Sunitinib-induced morpho-functional changes and drug effectiveness in malignant solitary fibrous tumours

Rosalin D. Spagnuolo, Silvia Brich, Fabio Bozzi, Elena Conca, Chiara Castelli, Marcella Tazzari, Roberta Maestro, Monica Brenca, Ambra V. Gualeni, Annunziata Gloghini, Silvia Stacchiotti, Marco A. Pierotti, Silvana Pilotti, Tiziana Negri

Research output: Contribution to journalArticle

Abstract

Sunitinib improves the outcomes of patients with solitary fibrous tumours (SFTs). The aim of this study was to investigate and contextualise sunitinib-induced morphofunctional changes in order to gain insights into the drug's mechanism of action. To this end, four surgical specimens obtained from two sunitinib-responsive patients with malignant SFT, and one primary cell culture obtained from fresh tumoral tissue and its stabilised cell line, were studied by means of immunohistochemistry, bright field in situ hybridisation, immunofluorescence/confocal microscopy, and biochemistry. The post-sunitinib surgical samples were characterised by two biologically relevant morpho-functional changes: clear areas and necrotic foci. The first were associated with the attenuation/loss of PDGFRB expression and decreased mTOR signalling, and corresponded to a pathological response. The second were associated with the over-expression of PDGFRB and VEGFA, strong mTOR signalling activation, and the appearance of HIF1a expression, hallmarks of pathological progression. The analysis clearly showed that sunitinib reduces the vascular supply network and inhibits tumoral cells. It also either induces autophagy, thus favouring drug response, or impairs autophagy as a result of lysosome sequestration, thus favouring disease progression. These distinct autophagic events were associated with different myeloid immune contextures. Finally, we also found that PDGFRB is one of the components of a complex that includes Beclin 1 and VPS34. The results of these tissue-based analyses provide new insights into sunitinib's mechanism of action in SFT patients.

Original languageEnglish
Pages (from-to)45015-45026
Number of pages12
JournalOncotarget
Volume7
Issue number29
DOIs
Publication statusPublished - 2016

Keywords

  • Autophagy
  • Efficacy of sunitinib
  • Immune cells
  • Malignant solitary fibrous tumours

ASJC Scopus subject areas

  • Oncology

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