PMID- 26934559 OWN - NLM STAT- MEDLINE DCOM- 20170131 LR - 20211203 IS - 1949-2553 (Electronic) IS - 1949-2553 (Linking) VI - 7 IP - 14 DP - 2016 Apr 5 TI - CXCR4/CXCL12/CXCR7 axis is functional in neuroendocrine tumors and signals on mTOR. PG - 18865-75 LID - 10.18632/oncotarget.7738 [doi] 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 drug-resistant. FAU - Circelli, Luisa AU - Circelli L AD - Molecolar Immunology and Immuneregulation, Istituto Nazionale per lo Studio e la Cura dei Tumori - IRCCS Naples "Fondazione G. Pascale", Naples, Italy. FAU - Sciammarella, Concetta AU - Sciammarella C AD - Departments of Clinical Medicine and Surgery, "Federico II" University of Naples, Italy. FAU - Guadagno, Elia AU - Guadagno E AD - Advanced Biomedical Sciences, Division of Pathology, "Federico II" University of Naples, Italy. FAU - Tafuto, Salvatore AU - Tafuto S AD - Abdominal Oncology, Istituto Nazionale per lo Studio e la Cura dei Tumori - IRCCS Naples "Fondazione G. Pascale", Naples, Italy. FAU - del Basso de Caro, Marialaura AU - del Basso de Caro M AD - Advanced Biomedical Sciences, Division of Pathology, "Federico II" University of Naples, Italy. FAU - Botti, Giovanni AU - Botti G AD - Molecolar Immunology and Immuneregulation, Istituto Nazionale per lo Studio e la Cura dei Tumori - IRCCS Naples "Fondazione G. Pascale", Naples, Italy. FAU - Pezzullo, Luciano AU - Pezzullo L AD - Thyroid and Parathyroid Surgery Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori - IRCCS Naples "Fondazione G. Pascale", Naples, Italy. FAU - Aria, Massimo AU - Aria M AD - Economics and Statistics, "Federico II" University of Naples, Naples, Italy. FAU - Ramundo, Valeria AU - Ramundo V AD - Departments of Clinical Medicine and Surgery, "Federico II" University of Naples, Italy. FAU - Tatangelo, Fabiana AU - Tatangelo F AD - Pathology, Istituto Nazionale per lo Studio e la Cura dei Tumori - IRCCS Naples "Fondazione G. Pascale", Naples, Italy. FAU - Losito, Nunzia Simona AU - Losito NS AD - Pathology, Istituto Nazionale per lo Studio e la Cura dei Tumori - IRCCS Naples "Fondazione G. Pascale", Naples, Italy. FAU - Ierano, Caterina AU - Ierano C AD - Molecolar Immunology and Immuneregulation, Istituto Nazionale per lo Studio e la Cura dei Tumori - IRCCS Naples "Fondazione G. Pascale", Naples, Italy. FAU - D'Alterio, Crescenzo AU - D'Alterio C AD - Molecolar Immunology and Immuneregulation, Istituto Nazionale per lo Studio e la Cura dei Tumori - IRCCS Naples "Fondazione G. Pascale", Naples, Italy. FAU - Izzo, Francesco AU - Izzo F AD - Abdominal Surgery, Istituto Nazionale per lo Studio e la Cura dei Tumori - IRCCS Naples "Fondazione G. Pascale", Naples, Italy. FAU - Ciliberto, Gennaro AU - Ciliberto G AD - Scientific Directorate, Istituto Nazionale per lo Studio e la Cura dei Tumori - IRCCS Naples "Fondazione G. Pascale", Naples, Italy. FAU - Colao, Annamaria AU - Colao A AD - Departments of Clinical Medicine and Surgery, "Federico II" University of Naples, Italy. FAU - Faggiano, Antongiulio AU - Faggiano A AD - Thyroid and Parathyroid Surgery Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori - IRCCS Naples "Fondazione G. Pascale", Naples, Italy. FAU - Scala, Stefania AU - Scala S AD - Molecolar Immunology and Immuneregulation, Istituto Nazionale per lo Studio e la Cura dei Tumori - IRCCS Naples "Fondazione G. Pascale", Naples, Italy. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - United States TA - Oncotarget JT - Oncotarget JID - 101532965 RN - 0 (ACKR3 protein, human) RN - 0 (CXCL12 protein, human) RN - 0 (CXCR4 protein, human) RN - 0 (Chemokine CXCL12) RN - 0 (Receptors, CXCR) RN - 0 (Receptors, CXCR4) RN - EC 2.7.1.1 (MTOR protein, human) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) SB - IM MH - Adult MH - Aged MH - Aged, 80 and over MH - Cell Line, Tumor MH - Cell Proliferation/physiology MH - Chemokine CXCL12/genetics/*metabolism MH - Humans MH - Immunohistochemistry MH - MCF-7 Cells MH - Male MH - Middle Aged MH - Neuroendocrine Tumors/genetics/*metabolism/pathology MH - Receptors, CXCR/genetics/*metabolism MH - Receptors, CXCR4/genetics/*metabolism MH - Signal Transduction MH - TOR Serine-Threonine Kinases/*genetics/*immunology/*metabolism PMC - PMC4951335 OTO - NOTNLM OT - NET OT - chemokine OT - clinical outcome OT - grading OT - mTOR COIS- CONFLICTS OF INTEREST The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported. EDAT- 2016/03/05 06:00 MHDA- 2017/02/01 06:00 PMCR- 2016/04/05 CRDT- 2016/03/03 06:00 PHST- 2015/09/18 00:00 [received] PHST- 2016/01/06 00:00 [accepted] PHST- 2016/03/03 06:00 [entrez] PHST- 2016/03/05 06:00 [pubmed] PHST- 2017/02/01 06:00 [medline] PHST- 2016/04/05 00:00 [pmc-release] AID - 7738 [pii] AID - 10.18632/oncotarget.7738 [doi] PST - ppublish SO - Oncotarget. 2016 Apr 5;7(14):18865-75. doi: 10.18632/oncotarget.7738.