title: Radiation impairs perineural invasion by modulating the nerve microenvironment.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors: Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.
authors: Richard L
authors: RL
authors: Bakst
authors: Nancy
authors: N
authors: Lee
authors: Shuangba
authors: S
authors: He
authors: Natalya
authors: N
authors: Chernichenko
authors: Chun-Hao
authors: CH
authors: Chen
authors: Gary
authors: G
authors: Linkov
authors: H Carl
authors: HC
authors: Le
authors: Jason
authors: J
authors: Koutcher
authors: Efsevia
authors: E
authors: Vakiani
authors: Richard J
authors: RJ
authors: Wong
mesh_terms: D000818:Animals; D003528:Carcinoma, Adenoid Cystic / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D060833:Cellular Microenvironment / Q000187:drug effects; D018920:Coculture Techniques; D004307:Dose-Response Relationship, Radiation; D005727:Ganglia, Spinal / Q000187:drug effects / Q000473:pathology* / Q000528:radiation effects*; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009361:Neoplasm Invasiveness; D009417:Nerve Tissue / Q000187:drug effects / Q000473:pathology* / Q000528:radiation effects*; D051096:Proto-Oncogene Proteins c-ret / Q000378:metabolism; D011827:Radiation; D012584:Sciatic Nerve / Q000187:drug effects / Q000473:pathology / Q000528:radiation effects
chemical_list: D051100:Glial Cell Line-Derived Neurotrophic Factor; D051096:Proto-Oncogene Proteins c-ret