The chemokine receptor CX3CR1 is involved in the neural tropism and malignant behavior of pancreatic ductal adenocarcinoma

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Abstract

Tumor perineural dissemination is a hallmark of human pancreatic ductal adenocarcinoma (PDAC) and represents a major source of local tumor recurrence after surgery. In this study, we provide in vitro and in vivo evidence that the chemokine receptor CX3CR1 may be involved in the neurotropism of PDAC cells to local peripheral nerves. Neoplastic cells from PDAC cell lines and surgical specimens express the chemokine receptor CX3CR1, absent in normal pancreatic ducts. Its unique ligand, the transmembrane chemokine CX3CL1, is expressed by neurons and nerve fibers. CX3CR1 + PDAC cell lines migrated in response to human recombinant CX3CL1 and specifically adhered to CX3CL1-expressing cells of neural origin via mechanisms involving activation of G proteins, β1 integrins, and focal adhesion kinase. In vivo experiments with transplanted PDAC showed that only CX3CR1-transfected tumor cells infiltrated the local peripheral nerves. Immunohistochemistry of CX3CR1 in PDAC specimens revealed that 90% of the samples were positive with a heterogeneous pattern of expression. High receptor score was significantly associated with more prominent tumor perineural infiltration evaluated histologically (P = 0.026). Regression analyses (univariate and multivariate) showed that high CX3CR1 expression and perineural invasion were strongly associated with local and earlier tumor recurrence (P = 0.007). Collectively, this study shows that the CX3CR1 receptor may be involved in PDAC tumor neurotropism and is a relevant and independent risk factor to predict an early local tumor relapse in resected patients. Thus, the CX3CR1-CX3CL1 axis could represent a valuable therapeutic target to prevent tumor perineural dissemination in pancreatic cancer.

Original languageEnglish
Pages (from-to)9060-9069
Number of pages10
JournalCancer Research
Volume68
Issue number21
DOIs
Publication statusPublished - Nov 1 2008

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Tropism
Chemokine Receptors
Adenocarcinoma
Neoplasms
Peripheral Nerves
Recurrence
Focal Adhesion Kinase 1
Chemokine CX3CL1
Cell Line
Pancreatic Ducts
Pancreatic Neoplasms
Nerve Fibers
GTP-Binding Proteins
Integrins
Immunohistochemistry
Regression Analysis
Ligands
Neurons

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

@article{e56367cd8a5b403297e7c5b9ac18a5ee,
title = "The chemokine receptor CX3CR1 is involved in the neural tropism and malignant behavior of pancreatic ductal adenocarcinoma",
abstract = "Tumor perineural dissemination is a hallmark of human pancreatic ductal adenocarcinoma (PDAC) and represents a major source of local tumor recurrence after surgery. In this study, we provide in vitro and in vivo evidence that the chemokine receptor CX3CR1 may be involved in the neurotropism of PDAC cells to local peripheral nerves. Neoplastic cells from PDAC cell lines and surgical specimens express the chemokine receptor CX3CR1, absent in normal pancreatic ducts. Its unique ligand, the transmembrane chemokine CX3CL1, is expressed by neurons and nerve fibers. CX3CR1 + PDAC cell lines migrated in response to human recombinant CX3CL1 and specifically adhered to CX3CL1-expressing cells of neural origin via mechanisms involving activation of G proteins, β1 integrins, and focal adhesion kinase. In vivo experiments with transplanted PDAC showed that only CX3CR1-transfected tumor cells infiltrated the local peripheral nerves. Immunohistochemistry of CX3CR1 in PDAC specimens revealed that 90{\%} of the samples were positive with a heterogeneous pattern of expression. High receptor score was significantly associated with more prominent tumor perineural infiltration evaluated histologically (P = 0.026). Regression analyses (univariate and multivariate) showed that high CX3CR1 expression and perineural invasion were strongly associated with local and earlier tumor recurrence (P = 0.007). Collectively, this study shows that the CX3CR1 receptor may be involved in PDAC tumor neurotropism and is a relevant and independent risk factor to predict an early local tumor relapse in resected patients. Thus, the CX3CR1-CX3CL1 axis could represent a valuable therapeutic target to prevent tumor perineural dissemination in pancreatic cancer.",
author = "Federica Marchesi and Lorenzo Piemonti and Giuseppe Fedele and Annarita Destro and Massimo Roncalli and Luca Albarello and Claudio Doglioni and Achille Anselmo and Andrea Doni and Paolo Bianchi and Luigi Laghi and Alberto Malesci and Luigi Cervo and MariaLuisa Malosio and Michele Reni and Alessandro Zerbi and {Di Carlo}, Valerio and Alberto Mantovani and Paola Allavena",
year = "2008",
month = "11",
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doi = "10.1158/0008-5472.CAN-08-1810",
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pages = "9060--9069",
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T1 - The chemokine receptor CX3CR1 is involved in the neural tropism and malignant behavior of pancreatic ductal adenocarcinoma

AU - Marchesi, Federica

AU - Piemonti, Lorenzo

AU - Fedele, Giuseppe

AU - Destro, Annarita

AU - Roncalli, Massimo

AU - Albarello, Luca

AU - Doglioni, Claudio

AU - Anselmo, Achille

AU - Doni, Andrea

AU - Bianchi, Paolo

AU - Laghi, Luigi

AU - Malesci, Alberto

AU - Cervo, Luigi

AU - Malosio, MariaLuisa

AU - Reni, Michele

AU - Zerbi, Alessandro

AU - Di Carlo, Valerio

AU - Mantovani, Alberto

AU - Allavena, Paola

PY - 2008/11/1

Y1 - 2008/11/1

N2 - Tumor perineural dissemination is a hallmark of human pancreatic ductal adenocarcinoma (PDAC) and represents a major source of local tumor recurrence after surgery. In this study, we provide in vitro and in vivo evidence that the chemokine receptor CX3CR1 may be involved in the neurotropism of PDAC cells to local peripheral nerves. Neoplastic cells from PDAC cell lines and surgical specimens express the chemokine receptor CX3CR1, absent in normal pancreatic ducts. Its unique ligand, the transmembrane chemokine CX3CL1, is expressed by neurons and nerve fibers. CX3CR1 + PDAC cell lines migrated in response to human recombinant CX3CL1 and specifically adhered to CX3CL1-expressing cells of neural origin via mechanisms involving activation of G proteins, β1 integrins, and focal adhesion kinase. In vivo experiments with transplanted PDAC showed that only CX3CR1-transfected tumor cells infiltrated the local peripheral nerves. Immunohistochemistry of CX3CR1 in PDAC specimens revealed that 90% of the samples were positive with a heterogeneous pattern of expression. High receptor score was significantly associated with more prominent tumor perineural infiltration evaluated histologically (P = 0.026). Regression analyses (univariate and multivariate) showed that high CX3CR1 expression and perineural invasion were strongly associated with local and earlier tumor recurrence (P = 0.007). Collectively, this study shows that the CX3CR1 receptor may be involved in PDAC tumor neurotropism and is a relevant and independent risk factor to predict an early local tumor relapse in resected patients. Thus, the CX3CR1-CX3CL1 axis could represent a valuable therapeutic target to prevent tumor perineural dissemination in pancreatic cancer.

AB - Tumor perineural dissemination is a hallmark of human pancreatic ductal adenocarcinoma (PDAC) and represents a major source of local tumor recurrence after surgery. In this study, we provide in vitro and in vivo evidence that the chemokine receptor CX3CR1 may be involved in the neurotropism of PDAC cells to local peripheral nerves. Neoplastic cells from PDAC cell lines and surgical specimens express the chemokine receptor CX3CR1, absent in normal pancreatic ducts. Its unique ligand, the transmembrane chemokine CX3CL1, is expressed by neurons and nerve fibers. CX3CR1 + PDAC cell lines migrated in response to human recombinant CX3CL1 and specifically adhered to CX3CL1-expressing cells of neural origin via mechanisms involving activation of G proteins, β1 integrins, and focal adhesion kinase. In vivo experiments with transplanted PDAC showed that only CX3CR1-transfected tumor cells infiltrated the local peripheral nerves. Immunohistochemistry of CX3CR1 in PDAC specimens revealed that 90% of the samples were positive with a heterogeneous pattern of expression. High receptor score was significantly associated with more prominent tumor perineural infiltration evaluated histologically (P = 0.026). Regression analyses (univariate and multivariate) showed that high CX3CR1 expression and perineural invasion were strongly associated with local and earlier tumor recurrence (P = 0.007). Collectively, this study shows that the CX3CR1 receptor may be involved in PDAC tumor neurotropism and is a relevant and independent risk factor to predict an early local tumor relapse in resected patients. Thus, the CX3CR1-CX3CL1 axis could represent a valuable therapeutic target to prevent tumor perineural dissemination in pancreatic cancer.

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U2 - 10.1158/0008-5472.CAN-08-1810

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