Radiation impairs perineural invasion by modulating the nerve microenvironment

• Published in: PloS one Vol. 7; no. 6; p. e39925
• Main Authors: Bakst, Richard L, Lee, Nancy, He, Shuangba, Chernichenko, Natalya, Chen, Chun-Hao, Linkov, Gary, Le, H Carl, Koutcher, Jason, Vakiani, Efsevia, Wong, Richard J
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 29-06-2012; Public Library of Science (PLoS)
• Subjects: Animal models; Animals; Biology; Brain-derived neurotrophic factor; Cancer; Cancer therapies; Carcinoma, Adenoid Cystic - metabolism; Carcinoma, Adenoid Cystic - pathology; Cell culture; Cell Line, Tumor; Cell Movement - drug effects; Cell Survival - drug effects; Cell Survival - radiation effects; Cellular Microenvironment - drug effects; Clinical medicine; Coculture Techniques; Dorsal root ganglia; Dose-Response Relationship, Radiation; Experimental design; Ganglia; Ganglia, Spinal - drug effects; Ganglia, Spinal - pathology; Ganglia, Spinal - radiation effects; Glial cell line-derived neurotrophic factor; Glial Cell Line-Derived Neurotrophic Factor - pharmacology; Glial Cell Line-Derived Neurotrophic Factor - secretion; Health aspects; Health physics; Histology; Humans; Implantation; In vivo methods and tests; Inhibition; Kinases; Male; Medicine; Mice; Mice, Inbred BALB C; Neoplasm Invasiveness; Nerve Tissue - drug effects; Nerve Tissue - pathology; Nerve Tissue - radiation effects; Nerves; Nervous system; Neuronal-glial interactions; Pancreatic cancer; Paracrine signalling; Pathogenesis; Preservation; Prognosis; Prostate cancer; Proto-Oncogene Proteins c-ret - metabolism; Radiation; Radiation (Physics); Radiation dosage; Radiation therapy; Radiotherapy; Rodents; Sciatic nerve; Sciatic Nerve - drug effects; Sciatic Nerve - pathology; Sciatic Nerve - radiation effects; Secretion; Studies; Surgery; Surgical implants; New York; United States > US
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0039925

Perineural invasion (PNI) by cancer cells is an ominous clinical event that is associated with increased local recurrence and poor prognosis. Although radiation therapy (RT) may be delivered along the course of an invaded nerve, the mechanisms through which radiation may potentially control PNI remain undefined.
An in vitro co-culture system of dorsal root ganglia (DRG) and pancreatic cancer cells was used as a model of PNI. An in vivo murine sciatic nerve model was used to study how RT to nerve or cancer affects nerve invasion by cancer.
Cancer cell invasion of the DRG was partially dependent on DRG secretion of glial-derived neurotrophic factor (GDNF). A single 4 Gy dose of radiation to the DRG alone, cultured with non-radiated cancer cells, significantly inhibited PNI and was associated with decreased GDNF secretion but intact DRG viability. Radiation of cancer cells alone, co-cultured with non-radiated nerves, inhibited PNI through predominantly compromised cancer cell viability. In a murine model of PNI, a single 8 Gy dose of radiation to the sciatic nerve prior to implantation of non-radiated cancer cells resulted in decreased GDNF expression, decreased PNI by imaging and histology, and preservation of sciatic nerve motor function.
Radiation may impair PNI through not only direct effects on cancer cell viability, but also an independent interruption of paracrine mechanisms underlying PNI. RT modulation of the nerve microenvironment may decrease PNI, and hold significant therapeutic implications for RT dosing and field design for patients with cancers exhibiting PNI.