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Perineural invasion in colorectal cancer: mechanisms of action and clinical relevance - PubMed

Review

Perineural invasion in colorectal cancer: mechanisms of action and clinical relevance

Hao Wang et al. Cell Oncol (Dordr). 2024 Feb.

Abstract

Background: In recent years, the significance of the nervous system in the tumor microenvironment has gained increasing attention. The bidirectional communication between nerves and cancer cells plays a critical role in tumor initiation and progression. Perineural invasion (PNI) occurs when tumor cells invade the nerve sheath and/or encircle more than 33% of the nerve circumference. PNI is a common feature in various malignancies and is associated with tumor invasion, metastasis, cancer-related pain, and unfavorable clinical outcomes. The colon and rectum are highly innervated organs, and accumulating studies support PNI as a histopathologic feature of colorectal cancer (CRC). Therefore, it is essential to investigate the role of nerves in CRC and comprehend the mechanisms of PNI to impede tumor progression and improve patient survival.

Conclusion: This review elucidates the clinical significance of PNI, summarizes the underlying cellular and molecular mechanisms, introduces various experimental models suitable for studying PNI, and discusses the therapeutic potential of targeting this phenomenon. By delving into the intricate interactions between nerves and tumor cells, we hope this review can provide valuable insights for the future development of CRC treatments.

Keywords: Colorectal innervation; Neurotrophins; Perineural invasion; Prognosis; Tumor microenvironment.

© 2023. The Author(s).

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Conflict of interest statement

The authors declare that no personal relationships or conflict of interests influence the work reported in this paper.

Figures

Fig. 1
Fig. 1

Extrinsic and intrinsic innervation of the colorectal tract. Extrinsic innervation incorporates sympathetic and parasympathetic/vagal input from the CNS. Intrinsic innervation is provided by the ENS, which innervates the entire gut wall via enteric neurons and enteric glial cells. Abbreviations: CNS, central nervous system; ENS, enteric nervous system; SMP, submucosal plexus; CM, circular muscle; MP, myenteric plexus; LM, longitudinal muscle

Fig. 2
Fig. 2

Perineural invasion in human colorectal cancer specimens. (A, B) Sections are stained with hematoxylin and eosin (H&E). Tumor cells surround and locate within the peripheral nerve sheath; (C) The expression of pan-neuronal marker PGP9.5 is detected by immunohistochemical. Asterisks indicate nerve fibers; arrows point to cancer cells invade to nerves sheath

Fig. 3
Fig. 3

The partial interaction mechanism between CRC cell and neurons. Neural cells could secret neurotrophic factors such as NGF, BDNF, and GDNF, which act on corresponding receptors TrkA, TrkB, and GFRα, thus promoting tumor proliferation and invasion. In turn, tumor cells release axon guidance molecules Slit2 and SEMA3D, which bind to receptors Robo1 and PlexinD1, inducing neurite outgrowth. Transmembrane proteins NCAM and L1CAM facilitate tumor-nerve adhesion, providing a possible route for PNI. Sympathetic and parasympathetic neurotransmitters act on adrenergic receptor and cholinergic receptor respectively, regulating tumor cell proliferation and progression

Fig. 4
Fig. 4

Cellular crosstalk in the TME. Schwann cells regulate tumor cell proliferation, invasion, and PNI through membrane protein (NCAM) and secretory proteins (TGF-β, LICAM, IL-8, NGF). Tumor cells and Schwann cells secrete CSF-1 or CCL2 to recruit macrophages to the site of PNI, which aggravates nerve injury and tumor invasion. In turn, macrophages release GDNF, promoting cancer migration. Macrophages also secret Slit3, which guides Schwann cells and fibroblasts in forming a peripheral nerve bridge during nerve injury. Both macrophages and fibroblasts can release LIF, which promotes Schwann cell migration and neural plasticity. Fibroblasts also stimulate Schwann cell proliferation and neural remodeling via secreting Slit2. Additionally, the combination of CXCL12 and CXCR4 induces Schwann cell migration and infiltration

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