title: Endoneurial macrophages induce perineural invasion of pancreatic cancer cells by secretion of GDNF and activation of RET tyrosine kinase receptor.
abstract: Perineural invasion of cancer cells (CPNI) is found in most patients with pancreatic adenocarcinomas (PDA), prostate, or head and neck cancers. These patients undergo palliative rather than curative treatment due to dissemination of cancer along nerves, well beyond the extent of any local invasion. Although CPNI is a common source of distant tumor spread and a cause of significant morbidity, its exact mechanism is undefined. Immunohistochemical analysis of specimens excised from patients with PDAs showed a significant increase in the number of endoneurial macrophages (EMΦ) that lie around nerves invaded by cancer compared with normal nerves. Video microscopy and time-lapse analysis revealed that EMΦs are recruited by the tumor cells in response to colony-stimulated factor-1 secreted by invading cancer cells. Conditioned medium (CM) of tumor-activated EMΦs (tEMΦ) induced a 5-fold increase in migration of PDA cells compared with controls. Compared with resting EMΦs, tEMΦs secreted higher levels of glial-derived neurotrophic factor (GDNF), inducing phosphorylation of RET and downstream activation of extracellular signal-regulated kinases (ERK) in PDA cells. Genetic and pharmacologic inhibition of the GDNF receptors GFRA1 and RET abrogated the migratory effect of EMΦ-CM and reduced ERK phosphorylation. In an in vivo CPNI model, CCR2-deficient mice that have reduced macrophage recruitment and activation showed minimal nerve invasion, whereas wild-type mice developed complete sciatic nerve paralysis due to massive CPNI. Taken together, our results identify a paracrine response between EMΦs and PDA cells that orchestrates the formation of cancer nerve invasion.
authors.affiliation: The Laboratory for Applied Cancer Research, Department of Pathology, Tel Aviv Medical Center, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Oren
authors.initials: O
authors.lastname: Cavel
authors.forename: Olga
authors.initials: O
authors.lastname: Shomron
authors.forename: Ayelet
authors.initials: A
authors.lastname: Shabtay
authors.forename: Joseph
authors.initials: J
authors.lastname: Vital
authors.forename: Leonor
authors.initials: L
authors.lastname: Trejo-Leider
authors.forename: Noam
authors.initials: N
authors.lastname: Weizman
authors.forename: Yakov
authors.initials: Y
authors.lastname: Krelin
authors.forename: Yuman
authors.initials: Y
authors.lastname: Fong
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Wong
authors.forename: Moran
authors.initials: M
authors.lastname: Amit
authors.forename: Ziv
authors.initials: Z
authors.lastname: Gil
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D004789:Enzyme Activation; D005260:Female; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000378:metabolism*; D006801:Humans; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009361:Neoplasm Invasiveness; D009420:Nervous System / Q000473:pathology*; D010190:Pancreatic Neoplasms / Q000201:enzymology* / Q000473:pathology*; D051096:Proto-Oncogene Proteins c-ret / Q000378:metabolism*; D017154:Stromal Cells / Q000473:pathology
chemical_list: C495039:GDNF protein, human; D051100:Glial Cell Line-Derived Neurotrophic Factor; D016173:Macrophage Colony-Stimulating Factor; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human