Paracrine Regulation of Pancreatic Cancer Cell Invasion by Peripheral Nerves

胶质细胞源性神经生长因子 背根神经节 医学 胰腺癌 神经营养因子 癌症 坐骨神经 病理 内科学 旁侵犯 内分泌学 解剖 受体
作者
Ziv Gil,Oren Cavel,Kaitlyn J. Kelly,Peter Brader,Avigail Rein,Sizhi Paul Gao,Diane L. Carlson,Jatin P. Shah,Yuman Fong,Richard J. Wong
出处
期刊:Journal of the National Cancer Institute [Oxford University Press]
卷期号:102 (2): 107-118 被引量:219
标识
DOI:10.1093/jnci/djp456
摘要

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.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.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.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.
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