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

doi:10.18632/oncotarget.7738

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

Istituto Nazionale Tumori Fondazione G. Pascale

Research output: Contribution to journal › Article

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 language	English
Pages (from-to)	18865-18875
Number of pages	11
Journal	Oncotarget
Volume	7
Issue number	14
DOIs	https://doi.org/10.18632/oncotarget.7738
Publication status	Published - 2016

Keywords

Chemokine
Clinical outcome
Grading
MTOR
NET

ASJC Scopus subject areas

Oncology

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10.18632/oncotarget.7738

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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

CXCR4/CXCL12/CXCR7 axis is functional in neuroendocrine tumors and signals on mTOR. / Circelli, Luisa; Sciammarella, Concetta; Guadagno, Elia; Tafuto, Salvatore; de Caro, Marialaura del Basso; Botti, Giovanni; Pezzullo, Luciano; Aria, Massimo; Ramundo, Valeria; Tatangelo, Fabiana ; Losito, Nunzia Simona ; Ieranò, Caterina; D'Alterio, Crescenzo; Izzo, Francesco ; Ciliberto, Gennaro; Colao, Annamaria; Faggiano, Antongiulio; Scala, Stefania.

In: Oncotarget, Vol. 7, No. 14, 2016, p. 18865-18875.

Research output: Contribution to journal › Article

Circelli, L, Sciammarella, C, Guadagno, E, Tafuto, S, de Caro, MDB, Botti, G, Pezzullo, L, Aria, M, Ramundo, V, Tatangelo, F , Losito, NS , 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, vol. 7, no. 14, pp. 18865-18875. https://doi.org/10.18632/oncotarget.7738

Circelli, Luisa ; Sciammarella, Concetta ; Guadagno, Elia ; Tafuto, Salvatore ; de Caro, Marialaura del Basso ; Botti, Giovanni ; Pezzullo, Luciano ; Aria, Massimo ; Ramundo, Valeria ; Tatangelo, Fabiana ; Losito, Nunzia Simona ; Ieranò, Caterina ; D'Alterio, Crescenzo ; Izzo, Francesco ; Ciliberto, Gennaro ; Colao, Annamaria ; Faggiano, Antongiulio ; Scala, Stefania. / CXCR4/CXCL12/CXCR7 axis is functional in neuroendocrine tumors and signals on mTOR. In: Oncotarget. 2016 ; Vol. 7, No. 14. pp. 18865-18875.

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title = "CXCR4/CXCL12/CXCR7 axis is functional in neuroendocrine tumors and signals on mTOR",

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.",

keywords = "Chemokine, Clinical outcome, Grading, MTOR, NET",

author = "Luisa Circelli and Concetta Sciammarella and Elia Guadagno and Salvatore Tafuto and {de Caro}, {Marialaura del Basso} and Giovanni Botti and Luciano Pezzullo and Massimo Aria and Valeria Ramundo and Fabiana Tatangelo and Losito, {Nunzia Simona} and Caterina Ieran{\`o} and Crescenzo D'Alterio and Francesco Izzo and Gennaro Ciliberto and Annamaria Colao and Antongiulio Faggiano and Stefania Scala",

year = "2016",

doi = "10.18632/oncotarget.7738",

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T1 - CXCR4/CXCL12/CXCR7 axis is functional in neuroendocrine tumors and signals on mTOR

AU - Circelli, Luisa

AU - Sciammarella, Concetta

AU - Guadagno, Elia

AU - Tafuto, Salvatore

AU - de Caro, Marialaura del Basso

AU - Botti, Giovanni

AU - Pezzullo, Luciano

AU - Aria, Massimo

AU - Ramundo, Valeria

AU - Tatangelo, Fabiana

AU - Losito, Nunzia Simona

AU - Ieranò, Caterina

AU - D'Alterio, Crescenzo

AU - Izzo, Francesco

AU - Ciliberto, Gennaro

AU - Colao, Annamaria

AU - Faggiano, Antongiulio

AU - Scala, Stefania

PY - 2016

Y1 - 2016

N2 - 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.

AB - 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.

KW - Chemokine

KW - Clinical outcome

KW - Grading

KW - MTOR

KW - NET

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