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 | |
| Publication status | Published - 2016 |
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Keywords
- Chemokine
- Clinical outcome
- Grading
- MTOR
- NET
ASJC Scopus subject areas
- Oncology
Cite this
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
}
TY - JOUR
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
UR - http://www.scopus.com/inward/record.url?scp=84975517640&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84975517640&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.7738
DO - 10.18632/oncotarget.7738
M3 - Article
AN - SCOPUS:84975517640
VL - 7
SP - 18865
EP - 18875
JO - Oncotarget
JF - Oncotarget
SN - 1949-2553
IS - 14
ER -