Oncotarget

Research Papers:

Osteotropism of neuroendocrine tumors: role of the CXCL12/CXCR4 pathway in promoting EMT in vitro

Mauro Cives, Davide Quaresmini, Francesca Maria Rizzo, Claudia Felici, Stella D'Oronzo, Valeria Simone and Franco Silvestris _

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Oncotarget. 2017; 8:22534-22549. https://doi.org/10.18632/oncotarget.15122

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Abstract

Mauro Cives1, Davide Quaresmini1, Francesca Maria Rizzo1, Claudia Felici1, Stella D’Oronzo1, Valeria Simone1, Franco Silvestris1

1Department of Biomedical Sciences and Human Oncology, University of Bari “A. Moro”, Bari, Italy

Correspondence to:

Franco Silvestris, email: francesco.silvestris@uniba.it

Keywords: carcinoid, bone metastasis, SDF-1, epithelial-mesenchymal transition, GPCR nuclear translocation

Received: August 31, 2016     Accepted: January 24, 2017     Published: February 06, 2017

ABSTRACT

Neuroendocrine tumors (NETs) metastasize to the skeleton in approximately 20% of patients. We have previously shown that the epithelial-mesenchymal transition (EMT) regulates the NET osteotropism and that CXCR4 overexpression predicts bone spreading. Here, we unravel the molecular mechanisms linking the activation of the CXCL12/CXCR4 axis to the bone colonization of NETs using cell lines representative of pancreatic (BON1, CM, QGP1), intestinal (CNDT 2.5), and bronchial origin (H727). By combining flow cytometry and ELISA, BON1, CM and QGP1 cells were defined as CXCR4high/CXCL12low, while H727 and CNDT 2.5 were CXCR4low/CXCL12high. CXCL12 was inert on cell proliferation, but significantly increased the in vitro osteotropism of CXCR4high/CXCL12low cells, as assessed by transwell assays with or without Matrigel membranes. In these cells, CXCL12 induced in vitro a marked EMT-like transcriptional shift with acquirement of a mesenchymal shape. The nuclei of CXCR4high/CXCL12low NET cells were typically enriched in non-phosphorylated CXCR4, particularly upon agonist stimulation. Silencing of CXCR4 via siRNA prevented the CXCL12-induced EMT in CXCR4high/CXCL12low NET cell lines resulting in the abrogation of both migration and transcriptional mesenchymal patterns. Our data suggest that CXCL12 conveys EMT-promoting signals in NET cells through CXCR4, which in turn regulates transcriptional, morphologic and functional modifications resulting in enhanced in vitro osteotropism of NET cells. Unique functions of CXCR4 may be segregated in relation to its subcellular localization and may acquire potential relevance in future in vivo studies.


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