • Cell Biology
  • Medicine(all)

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    Borsi, E., Perrone, G., Terragna, C., Martello, M., Zamagni, E., Tacchetti, P., Pantani, L., Brioli, A., Dico, A. F., Zannetti, B. A., Rocchi, S., & Cavo, M. (2014). HIF-1α inhibition blocks the cross talk between multiple myeloma plasma cells and tumor microenvironment. Experimental Cell Research, 328(2), 444-455. https://doi.org/10.1016/j.yexcr.2014.09.018