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.
Highlights
Solid tumors disseminate in 4 main ways: direct invasion, lymphatic spread, hematogenic spread, and through nerves
As pancreatic ductal adenocarcinoma (PDA) cells express glial-derived neurotrophic factor (GDNF) receptors, and given that previous data suggested that GDNF is involved in cancer perineural invasion (CPNI), we investigated the secretion of GDNF by resting EMÈs, A
As recombinant human GDNF induced migration of MiaPaCa2 cells at similar doses (Fig. 5B), we further investigated the involvement of the GDNF receptor GDNF family receptor a-1 (GFRa1) in PDA cells migration by using siRNA oligonucleotides directed against expression of GFRa1 (Fig. 5C) MiaPaCa2 cells transfected with siGFRa1 exhibited a significant decrease in cancer cell migration compared with noncoding siRNA (Fig. 5D)
Summary
Solid tumors disseminate in 4 main ways: direct invasion, lymphatic spread, hematogenic spread, and through nerves. The spread of cancer cells along nerves is a frequent pathologic finding and a significant cause of morbidity and mortality [1], conferring poor prognosis to patients with carcinomas of the gastrointestinal tracts, head and neck, pancreas, and prostate [2]. Authors' Affiliations: 1The Laboratory for Applied Cancer Research, 2Department of Pathology, Tel Aviv Medical Center, Tel Aviv University, Tel Aviv, Israel; 3Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York; and 4Department of Otolaryngology Head and Neck Surgery, Rambam Medical Center, Rappaport School of Medicine, the Technion-Israel Insitute of Technology, Haifa, Israel. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).
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