Oncotarget

Research Papers:

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 _

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Oncotarget. 2016; 7:18865-18875. https://doi.org/10.18632/oncotarget.7738

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Abstract

Luisa Circelli1,*, Concetta Sciammarella2,*, Elia Guadagno3, Salvatore Tafuto4, Marialaura del Basso de Caro3, Giovanni Botti1, Luciano Pezzullo5, Massimo Aria6, Valeria Ramundo2, Fabiana Tatangelo7, Nunzia Simona Losito7, Caterina Ieranò1, Crescenzo D’Alterio1, Francesco Izzo8, Gennaro Ciliberto9, Annamaria Colao2, Antongiulio Faggiano5, Stefania Scala1

1Molecolar Immunology and Immuneregulation, Istituto Nazionale per lo Studio e la Cura dei Tumori - IRCCS Naples “Fondazione G. Pascale”, Naples, Italy

2Departments of Clinical Medicine and Surgery, “Federico II” University of Naples, Italy

3Advanced Biomedical Sciences, Division of Pathology, “Federico II” University of Naples, Italy

4Abdominal Oncology, Istituto Nazionale per lo Studio e la Cura dei Tumori - IRCCS Naples “Fondazione G. Pascale”, Naples, Italy

5Thyroid and Parathyroid Surgery Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori - IRCCS Naples “Fondazione G. Pascale”, Naples, Italy

6Economics and Statistics, “Federico II” University of Naples, Naples, Italy

7Pathology, Istituto Nazionale per lo Studio e la Cura dei Tumori - IRCCS Naples “Fondazione G. Pascale”, Naples, Italy

8Abdominal Surgery, Istituto Nazionale per lo Studio e la Cura dei Tumori - IRCCS Naples “Fondazione G. Pascale”, Naples, Italy

9Scientific Directorate, Istituto Nazionale per lo Studio e la Cura dei Tumori - IRCCS Naples “Fondazione G. Pascale”, Naples, Italy

*These authors have contributed equally to this work

Correspondence to:

Stefania Scala, e-mail: s.scala@istitutotumori.na.it

Antongiulio Faggiano, e-mail: afaggian@unina.it

Keywords: chemokine, mTOR, NET, clinical outcome, grading

Received: September 18, 2015     Accepted: January 06, 2016     Published: February 26, 2016

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 drug-resistant.

Author Information

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
Primary Contact  _


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