NGF-mediated crosstalk: unraveling the influence of metabolic deregulation on the interplay between neural and pancreatic cancer cells and its impact on patient outcomes

Abstract

Neural invasion is one of the most common routes of invasion in pancreatic cancer and it is responsible for the high rate of tumor recurrence after surgery and the pain generation associated with pancreatic cancer. Several molecules implicated in neural invasion are also responsible for pain onset including NGF belonging to the family of neutrophins. NGF released by cancer cells can sensitize sensory nerves which in turn results in severe pain. NGF receptors, TrkA and P75^NTR, are expressed on both PDAC cells and nerves, strongly suggesting their role in neural invasion. The crosstalk between the nervous system and cancer cells has emerged as an important regulator of pancreatic cancer and its microenvironment. Nerve cells influence the pancreatic tumor microenvironment and these interactions are important for cancer metabolism reprogramming and tumor progression. In this review, we summarized the current knowledge on the interaction between nerves and pancreatic cancer cells and its impact on cancer metabolism.

Keywords: NGF; metabolism; neural invasion; pain; pancreatic cancer.

FIGURE 1

Pancreatic cancer and its innervation: In PDAC, nerve fibers include axons originating from the sympathetic and parasympathetic efferent nerve fibres, spinal and vagal afferent nerve fibres and also nerve fibres from the enteric nervous system. Created in BioRender. Garajová et al. (2024) https://BioRender.com/r60e612.

FIGURE 2

NGF interplay. NGF production is stimulated by different factors: metabolic (chronic hyperglycemia), neuronal (NE release) and directly by cells (SCs and PDAC cells). Chronic hyperglycaemia leads to axonal damage and demyelination and NGF overproduction by tumour cells. Hyperglycemia impair SCs proliferation and migration, as well as axon regeneration contributing to PDAC progression and aggravate the neural invasion process via nerve damage and inflammation. Catecholamines activate ADRB2 expressed on PDACs, resulting in NGF and BDNF overexpression, which in turn promotes neural invasion. NGF produced by PDACs binds TRKA receptors (with high affinity) and p75 NTR receptors (with low affinity) both expressed on PDACs and nerves establishing an autocrine and paracrine stimulation mechanism, respectively. TrkA receptor activates PI3K/AKT/mTOR pathway that mediates cell migration, invasion, neural invasion and GLUT1 upregulation favoring Warburg effect. p75NTR receptor activates JNK signaling that mediates cell survival. NGF produced by PDACs binds TRPV1 receptor causing severe pain. TRPV1 receptor is expressed on the sensory ganglia and in central nervous system, as well as by PDACs. Its stimulation leads to pain signals conduction and it induces the secretion of pain related neurotransmitters such as substance P and CGRP. Abbreviations: ADRB2, beta-2 adrenoceptor; CGRP, calcitonin gene related peptide; Glucose Transporter Type 1, GLUT 1; NGF, nerve growth factor; TrkA, tropomyosin receptor kinase A; p75NTR, p75 neurotrophin receptor; PDAC, pancreatic ductal adenocarcinoma; PI3K, phosphatidylinositol 3-kinases; JNK, c-jun N-terminal kinase; mTOR, mammalian target of rapamycine; NE, norepinephrine; TRPV1, transient receptor potential cation channel subfamily V member 1, SCs, Schwan cells.

FIGURE 3

Nerves in the pancreatic cancer tumor microenvironment. Pancreatic cancer tumor microenvironment is characterized by an intricate crosstalk between cancer cells, cancer-associated fibroblasts, endothelial and immune cells and lead to decreasing of antitumor immunity and increase of tumor angiogenesis, neural remodeling, and cancer progression. Created in BioRender. Garajová et al. (2024) https://BioRender.com/c65d328.

FIGURE 4

Metabolic deregulation in PDAC. The main metabolic deregulation in PDAC include deregulation of glucose metabolism, deregulation of fatty acids metabolism and alternative metabolic pathways such as autophagy. Created in BioRender. Garajová et al. (2024) https://BioRender.com/d53d820.