CXCR4/CXCL12/CXCR7 axis is functional in neuroendocrine tumors and signals on mTOR

Luisa Circelli, Concetta Sciammarella, Elia Guadagno, Salvatore Tafuto, Marialaura del Basso de Caro, Giovanni Botti, Luciano Pezzullo, Massimo Aria, Valeria Ramundo, Fabiana Tatangelo, Nunzia Simona Losito, Caterina Ieranò, Crescenzo D'Alterio, Francesco Izzo, Gennaro Ciliberto, Annamaria Colao, Antongiulio Faggiano, Stefania Scala

Research output: Contribution to journalArticle

Abstract

Objective: To evaluate the possible crosstalk between C-X-C chemokine receptor 4 (CXCR4)/C-X-C motif chemokine 12 (CXCL12)/C-X-C chemokine receptor 7 (CXCR7) axis with the mammalian target of rapamycin (mTOR) pathway in neuroendocrine tumors (NETs). Methods: Sixty-one human NETs were included into the study. CXCR4/CXCL12/CXCR7 axis and mTOR pathway were assessed by qRT-PCR and immunohistochemistry (IHC). The effect of mTOR inhibitor, RAD001, was evaluated on CXCR4 pathway through proliferation and p-Erk and p-AKT induction. Results: CXCR4/CXCL12/CXCR7 axis and p-mTOR were found to be active and correlated with grading, Ki67 index and tumor stage. mTOR pathway activation significantly correlated with poor prognosis. In human NET cells, CXCL12 induced mTOR signalling while AMD3100 (CXCR4-antagonist) impaired it. The mTOR-antagonist, RAD001, impaired the CXCL12- dependent induction of CXCR4 downstream effectors. Combination of AMD3100 and RAD001 potentiate cell growth inhibition. Conclusions: CXCR4/CXCL12/CXCR7 axis is active in NETs and signals on mTOR. CXCR4 might be considered a prognostic factor in NETs. Combined treatment with AMD3100 and RAD001 may provide clinical benefits in NET patients with drugresistant.

Original languageEnglish
Pages (from-to)18865-18875
Number of pages11
JournalOncotarget
Volume7
Issue number14
DOIs
Publication statusPublished - 2016

Keywords

  • Chemokine
  • Clinical outcome
  • Grading
  • MTOR
  • NET

ASJC Scopus subject areas

  • Oncology

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  • Cite this

    Circelli, L., Sciammarella, C., Guadagno, E., Tafuto, S., de Caro, M. D. B., Botti, G., Pezzullo, L., Aria, M., Ramundo, V., Tatangelo, F., Losito, N. S., Ieranò, C., D'Alterio, C., Izzo, F., Ciliberto, G., Colao, A., Faggiano, A., & Scala, S. (2016). CXCR4/CXCL12/CXCR7 axis is functional in neuroendocrine tumors and signals on mTOR. Oncotarget, 7(14), 18865-18875. https://doi.org/10.18632/oncotarget.7738