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 drug-resistant.
authors.affiliation: Molecolar Immunology and Immuneregulation, Istituto Nazionale per lo Studio e la Cura dei Tumori - IRCCS Naples "Fondazione G. Pascale", Naples, Italy.
authors.forename: Luisa
authors.initials: L
authors.lastname: Circelli
authors.affiliation: Departments of Clinical Medicine and Surgery, "Federico II" University of Naples, Italy.
authors.forename: Concetta
authors.initials: C
authors.lastname: Sciammarella
authors.affiliation: Advanced Biomedical Sciences, Division of Pathology, "Federico II" University of Naples, Italy.
authors.forename: Elia
authors.initials: E
authors.lastname: Guadagno
authors.affiliation: Abdominal Oncology, Istituto Nazionale per lo Studio e la Cura dei Tumori - IRCCS Naples "Fondazione G. Pascale", Naples, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Tafuto
authors.affiliation: Advanced Biomedical Sciences, Division of Pathology, "Federico II" University of Naples, Italy.
authors.forename: Marialaura
authors.initials: M
authors.lastname: del Basso de Caro
authors.affiliation: Molecolar Immunology and Immuneregulation, Istituto Nazionale per lo Studio e la Cura dei Tumori - IRCCS Naples "Fondazione G. Pascale", Naples, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Botti
authors.affiliation: Thyroid and Parathyroid Surgery Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori - IRCCS Naples "Fondazione G. Pascale", Naples, Italy.
authors.forename: Luciano
authors.initials: L
authors.lastname: Pezzullo
authors.affiliation: Economics and Statistics, "Federico II" University of Naples, Naples, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Aria
authors.affiliation: Departments of Clinical Medicine and Surgery, "Federico II" University of Naples, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Ramundo
authors.affiliation: Pathology, Istituto Nazionale per lo Studio e la Cura dei Tumori - IRCCS Naples "Fondazione G. Pascale", Naples, Italy.
authors.forename: Fabiana
authors.initials: F
authors.lastname: Tatangelo
authors.affiliation: Pathology, Istituto Nazionale per lo Studio e la Cura dei Tumori - IRCCS Naples "Fondazione G. Pascale", Naples, Italy.
authors.forename: Nunzia Simona
authors.initials: NS
authors.lastname: Losito
authors.affiliation: Molecolar Immunology and Immuneregulation, Istituto Nazionale per lo Studio e la Cura dei Tumori - IRCCS Naples "Fondazione G. Pascale", Naples, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Ieranò
authors.affiliation: Molecolar Immunology and Immuneregulation, Istituto Nazionale per lo Studio e la Cura dei Tumori - IRCCS Naples "Fondazione G. Pascale", Naples, Italy.
authors.forename: Crescenzo
authors.initials: C
authors.lastname: D'Alterio
authors.affiliation: Abdominal Surgery, Istituto Nazionale per lo Studio e la Cura dei Tumori - IRCCS Naples "Fondazione G. Pascale", Naples, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Izzo
authors.affiliation: Scientific Directorate, Istituto Nazionale per lo Studio e la Cura dei Tumori - IRCCS Naples "Fondazione G. Pascale", Naples, Italy.
authors.forename: Gennaro
authors.initials: G
authors.lastname: Ciliberto
authors.affiliation: Departments of Clinical Medicine and Surgery, "Federico II" University of Naples, Italy.
authors.forename: Annamaria
authors.initials: A
authors.lastname: Colao
authors.affiliation: Thyroid and Parathyroid Surgery Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori - IRCCS Naples "Fondazione G. Pascale", Naples, Italy.
authors.forename: Antongiulio
authors.initials: A
authors.lastname: Faggiano
authors.affiliation: Molecolar Immunology and Immuneregulation, Istituto Nazionale per lo Studio e la Cura dei Tumori - IRCCS Naples "Fondazione G. Pascale", Naples, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Scala
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D054377:Chemokine CXCL12 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D061986:MCF-7 Cells; D008297:Male; D008875:Middle Aged; D018358:Neuroendocrine Tumors / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D054387:Receptors, CXCR / Q000235:genetics / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism*
chemical_list: C501896:ACKR3 protein, human; C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D054387:Receptors, CXCR; D019718:Receptors, CXCR4; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases
keywords: NET; chemokine; clinical outcome; grading; mTOR