title: The severity of neural invasion is associated with shortened survival in colon cancer.
abstract: OBJECTIVE
  Neural invasion (NI) is a histopathologic feature of colon cancer that receives little consideration. Therefore, we conducted a morphologic and functional characterization of NI in colon cancer.
  
  
  METHODS
  NI was investigated in 673 patients with colon cancer. Localization and severity of NI was determined and related to patient's prognosis and survival. The neuro-affinity of colon cancer cells (HT29, HCT-116, SW620, and DLD-1) was compared with pancreatic cancer (T3M4 and SU86.86) and rectal cancer cells (CMT-93) in the in vitro three-dimensional (3D)-neural-migration assay and analyzed via live-cell imaging. Immunoreactivity of the neuroplasticity marker GAP-43, and the neurotrophic-chemoattractant factors Artemin and nerve growth factor (NGF), was quantified in colon cancer and pancreatic cancer nerves. Dorsal root ganglia of newborn rats were exposed to supernatants of colon cancer, rectal cancer, and pancreatic cancer cells and neurite density was determined.
  
  
  RESULTS
  NI was detected in 210 of 673 patients (31.2%). Although increasing NI severity scores were associated with a significantly poorer survival, presence of NI was not an independent prognostic factor in colon cancer. In the 3D migration assay, colon cancer and rectal cancer cells showed much less neurite-targeted migration when compared with pancreatic cancer cells. Supernatants of pancreatic cancer and rectal cancer cells induced a much higher neurite density than those of colon cancer cells. Accordingly, NGF, Artemin, and GAP-43 were much more pronounced in nerves in pancreatic cancer than in colon cancer.
  
  
  CONCLUSIONS
  NI is not an independent prognostic factor in colon cancer. The lack of a considerable biologic affinity between colon cancer cells and neurons, the low expression profile of colonic nerves for chemoattractant molecules, and the absence of a major neuroplasticity in colon cancer may explain the low prevalence and impact of NI in colon cancer.
authors.affiliation: Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Liebl
authors.forename: Ihsan Ekin
authors.initials: IE
authors.lastname: Demir
authors.forename: Robert
authors.initials: R
authors.lastname: Rosenberg
authors.forename: Alexandra
authors.initials: A
authors.lastname: Boldis
authors.forename: Esra
authors.initials: E
authors.lastname: Yildiz
authors.forename: Kristina
authors.initials: K
authors.lastname: Kujundzic
authors.forename: Timo
authors.initials: T
authors.lastname: Kehl
authors.forename: Dominic
authors.initials: D
authors.lastname: Dischl
authors.forename: Tibor
authors.initials: T
authors.lastname: Schuster
authors.forename: Matthias
authors.initials: M
authors.lastname: Maak
authors.forename: Karen
authors.initials: K
authors.lastname: Becker
authors.forename: Rupert
authors.initials: R
authors.lastname: Langer
authors.forename: Melanie
authors.initials: M
authors.lastname: Laschinger
authors.forename: Helmut
authors.initials: H
authors.lastname: Friess
authors.forename: Güralp O
authors.initials: GO
authors.lastname: Ceyhan
mesh_terms: D045744:Cell Line, Tumor; D002465:Cell Movement; D003110:Colonic Neoplasms / Q000378:metabolism / Q000401:mortality* / Q000473:pathology*; D006801:Humans; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D009414:Nerve Growth Factors / Q000378:metabolism; D009417:Nerve Tissue / Q000473:pathology*; D009474:Neurons / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology; D011379:Prognosis; D012004:Rectal Neoplasms / Q000378:metabolism / Q000473:pathology; D014407:Tumor Cells, Cultured
chemical_list: D009414:Nerve Growth Factors