Targeting Perineural Invasion in Pancreatic Cancer
1
Medical Oncology Unit, University Hospital of Parma, 43126 Parma, Italy
2
Department of Medical Oncology, Lab of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, VU University Medical Center (VUmc), 1007 MB Amsterdam, The Netherlands
3
Cancer Pharmacology Lab, AIRC Start-Up Unit, Fondazione Pisana per la Scienza, San Giuliano Terme PI, 56017 Pisa, Italy
*
Author to whom correspondence should be addressed.
Cancers 2024, 16(24), 4260; https://doi.org/10.3390/cancers16244260
Submission received: 18 November 2024
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Revised: 16 December 2024
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Accepted: 18 December 2024
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Published: 21 December 2024
(This article belongs to the Special Issue Clinical Applications of Molecular Subtyping of Pancreatic Cancer)
Simple Summary
Pancreatic cancer is a leading cause of cancer death worldwide with an increasing incidence. Neural invasion is present in almost all pancreatic cancers. Clinically, it is translated into intractable pain and worse outcomes. Here, we highlight the importance of peripheral nerves in the pancreatic tumor microenvironment influencing the initiation and dissemination of pancreatic cancer. Furthermore, both autonomic (sympathetic and parasympathetic) and afferent nerves modulate different signaling pathways promoting tumor survival and immune escape. For this reason, exploring the potential synergistic benefits of anti-neurogenic therapies combined with chemotherapy or immunotherapy might inhibit both pancreatic cancer progression and alleviate cancer-related pain.
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.
