Colorectal Cancer Cells Adhere to and Migrate Along the Neurons of the Enteric Nervous System

Abstract

Background & AimsIn several types of cancers, tumor cells invade adjacent tissues by migrating along the resident nerves of the tumor microenvironment. This process, called perineural invasion, typically occurs along extrinsic nerves, with Schwann cells providing physical guidance for the tumor cells. However, in the colorectal cancer microenvironment, the most abundant nervous structures belong to the nonmyelinated intrinsic enteric nervous system (ENS). In this study, we investigated whether colon cancer cells interact with the ENS.MethodsTumor epithelial cells (TECs) from human primary colon adenocarcinomas and cell lines were cocultured with primary cultures of ENS and cultures of human ENS plexus explants. By combining confocal and atomic force microscopy, as well as video microscopy, we assessed tumor cell adhesion and migration on the ENS. We identified the adhesion proteins involved using a proteomics approach based on biotin/streptavidin interaction, and their implication was confirmed further using selective blocking antibodies.ResultsTEC adhered preferentially and with stronger adhesion forces to enteric nervous structures than to mesenchymal cells. TEC adhesion to ENS involved direct interactions with enteric neurons. Enteric neuron removal from ENS cultures led to a significant decrease in tumor cell adhesion. TECs migrated significantly longer and further when adherent on ENS compared with on mesenchymal cells, and their trajectory faithfully followed ENS structures. Blocking N-cadherin and L1CAM decreased TEC migration along ENS structures.ConclusionsOur data show that the enteric neuronal network guides tumor cell migration, partly via L1CAM and N-cadherin. These results open a new avenue of research on the underlying mechanisms and consequences of perineural invasion in colorectal cancer.

Clinicopathological Analysis and Prognostic Assessment of Transcobalamin I (TCN1) in Patients with Colorectal Tumors

“…Nerve invasion was also a risk factor for patient survival in this study. The enteric neural network guides tumor cell migration, in part through the L1 cell adhesion molecule (L1CAM) and N-cadherin [ 28 ]. These results open new avenues to study the underlying mechanisms and progression of nerve invasion by CRC.…”

L1CAM as an E-selectin Ligand in Colon Cancer

“…Furthermore, blocking L1CAM decreases adherence and migration of tumor cells from colon adenocarcinoma to the nervous system showing involvement of L1CAM in perineural invasion in CRC. [ 81 ]. In our study, we showed that an increase in sLe X led to high E-selectin ligand expression and, curiously, resulted in increased L1CAM levels in SW620FUT6 cells.…”

The Emerging Role of Nerves and Glia in Colorectal Cancer

“…PNI, however, is believed to arise via extrinsic nerve bundles from the PNS [ 39 ]; a physical interaction between enteric neurons and CRC cells has been described. Enteric neurons express N-cadherin and L1CAM, which were identified as important molecules for the adhesion and migration of CRC cells [ 40 ]. However, deletion of these molecules did not completely abrogate PNI, suggesting that other (unknown) molecules must be involved as well.…”

“…Moreover, activation of AMPA-receptors on glioma cells stimulates the release of glutamate from the glioma cells themselves, thereby activating AMPA-receptors in an autocrine fashion and further activating neurons. Although there is currently no evidence for functional synapses between neurons and CRC cells, enteric neurons have been observed in close proximity to tumor cells [ 40 ]. Moreover, increased glutamate receptor expression has been associated with CRC [ 68 ].…”