Radiation impairs perineural invasion by modulating the nerve microenvironment

PLoS One. 2012;7(6):e39925. doi: 10.1371/journal.pone.0039925. Epub 2012 Jun 29.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Carcinoma, Adenoid Cystic / metabolism
  • Carcinoma, Adenoid Cystic / pathology
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Survival / drug effects
  • Cell Survival / radiation effects
  • Cellular Microenvironment* / drug effects
  • Coculture Techniques
  • Dose-Response Relationship, Radiation
  • Ganglia, Spinal / drug effects
  • Ganglia, Spinal / pathology*
  • Ganglia, Spinal / radiation effects*
  • Glial Cell Line-Derived Neurotrophic Factor / metabolism
  • Glial Cell Line-Derived Neurotrophic Factor / pharmacology
  • Humans
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Neoplasm Invasiveness
  • Nerve Tissue / drug effects
  • Nerve Tissue / pathology*
  • Nerve Tissue / radiation effects*
  • Proto-Oncogene Proteins c-ret / metabolism
  • Radiation*
  • Sciatic Nerve / drug effects
  • Sciatic Nerve / pathology
  • Sciatic Nerve / radiation effects

Substances

  • Glial Cell Line-Derived Neurotrophic Factor
  • Proto-Oncogene Proteins c-ret