Comprehensive characterization of tumor innervation in colorectal cancer

Purpose Complex innervation occurs at colorectal cancer (CRC) sites, and these nerves play a certain role in the occurrence and development of tumors. This study aimed to reveal the morphological changes in the nervous system in CRC and the corresponding clinical relevance of these changes. Methods The neurofilament-specific marker NF-L and glial cell-specific marker S100β were used to define infiltrated nerves by immunofluorescence analysis in a CRC cohort (n = 155). Neural density and diameter at off-tumor and on-tumor sites (including core regions and peritumoral regions) were quantified. Results In CRC, tumor cells frequently erode surrounding nerves, causing interruption of the submucosal and muscular plexus, as well as deformation of nerve fibers. Compared to off-tumor sites, on-tumor sites showed decreased nerve density and increased nerve diameter. At on-tumor sites, the nerve density at the core region was significantly lower than the peritumoral nerve density. According to the subgroup analysis, KRAS mutations were associated with decreased nerve density in the core region. The presence of perineural invasion (PNI) was associated with larger nerve diameters and greater nerve densities in the core region. As the tumor size increased, the nerve density decreased in both the core and peritumoral regions. With increasing T stage (infiltration depth) from T1 to T3, the nerve diameter increased in both the core and peritumoral regions, while the opposite trend was found for the peritumoral nerve density. Similar results were also found for stages I to III (AJCC stage). In patients with metastasis (M1 or stage IV), the nerve density increased in the core region. Conclusion Our study revealed the landscape of innervation in CRC and its clinical associations, thus providing a reference for subsequent mechanistic research on nerve-cancer interactions and the development of nerve-based antitumor drugs.