Paracrine regulation of pancreatic cancer cell invasion by peripheral nerves Journal Article
| Authors: | Gil, Z.; Cavel, O.; Kelly, K.; Brader, P.; Rein, A.; Gao, S. P.; Carlson, D.; Shah, J. P.; Fong, Y.; Wong, R. J. |
| Article Title: | Paracrine regulation of pancreatic cancer cell invasion by peripheral nerves |
| Abstract: | BackgroundThe ability of cancer to infiltrate along nerves is a common clinical observation in pancreas, head and neck, prostate, breast, and gastrointestinal carcinomas. For these tumors, nerves may provide a conduit for local cancer progression into the central nervous system. Although neural invasion is associated with poor outcome, the mechanism that triggers it is unknown.MethodsWe used an in vitro Matrigel dorsal root ganglion and pancreatic cancer cell coculture model to assess the dynamic interactions between nerves and cancer cell migration and the role of glial cell-derived neurotrophic factor (GDNF). An in vivo murine sciatic nerve model was used to study how nerve invasion affects sciatic nerve function.ResultsNerves induced a polarized neurotrophic migration of cancer cells (PNMCs) along their axons, which was more efficient than in the absence of nerves (migration distance: mean=187.1 μm, 95% confidence interval [CI]=148 to 226 μm vs 14.4 μm, 95% CI = 9.58 to 19.22 μm, difference = 143 μm; P <. 001; n = 20). PNMC was induced by secretion of GDNF, via phosphorylation of the RET-Ras-mitogen-activated protein kinase pathway. Nerves from mice deficient in GDNF had reduced ability to attract cancer cells (nerve invasion index: wild type vs gdnf+/-, mean = 0.76, 95% CI = 0.75 to 0.77 vs 0.43, 95% CI = 0.42 to 0.44; P <. 001; n = 60-66). Tumor specimens excised from patients with neuroinvasive pancreatic carcinoma had higher expression of the GDNF receptors RET and GRFα1 as compared with normal tissue. Finally, systemic therapy with pyrazolopyrimidine-1, a tyrosine kinase inhibitor targeting the RET pathway, suppressed nerve invasion toward the spinal cord and prevented paralysis in mice.ConclusionThese data provide evidence for paracrine regulation of pancreatic cancer invasion by nerves, which may have important implications for potential therapy directed against nerve invasion by cancer. |
| Keywords: | immunohistochemistry; mitogen activated protein kinase; controlled study; human tissue; protein expression; unclassified drug; human cell; nonhuman; pancreatic neoplasms; adenocarcinoma; mouse; animals; mice; animal tissue; animal experiment; animal model; rna, small interfering; rna interference; mice, inbred balb c; transduction, genetic; protein tyrosine kinase inhibitor; pancreas carcinoma; fluorescent antibody technique; enzyme phosphorylation; regulatory mechanism; nerve fiber; nucleotide sequence; newborn; lentivirus; immunoblotting; paracrine signaling; protein secretion; ras protein; invasive carcinoma; neoplasm invasiveness; mitogen-activated protein kinases; protein ret; proto-oncogene proteins c-ret; peripheral nerve; paralysis; coculture; spinal ganglion; glial cell line derived neurotrophic factor; glial cell line derived neurotrophic factor receptor; pyrazolopyrimidine 1; pyrazolopyrimidine derivative; sciatic nerve; ganglia, spinal; glial cell line-derived neurotrophic factor; glial cell line-derived neurotrophic factor receptors; nerve tissue; nervous system neoplasms; paracrine communication |
| Journal Title: | JNCI: Journal of the National Cancer Institute |
| Volume: | 102 |
| Issue: | 2 |
| ISSN: | 0027-8874 |
| Publisher: | Oxford University Press |
| Date Published: | 2010-01-20 |
| Start Page: | 107 |
| End Page: | 118 |
| Language: | English |
| DOI: | 10.1093/jnci/djp456 |
| PUBMED: | 20068194 |
| PROVIDER: | scopus |
| PMCID: | PMC2911041 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 6" - "Export Date: 20 April 2011" - "CODEN: JNCIA" - "Source: Scopus" |
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