Journal
PANCREAS
Volume 47, Issue 7, Pages 856-863Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/MPA.0000000000001090
Keywords
inflammation; metastasis; nerve growth factor; pancreatic ductal adenocarcinoma; perineural invasion
Categories
Funding
- National Cancer Institute [CA177857]
- Hirshberg Foundation
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Objectives In patients with pancreatic ductal adenocarcinoma (PDAC), increased expression of proinflammatory neurotrophic growth factors (eg, nerve growth factor [NGF]) correlates with a poorer prognosis, perineural invasion, and, with regard to NGF, pain severity. We hypothesized that NGF sequestration would reduce inflammation and disease in the KPC mouse model of PDAC. Methods Following biweekly injections of NGF antibody or control immunoglobulin G, beginning at 4 or 8 weeks of age, inflammation and disease stage were assessed using histological, protein expression, and quantitative polymerase chain reaction analyses. Results In the 8-week anti-NGF group, indicators of neurogenic inflammation in the dorsal root ganglia (substance P and calcitonin gene-related peptide) and spinal cord (glial fibrillary acidic protein) were significantly reduced. In the 4-week anti-NGF group, TRPA1 mRNA in dorsal root ganglia and spinal phosphorylated ERK protein were elevated, but glial fibrillary acidic protein expression was unaffected. In the 8-week anti-NGF group, there was a 40% reduction in the proportion of mice with microscopic perineural invasion, and no macrometastases were observed. Conclusions Anti-NGF treatment beginning at 4 weeks may increase inflammation and negatively impact disease. Treatment starting at 8 weeks (after disease onset), however, reduces neural inflammation, neural invasion, and metastasis. These data indicate that NGF impacts PDAC progression and metastasis in a temporally dependent manner.
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