Abstract
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. 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. 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. 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.
Highlights
In the 3D migration assay, colon cancer and rectal cancer cells showed much less neuritetargeted migration when compared with pancreatic cancer cells
Neural invasion (NI) is a well-known route of cancer spread in malignant diseases, especially in cancers of the head/neck [1,2,3], prostate [4, 5], and pancreatic cancer [6,7,8,9,10,11,12]
We investigated the activities of the colon cancer cells, the rectal cancer cell CMT-93, the pancreatic cancer cells T3M4 and SU86.86, and the dorsal root ganglia (DRG) via digital time-lapse microscopy over a total observation time of 72 hours per movement front at Â100 magnification
Summary
Neural invasion (NI) is a well-known route of cancer spread in malignant diseases, especially in cancers of the head/neck [1,2,3], prostate [4, 5], and pancreatic cancer [6,7,8,9,10,11,12]. Since its initial recognition in the 19th century, the interest in NI has gradually increased, and recent large-scale studies have identified it as a key pathologic feature with a variable impact on patient prognosis [6, 13]. As a result of intensifying research on NI, the update of the 7th edition of the tumor–node–metastasis (TNM) classification of malig-. Authors' Affiliations: 1Department of Surgery, 2Institute of Medical Statistics and Epidemiology, and 3Institute of Pathology, Klinikum rechts der Isar, Technische Universita€t Mu€nchen, Munich, Germany. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).
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