Neuroepithelial Interactions in Cancer

Abstract

Nerves not only regulate the homeostasis and energetic metabolism of normal epithelial cells but also are critical for cancer, as cancer recapitulates the biology of neural regulation of epithelial tissues. Cancer cells rarely develop in denervated organs, and denervation affects tumorigenesis, in vivo and in humans. Axonogenesis occurs to supply the new malignant epithelial growth with nerves. Neurogenesis happens later, first in ganglia around organs or the spinal column and subsequently through recruitment of neuroblasts from the central nervous system. The hallmark of this stage is regulation of homeostasis and energetic metabolism. Perineural invasion is the most efficient interaction between cancer cells and nerves. The hallmark of this stage is increased proliferation and decreased apoptosis. Finally, carcinoma cells transdifferentiate into a neuronal profile in search of neural independence. The latter is the last stage in neuroepithelial interactions. Treatments for cancer must address the biology of neural regulation of cancer. Expected final online publication date for the Annual Review of Pathology: Mechanisms of Disease, Volume 18 is January 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

A CRISPR/Cas9-Based Assay for High-Throughput Studies of Cancer-Induced Innervation

“…The interactions between the nervous system and cancer are reciprocal, and the neuro-epithelial interface established during cancer innervation needs to be further explored to develop new anti-cancer therapies that account for the neuronal component of cancer [ 3 , 6 , 12 ]. Cancer innervation is composed of two distinguishable processes: perineural invasion (PNI) and cancer neurogenesis (CNG) [ 13 ].…”

“…Perineural invasion consists in the infiltration of cancer cells around preexisting nerves, which is commonly observed in cancers located in highly innervated tissues such as pancreatic cancer, [ 14 ] prostate cancer, [ 15 ] head and neck cancer, [ 13 ] and colorectal cancer [ 16 ]. During perineural invasion, cancer cells establish a new nerve-cancer interface by stimulating neuronal cells, which sprout into the cancer stroma to form a new intratumoral network [ 12 ]. Cancer tissue can also induce phenotypic changes in the neurons that innervated the original tissue.…”

“…The crosstalk between neurons and cancer cells can occur through direct or indirect interactions and can even be mediated by various elements of the cancer microenvironment [ 6 ]. Cancer cells have been observed to produce neurotropic and axon guidance molecules, which promote the growth of intratumoral axons [ 12 , 13 , 15 , 19 , 20 ]. Their functions in cancer biology depend on multiple factors, including the type of cancer, the nature of the involved neurons, and the mechanisms leading to their aberrant expression in cancer cells will require further investigation [ 21 , 22 , 23 ].…”

“…Their functions in cancer biology depend on multiple factors, including the type of cancer, the nature of the involved neurons, and the mechanisms leading to their aberrant expression in cancer cells will require further investigation [ 21 , 22 , 23 ]. Seminal studies have implicated the role of Semaphorins in cancer-induced neurogenesis and aggressivity [ 12 , 15 , 24 ], and in our previous study, we identified the TGFβ pathway as a mediator of cancer innervation, promoting the expression of the Semaphorin-4F in breast cancer cells and leading to increased cancer innervation associated with enhanced metastasis [ 19 ]. ER-stress has also been recently identified to promote the production of proBDNF in human prostate, colon, and pancreatic cancer and is linked to cancer innervation [ 25 ].…”

“…Additional studies demonstrated how other axon guidance molecules are involved in cancer innervation, such as Plexin B3 produced by breast cancer cells [ 26 ] or EphrinB1 secreted by head and neck squamous cell carcinoma through exosomes [ 13 ]. Overall, in the growing field of cancer neuroscience, while several mechanisms have been identified, there is still a need to prospect for the exact mechanisms and how they can vary according to the biological context [ 12 , 27 ]. Importantly, potential therapeutic targets associated with cancer innervation will require further investigation, and the development of new and accurate assays to study their impact on cancer innervation and how they can be disrupted therapeutically is essential.…”