Radiation impairs perineural invasion by modulating the nerve microenvironment Journal Article


Authors: Bakst, R. L.; Lee, N.; He, S.; Chernichenko, N.; Chen, C. H.; Linkov, G.; Le, H. C.; Koutcher, J.; Vakiani, E.; Wong, R. J.
Article Title: Radiation impairs perineural invasion by modulating the nerve microenvironment
Abstract: Purpose: 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. Experimental Design: 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. Results: 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. Conclusions: 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. © 2012 Bakst et al.
Keywords: human cell; nonhuman; cancer radiotherapy; radiation dose; animal cell; mouse; animals; mice; cell viability; cell survival; radiation; in vivo study; neuromodulation; in vitro study; cell line, tumor; mice, inbred balb c; histology; dose-response relationship, radiation; cancer invasion; brain derived neurotrophic factor; cancer cell; murinae; paracrine signaling; cell movement; pancreas adenocarcinoma; neoplasm invasiveness; motor performance; proto-oncogene proteins c-ret; carcinoma, adenoid cystic; perineural invasion; coculture; coculture techniques; tumor microenvironment; spinal ganglion; sciatic nerve; ganglia, spinal; glial cell line-derived neurotrophic factor; nerve tissue; cellular microenvironment
Journal Title: PLoS ONE
Volume: 7
Issue: 6
ISSN: 1932-6203
Publisher: Public Library of Science  
Date Published: 2012-01-01
Start Page: e39925
Language: English
DOI: 10.1371/journal.pone.0039925
PROVIDER: scopus
PMCID: PMC3386941
PUBMED: 22768171
DOI/URL:
Notes: --- - "Export Date: 1 August 2012" - "Source: Scopus"
Altmetric Score
MSK Authors
  1. Nancy Y. Lee
    550 Lee
  2. Richard J Wong
    230 Wong
  3. Richard L Bakst
    15 Bakst
  4. Chun-Hao Chen
    35 Chen
  5. Hongbiao Carl Lekaye
    24 Lekaye
  6. Jason A Koutcher
    235 Koutcher
  7. Shuangba He
    11 He
  8. Efsevia Vakiani
    164 Vakiani
  9. Gary Linkov
    6 Linkov