Sunitinib-induced morpho-functional changes and drug effectiveness in malignant solitary fibrous tumours
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Rosalin D. Spagnuolo1, Silvia Brich2,1, Fabio Bozzi1, Elena Conca1, Chiara Castelli3, Marcella Tazzari3, Roberta Maestro4, Monica Brenca4, Ambra V. Gualeni5, Annunziata Gloghini5, Silvia Stacchiotti6, Marco A. Pierotti7, Silvana Pilotti1,*, Tiziana Negri1,*
1Laboratory of Experimental Molecular Pathology, Department of Diagnostic Pathology and Laboratory, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
2MOSE-DEA, University of Trieste, Trieste, Italy
3Department of Experimental Oncology and Molecular Medicine, Unit of Immunotherapy of Human Tumours, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
4Experimental Oncology 1, Centro di Riferimento Oncologico, Aviano, Italy
5Department of Diagnostic Pathology and Laboratory, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
6Adult Mesenchymal Tumour and Rare Cancer Medical Oncology Unit, Cancer Medicine Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
7Scientific Directorate, Fondazione Città della Speranza, Padua, Italy
*These authors have contributed equally and share senior authorship
Silvana Pilotti, email: firstname.lastname@example.org
Tiziana Negri, email: email@example.com
Keywords: malignant solitary fibrous tumours, efficacy of sunitinib, autophagy, immune cells
Received: August 25, 2015 Accepted: January 22, 2016 Published: February 20, 2016
Sunitinib improves the outcomes of patients with solitary fibrous tumours (SFTs). The aim of this study was to investigate and contextualise sunitinib-induced morpho-functional 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 HIF1α 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.
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