Investigation of Schwann cells at neoplastic cell sites before the onset of cancer invasion

J Natl Cancer Inst. 2014 Aug 8;106(8):dju184. doi: 10.1093/jnci/dju184. Print 2014 Aug.


Background: In neural invasion (NI), cancer cells are classically assumed to actively invade nerves and to cause local recurrence and pain. However, the opposite possibility, that nerves may reach cancer cells even in their preinvasive stage and thereby promote cancer spread, has not yet been genuinely considered. The present study analyzes the reaction of Schwann cells of peripheral nerves to carcinogenesis in pancreatic cancer and colon cancer.

Methods: Two novel 3D migration and Schwann cell outgrowth assays were developed to monitor the timing and the specificity of Schwann cell migration and cancer invasion toward peripheral neurons through digital-time-lapse microscopy and after blockade of nerve growth factor (NGF) signalling via siRNA or a small-molecule inhibitor of the p75(NTR) receptor. The frequency and emergence of the Schwann cell markers Sox10, S100, ALDH1L1, and glial-fibrillary-acidic-protein (GFAP) around cancer precursor lesions were studied in human and conditional murine pancreatic and colon cancer specimens using multiple immunolabeling.

Results: Schwann cells migrated toward pancreatic and colon cancer cells, but not toward benign cells, before the onset of cancer migration toward peripheral neurons. This chemoattraction was inhibited after blockade of p75(NTR)-signaling on Schwann and pancreatic cancer cells. Schwann cells were specifically detected around murine and human pancreatic intraepithelial neoplasias (PanINs) (mean percent of murine PanINs surrounded by Schwann cells = 78.9%, 95% CI = 70.9 to 86.8%, and mean percent of human PanINs surrounded by Schwann cells = 52.5%, 95% CI = 14.7 to 90.4%; human: n = 44, murine: n = 14) and intestinal adenomas (mean percent of murine adenomas surrounded by Schwann cells = 64.2%, 95% CI = 28.6 to 99.8%, and mean percent of human adenomas surrounded by Schwann cells = 17.2%, 95% CI = -126.9 to 161.4; human: n = 36, murine: n = 12). The Schwann cell presence in this premalignant stage was associated with the frequency of NI in the malignant phase.

Conclusions: Schwann cells have particular and specific affinity to cancer cells. Emergence of Schwann cells in the premalignant phase of pancreatic and colon cancer implies that, in contrast with the traditional assumption, nerves-and not cancer cells-migrate first during NI.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aldehyde Dehydrogenase / metabolism
  • Aldehyde Dehydrogenase 1 Family
  • Animals
  • Cell Movement*
  • Colonic Neoplasms / metabolism
  • Colonic Neoplasms / pathology*
  • Glial Fibrillary Acidic Protein
  • Humans
  • Immunohistochemistry
  • Isoenzymes / metabolism
  • Mice
  • Neoplasm Invasiveness
  • Nerve Tissue Proteins / metabolism
  • Oxidoreductases Acting on CH-NH Group Donors
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Neoplasms / pathology*
  • Precancerous Conditions / metabolism
  • Precancerous Conditions / pathology*
  • Retinal Dehydrogenase / metabolism
  • S100 Proteins / metabolism
  • SOXE Transcription Factors / metabolism
  • Schwann Cells / metabolism
  • Schwann Cells / pathology*


  • Glial Fibrillary Acidic Protein
  • Isoenzymes
  • Nerve Tissue Proteins
  • S100 Proteins
  • SOX10 protein, human
  • SOXE Transcription Factors
  • Sox10 protein, mouse
  • glial fibrillary astrocytic protein, mouse
  • Aldehyde Dehydrogenase 1 Family
  • Aldehyde Dehydrogenase
  • ALDH1A1 protein, human
  • ALDH1A1 protein, mouse
  • Retinal Dehydrogenase
  • Oxidoreductases Acting on CH-NH Group Donors
  • formyltetrahydrofolate dehydrogenase