CXCR4/CXCL12/CXCR7 Axis is Functional in Neuroendocrine Tumors and Signals on MTOR

Overview

Journal Oncotarget

Specialty Oncology

Date 2016 Mar 3

PMID 26934559

Citations 21

Authors

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 Ierano

Crescenzo DAlterio

Francesco Izzo

Gennaro Ciliberto

Annamaria Colao

Antongiulio Faggiano

Stefania Scala

Affiliations

Soon will be listed here.

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.

Citing Articles

CXCR4: From Signaling to Clinical Applications in Neuroendocrine Neoplasms.

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PMID: 38791878 PMC: 11120359. DOI: 10.3390/cancers16101799.

Expression and clinical value of CXCR4 in high grade gastroenteropancreatic neuroendocrine neoplasms.

Pang C, Li Y, Shi M, Fan Z, Gao X, Meng Y Front Endocrinol (Lausanne). 2024; 15:1281622.

PMID: 38524630 PMC: 10960360. DOI: 10.3389/fendo.2024.1281622.

Mechanisms of Resistance in Gastroenteropancreatic Neuroendocrine Tumors.

Shi C, Morse M Cancers (Basel). 2022; 14(24).

PMID: 36551599 PMC: 9776394. DOI: 10.3390/cancers14246114.

Immunohistochemical expression of chemokine receptor in neuroendocrine neoplasms (CXCR4) of the gastrointestinal tract: a retrospective study of 71 cases.

Popa O, Taban S, Dema A, Plopeanu A, Barna R, Cornianu M Rom J Morphol Embryol. 2021; 62(1):151-157.

PMID: 34609417 PMC: 8597374. DOI: 10.47162/RJME.62.1.14.

CXCR4-Directed PET/CT in Patients with Newly Diagnosed Neuroendocrine Carcinomas.

Weich A, Werner R, Buck A, Hartrampf P, Serfling S, Scheurlen M Diagnostics (Basel). 2021; 11(4).

PMID: 33805264 PMC: 8067200. DOI: 10.3390/diagnostics11040605.

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