Synapse - Inflammatory monocytes promote perineural invasion via CCL2-mediated recruitment and cathepsin B expression

Inflammatory monocytes promote perineural invasion via CCL2-mediated recruitment and cathepsin B expression Journal Article

Authors:	Bakst, R. L.; Xiong, H.; Chen, C. H.; Deborde, S.; Lyubchik, A.; Zhou, Y.; He, S.; McNamara, W.; Lee, S. Y.; Olson, O. C.; Leiner, I. M.; Marcadis, A. R.; Keith, J. W.; Al-Ahmadie, H. A.; Katabi, N.; Gil, Z.; Vakiani, E.; Joyce, J. A.; Pamer, E.; Wong, R. J.
Article Title:	Inflammatory monocytes promote perineural invasion via CCL2-mediated recruitment and cathepsin B expression
Abstract:	Perineural invasion (PNI) is an ominous event strongly linked to poor clinical outcome. Cells residing within peripheral nerves collaborate with cancer cells to enable PNI, but the contributing conditions within the tumor microenvironment are not well understood. Here, we show that CCR2-expressing inflammatory monocytes (IM) are preferentially recruited to sites of PNI, where they differentiate into macrophages and potentiate nerve invasion through a cathepsin B–mediated process. A series of adoptive transfer experiments with genetically engineered donors and recipients demonstrated that IM recruitment to nerves was driven by CCL2 released from Schwann cells at the site of PNI, but not CCL7, an alternate ligand for CCR2. Interruption of either CCL2–CCR2 signaling or cathepsin B function significantly impaired PNI in vivo. Correlative studies in human specimens demonstrated that cathepsin B–producing macrophages were enriched in invaded nerves, which was associated with increased local tumor recurrence. These findings deepen our understanding of PNI pathogenesis and illuminate how PNI is driven in part by corruption of a nerve repair program. Further, they support the exploration of inhibiting IM recruitment and function as a targeted therapy for PNI. ©2017 AACR.
Keywords:	signal transduction; controlled study; human tissue; protein expression; human cell; major clinical study; genetics; pathogenesis; cancer growth; nonhuman; pancreatic neoplasms; animal cell; mouse; animal; metabolism; animals; mice, knockout; animal tissue; cell line; animal experiment; animal model; inflammation; in vivo study; pathology; cell line, tumor; mice, inbred c57bl; c57bl mouse; immune response; xenograft; nude mouse; mice, nude; tumor recurrence; pancreas tumor; tumor cell line; neoplasms, experimental; transplantation, heterologous; cell migration; innate immunity; neoplasm invasiveness; tumor promotion; experimental neoplasm; cathepsin b; schwann cell; peripheral nerves; c57bl 6 mouse; monocyte; monocytes; monocyte chemotactic protein 3; macrophage; macrophages; peripheral nerve; nerve regeneration; chemokine receptor ccr2; receptors, ccr2; perineural invasion; monocyte chemotactic protein 1; chemokine ccl2; knockout mouse; tumor microenvironment; schwann cells; tumor invasion; humans; human; priority journal; article; kpc cell line; mia paca-2 cell line; panc02 cell line
Journal Title:	Cancer Research
Volume:	77
Issue:	22
ISSN:	0008-5472
Publisher:	American Association for Cancer Research
Date Published:	2017-11-15
Start Page:	6400
End Page:	6414
Language:	English
DOI:	10.1158/0008-5472.can-17-1612
PUBMED:	28951461
PROVIDER:	scopus
PMCID:	PMC5831809
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85033771852&doi=10.1158%2f0008-5472.CAN-17-1612&partnerID=40&md5=708bf9acdf97d010ed9d1d64b45561c1
Notes:	Article -- Export Date: 2 January 2018 -- Source: Scopus