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, beta1 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.
authors.affiliation: Department of Immunology and Inflammation, IRCCS Clinical Institute Humanitas, Rozzano, Milano, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Marchesi
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Piemonti
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Fedele
authors.forename: Annarita
authors.initials: A
authors.lastname: Destro
authors.forename: Massimo
authors.initials: M
authors.lastname: Roncalli
authors.forename: Luca
authors.initials: L
authors.lastname: Albarello
authors.forename: Claudio
authors.initials: C
authors.lastname: Doglioni
authors.forename: Achille
authors.initials: A
authors.lastname: Anselmo
authors.forename: Andrea
authors.initials: A
authors.lastname: Doni
authors.forename: Paolo
authors.initials: P
authors.lastname: Bianchi
authors.forename: Luigi
authors.initials: L
authors.lastname: Laghi
authors.forename: Alberto
authors.initials: A
authors.lastname: Malesci
authors.forename: Luigi
authors.initials: L
authors.lastname: Cervo
authors.forename: Marialuisa
authors.initials: M
authors.lastname: Malosio
authors.forename: Michele
authors.initials: M
authors.lastname: Reni
authors.forename: Alessandro
authors.initials: A
authors.lastname: Zerbi
authors.forename: Valerio
authors.initials: V
authors.lastname: Di Carlo
authors.forename: Alberto
authors.initials: A
authors.lastname: Mantovani
authors.forename: Paola
authors.initials: P
authors.lastname: Allavena
mesh_terms: D000230:Adenocarcinoma / Q000473:pathology*; D000818:Animals; D000073883:CX3C Chemokine Receptor 1; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002633:Chemotaxis; D019204:GTP-Binding Proteins / Q000502:physiology; D006801:Humans; D007150:Immunohistochemistry; D019012:Integrin beta1 / Q000502:physiology; D051379:Mice; D018613:Microscopy, Confocal; D009420:Nervous System / Q000473:pathology*; D010190:Pancreatic Neoplasms / Q000473:pathology*; D019707:Receptors, Chemokine / Q000502:physiology*
chemical_list: D000073883:CX3C Chemokine Receptor 1; C095235:CX3CR1 protein, human; D019012:Integrin beta1; D019707:Receptors, Chemokine; D019204:GTP-Binding Proteins