Up-regulation of glial cell line-derived neurotrophic factor (GDNF) following traumatic spinal cord injury

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 (EMÈ) that lie around nerves invaded by cancer compared with normal nerves. Video microscopy and time-lapse analysis revealed that EMÈs are recruited by the tumor cells in response to colony-stimulated factor-1 secreted by invading cancer cells. Conditioned medium (CM) of tumoractivated EMÈs (tEMÈ) induced a 5-fold increase in migration of PDA cells compared with controls. Compared with resting EMÈs, tEMÈs 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 EMÈ-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 EMÈs and PDA cells that orchestrates the formation of cancer nerve invasion. Cancer Res; 72(22); 5733-43. Ó2012 AACR.

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“…5A). This finding is in agreement with previous data showing an increase in GDNF secretion by activated EMÈ (37)(38)(39)(40).…”

Section: Emès Induce Pda Migration By Secretion Of Gdnf and Activatiosupporting

confidence: 94%

Endoneurial Macrophages Induce Perineural Invasion of Pancreatic Cancer Cells by Secretion of GDNF and Activation of RET Tyrosine Kinase Receptor

et al. 2012

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“…Our data indicated that grafted NIH3T3-TG persisted and secreted GDNF in the injured spinal cord 3 wk after transplantation. An immediate upregulation of GDNF transcript after SCI followed by an increase in its protein expression in microglia and macrophages 1 d after injury have been reported (31), suggesting that endogenous GDNF could provide neuronal protection after the insult. GDNF detected 3 wk after transplantation was most likely secreted by the engrafted NIH3T3-TG cells.…”

Section: Discussionmentioning

confidence: 89%

A Novel Cell-Based Therapy for Contusion Spinal Cord Injury Using GDNF-Delivering NIH3T3 Cells with Dual Reporter Genes Monitored by Molecular Imaging

Lo¹,

Hsu²,

et al. 2008

J Nucl Med

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This aim of our study was to evaluate a novel cell-based therapy for contusion spinal cord injury (SCI) using embryonic-derived NIH3T3 cells, which endogenously express glial cell line-derived neurotrophic factor (GDNF). Methods: Proliferation and differentiation of transplanted NIH3T3 cells and their anti-apoptotic effects were examined after their engraftment into the spinal cords of Long-Evans rats subjected to acute SCI at the T10 vertebral level by a New York University impactor device. NIH3T3 cells were initially engineered to contain dual reporter genes, namely thymidine kinase (T) and enhanced green fluorescence protein (G), for in vivo cell tracking by both nuclear and fluorescence imaging modalities. Results: Planar and fluorescence imaging demonstrated that transplanted NIH3T3-TG cells at the L1 vertebral level migrated 2 cm distal to the injury site as early as 2 h, and the signals persisted for 48 h after SCI. The expression of GDNF by NIH3T3-TG cells was then confirmed by immunohistochemical analysis both in vitro and in vivo. GDNFsecreting NIH3T3-TG transplant provided anti-apoptotic effects in the injured cord over the period of 3 wk. Finally, NIH3T3-TG cells cultured under neuronal differentiation medium exhibited both morphologic and genetic resemblance to neuronal cells. Conclusion: GDNF-secreting NIH3T3-TG cells in combination with molecular imaging could be a platform for developing therapeutic tools for acute SCI.

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“…Up-regulation of GDNF by astrocytes or microglial cells occurs in several injury models (Liberatore et al, 1997;Batchelor et al, 1999;Bresjanac and Antauer, 2000;Satake et al, 2000;Wei et al, 2000;Miyazaki et al, 2001;Ikeda et al, 2002;Marco et al, 2002;Hashimoto et al, 2005a). This switch in the production of GDNF from neurons to glial cells may provide a local mechanism to limit neuronal loss and promote regeneration.…”

Section: Gdnf Expression Upon Nigrostriatal Injury: Role Of Neuronglimentioning

confidence: 99%

Driving GDNF expression: The green and the red traffic lights

Saavedra

Baltazar

Duarte

2008

Progress in Neurobiology

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Up-regulation of glial cell line-derived neurotrophic factor (GDNF) following traumatic spinal cord injury

Cited by 94 publications

References 6 publications

Endoneurial Macrophages Induce Perineural Invasion of Pancreatic Cancer Cells by Secretion of GDNF and Activation of RET Tyrosine Kinase Receptor

Endoneurial Macrophages Induce Perineural Invasion of Pancreatic Cancer Cells by Secretion of GDNF and Activation of RET Tyrosine Kinase Receptor

A Novel Cell-Based Therapy for Contusion Spinal Cord Injury Using GDNF-Delivering NIH3T3 Cells with Dual Reporter Genes Monitored by Molecular Imaging

Driving GDNF expression: The green and the red traffic lights

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