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.
Highlights
Pancreatic ductal adenocarcinoma (PDAC), the fourth leading cause of cancer-related deaths in the Western world, is a highly aggressive and chemoresistant disease, with a 5-year survival rateNote: Supplementary data for this article are available at Cancer Research Online.F
In the context of a transcriptional profiling aimed at exploring the chemokine system in pancreatic cancer, we found that the chemokine receptor CX3CR1 is up-regulated in selected PDAC cell lines
In PDAC patients, high receptor expression is associated with a marked perineural invasion and with earlier local tumor recurrence, supporting the concept that CX3CR1 is an important determinant of tumor neurotropism and malignant behavior in pancreatic cancer
Summary
Pancreatic ductal adenocarcinoma (PDAC), the fourth leading cause of cancer-related deaths in the Western world, is a highly aggressive and chemoresistant disease, with a 5-year survival rate. Members of the glial cell–derived neurotrophic factor family, including Artemin, were shown to favor pancreatic cancer invasion of peripheral nerves [10] and promote the growth and survival of neoplastic cells [11]. Chemokines and their receptors have been implicated in tumor growth and tumor cell invasion of surrounding organs. In PDAC patients, high receptor expression is associated with a marked perineural invasion and with earlier local tumor recurrence, supporting the concept that CX3CR1 is an important determinant of tumor neurotropism and malignant behavior in pancreatic cancer
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
