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Upregulation of RET induces perineurial invasion of pancreatic adenocarcinoma
- Source :
- Oncogene. 36(23)
- Publication Year :
- 2016
-
Abstract
- Tumor spread along nerves, a phenomenon known as perineurial invasion, is common in various cancers including pancreatic ductal adenocarcinoma (PDAC). Neural invasion is associated with poor outcome, yet its mechanism remains unclear. Using the transgenic Pdx-1-Cre/KrasG12D /p53R172H (KPC) mouse model, we investigated the mechanism of neural invasion in PDAC. To detect tissue-specific factors that influence neural invasion by cancer cells, we characterized the perineurial microenvironment using a series of bone marrow transplantation (BMT) experiments in transgenic mice expressing single mutations in the Cx3cr1, GDNF and CCR2 genes. Immunolabeling of tumors in KPC mice of different ages and analysis of human cancer specimens revealed that RET expression is upregulated during PDAC tumorigenesis. BMT experiments revealed that BM-derived macrophages expressing the RET ligand GDNF are highly abundant around nerves invaded by cancer. Inhibition of perineurial macrophage recruitment, using the CSF-1R antagonist GW2580 or BMT from CCR2-deficient donors, reduced perineurial invasion. Deletion of GDNF expression by perineurial macrophages, or inhibition of RET with shRNA or a small-molecule inhibitor, reduced perineurial invasion in KPC mice with PDAC. Taken together, our findings show that RET is upregulated during pancreas tumorigenesis and its activation induces cancer perineurial invasion. Trafficking of BM-derived macrophages to the perineurial microenvironment and secretion of GDNF are essential for pancreatic cancer neural spread.
- Subjects :
- 0301 basic medicine
Cancer Research
endocrine system diseases
Apoptosis
Biology
Adenocarcinoma
medicine.disease_cause
Nervous System
03 medical and health sciences
Mice
0302 clinical medicine
Pancreatic cancer
Genetics
medicine
Glial cell line-derived neurotrophic factor
Tumor Cells, Cultured
Animals
Humans
Neoplasm Invasiveness
Molecular Biology
Cell Proliferation
Macrophages
Proto-Oncogene Proteins c-ret
Cancer
medicine.disease
Mice, Inbred C57BL
Pancreatic Neoplasms
030104 developmental biology
medicine.anatomical_structure
030220 oncology & carcinogenesis
Cancer cell
Immunology
Cancer research
biology.protein
Female
Pancreas
Carcinogenesis
Carcinoma, Pancreatic Ductal
Subjects
Details
- ISSN :
- 14765594
- Volume :
- 36
- Issue :
- 23
- Database :
- OpenAIRE
- Journal :
- Oncogene
- Accession number :
- edsair.doi.dedup.....ed1fe3bcfc288e16e4a4980667b29ecb