Paracrine regulation of pancreatic cancer cell invasion by peripheral nerves.
BACKGROUND
The 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.


METHODS
We 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.


RESULTS
Nerves 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 microm, 95% confidence interval [CI] = 148 to 226 microm vs 14.4 microm, 95% CI = 9.58 to 19.22 microm, difference = 143 microm; 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 GRFalpha1 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.


CONCLUSIONS
These 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.
Gil
Ziv
Z
Department of Otolaryngology, Head and Neck Surgery, Tel Aviv Sourasky Medical Center, 6 Weizmann St, Tel Aviv, 64239, Israel. gilz@tasmc.health.gov.il
Cavel
Oren
O
Kelly
Kaitlyn
K
Brader
Peter
P
Rein
Avigail
A
Gao
Sizhi P
SP
Carlson
Diane L
DL
Shah
Jatin P
JP
Fong
Yuman
Y
Wong
Richard J
RJ
D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology; D000818:Animals; D005455:Fluorescent Antibody Technique; D005727:Ganglia, Spinal / Q000378:metabolism / Q000473:pathology; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D016086:Lentivirus; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009417:Nerve Tissue / Q000378:metabolism* / Q000473:pathology; D009423:Nervous System Neoplasms / Q000378:metabolism* / Q000556:secondary*; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D019899:Paracrine Communication; D051096:Proto-Oncogene Proteins c-ret / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D012584:Sciatic Nerve / Q000378:metabolism / Q000473:pathology; D014161:Transduction, Genetic
C494987:GFRA1 protein, human; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D034741:RNA, Small Interfering; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human; D020928:Mitogen-Activated Protein Kinases