Targeting Perineural Invasion in Pancreatic Cancer

Abstract

Pancreatic cancer is an aggressive tumor with dismal prognosis. Neural invasion is one of the pathological hallmarks of pancreatic cancer. Peripheral nerves can modulate the phenotype and behavior of the malignant cells, as well as of different components of the tumor microenvironment, and thus affect tumor growth and metastasis. From a clinical point of view, neural invasion is translated into intractable pain and represents a predictor of tumor recurrence and poor prognosis. Several molecules are implicated in neural invasion and pain onset in PDAC, including neutrophins (e.g., NGF), chemokines, adhesion factors, axon-guidance molecules, different proteins, and neurotransmitters. In this review, we discuss the role of nerves within the pancreatic cancer microenvironment, highlighting how infiltrating nerve fibers promote tumor progression and metastasis, while tumor cells, in turn, drive nerve outgrowth in a reciprocal interaction that fuels tumor advancement. We outline key molecules involved in neural invasion in pancreatic cancer and, finally, explore potential therapeutic strategies to target neural invasion, aiming to both inhibit cancer progression and alleviate cancer-associated pain.

Keywords: cancer pain; neural invasion; pancreatic ductal adenocarcinoma; tumor microenvironment.

Figure 1

Innervation of pancreatic cancer. In pancreatic ductal adenocarcinoma, nerve fibers include axons originating from sympathetic and parasympathetic nerve fibers, sensory afferent nerve fibers, and also nerve fibers from the enteric nervous system. Neurotransmitters are released from parasympathetic fibers (ACH), sympathetic fibers (NE), sensory fibers (SP, CGRP), and enteric fibers (ACH, serotonin). Abbreviations: NE, noradrenaline; ACH, acetylcholine; SP, substance P; CGRP, calcitonin gene-related peptide. Created in BioRender. Garajova, I. (2024). https://BioRender.com/r29r619 (accessed on 11 December 2024).

Figure 2

Tumor cells can be present in different spaces of the neuron sheath, including the endoneurium, perineurium, or epineurium. Created in BioRender. Garajova, I. (2024). https://BioRender.com/i31r247 (accessed on 11 December 2024).

Figure 3

NGF/TrkA signaling pathway in PDAC. NGF acts on TrkA receptor and p75NTR receptors with subsequent activation of different signaling pathways. Abbreviations: TrkA, tropomyosin receptor kinase A; TrkB, tropomyosin receptor kinase B; TrkC, tropomyosin receptor kinase C; neurotrophin-3 (NT-3); neurotrophin-4/5 (NT-4/5); GDNF, glial-derived neurotrophic factor; NGF, nerve growth factor; MAPK, mitogen-activated protein kinase; PI3K, phosphatidylinositol-3-kinase; PLCγ, phospholipase Cγ; JNK, c-Jun N-terminal kinase; NF-κB, nuclear factor-κB; BDNF, brain-derived neurotrophic factor. Created in BioRender. Garajova, I. (2024). https://BioRender.com/s57o562 (accessed on 11 December 2024).

Figure 4

Activation of TRPV1 in sensory nerves by NGF. TRPV1 is expressed by sensory afferents that have cell bodies in vagus nerve, trigeminal ganglia, and dorsal root ganglia. TRPV1 activation initiates downstream signaling of three major pathways including PI3K, TAK-1, and JAK signaling pathways. TRPV1 activation is required for release of neuropeptides such as SP and CGRP. Abbreviations: TRPV1, transient receptor potential vanilloid; PI3K, phosphatidylinositol-3-kinase; TAK-1, transforming growth factor-activated kinase 1; JAK, Janus kinase; SP, substance P; CGRP, calcitonin gene-related peptide. Created in BioRender. Garajova, I. (2024). https://BioRender.com/z29w911 (accessed on 11 December 2024).

Figure 5

The nerves in the pancreatic cancer tumor microenvironment. The nerves influence other components of the tumor microenvironment, in particular cancer cells, immune cells, fibroblasts, and endothelial cells. Created in BioRender. Garajova, I. (2024). https://BioRender.com/k18n399 (accessed on 11 December 2024).

Figure 6

Molecules involved in neural invasion. Several molecules are involved in neural invasion in PDAC, including neutrophins, adhesion factors, proteins, chemokines, axon-guidance molecules, neurotransmitters, and neuropeptides. Created in BioRender. Garajova, I. (2024). https://BioRender.com/k54v075 (accessed on 11 December 2024).

Figure 7

Possibilities in NGF/TrkA signaling pathway inhibition. A possible site of NGF/TrkA inhibition: (1) NGF-capturing drugs. (2) Inhibitors of NGF binding to TrkA. (3) TrkA inhibitors. (4) Inhibitors of activated signaling pathways. Created in BioRender. Garajova, I. (2024). https://BioRender.com/f74a942 (accessed on 11 December 2024).