Neural Component of the Tumor Microenvironment in Pancreatic Ductal Adenocarcinoma

Simple Summary Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal cancers worldwide, with a poor prognosis and an increasing incidence. Recently, the tumor microenvironment, including its neural component, has gained the attention of cancer researchers. Neural regulation of pancreatic cancer carcinogenesis is, however, poorly understood. Only lately have the diversified autonomic nerve fibers been noticed in cancer research. Targeting sympathetic and parasympathetic nerves in various malignancies, including PDAC, may bring new therapies into clinical practice. Omnipresent perineural invasion in pancreatic cancer is associated with a poor prognosis. Moreover, novel quantification with a distinction between perineural and endoneural invasion could help stratify the risk of relapse and mortality for patients with this cancer. Newly described biologic phenomena-cancer-related axonogenesis and neurogenesis-are understudied in pancreatic cancer. This review aims to summarize and integrate the role of nerves in PDAC. Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive primary malignancy of the pancreas, with a dismal prognosis and limited treatment options. It possesses a unique tumor microenvironment (TME), generating dense stroma with complex elements cross-talking with each other to promote tumor growth and progression. Diversified neural components makes for not having a full understanding of their influence on its aggressive behavior. The aim of the study was to summarize and integrate the role of nerves in the pancreatic tumor microenvironment. The role of autonomic nerve fibers on PDAC development has been recently studied, which resulted in considering the targeting of sympathetic and parasympathetic pathways as a novel treatment opportunity. Perineural invasion (PNI) is commonly found in PDAC. As the severity of the PNI correlates with a poorer prognosis, new quantification of this phenomenon, distinguishing between perineural and endoneural invasion, could feature in routine pathological examination. The concepts of cancer-related neurogenesis and axonogenesis in PDAC are understudied; so, further research in this field may be warranted. A better understanding of the interdependence between the neural component and cancer cells in the PDAC microenvironment could bring new nerve-oriented treatment options into clinical practice and improve outcomes in patients with pancreatic cancer. In this review, we aim to summarize and integrate the current state of knowledge and future challenges concerning nerve-cancer interactions in PDAC.

Automated summary

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with limited treatment options and poor prognosis. The tumor microenvironment in PDAC is characterized by a dense stroma and intricate cross-talk between various elements. Despite the presence of neural components, their role in PDAC remains poorly understood. Recent studies have explored the targeting of autonomic nerves as a novel treatment approach for PDAC. Perineural invasion is a common feature in PDAC and its severity is associated with a worse prognosis. Quantification methods that distinguish between perineural and endoneural invasion could potentially improve risk assessment for PDAC patients. The concepts of cancer-related neurogenesis and axonogenesis in PDAC are understudied and warrant further research. Understanding the interplay between nerves and cancer cells in the PDAC microenvironment could lead to new nerve-oriented treatment strategies and improved outcomes. This review aims to summarize the current knowledge and future challenges in the field of nerve-cancer interactions in PDAC.