Perineural Invasion in Pancreatic Ductal Adenocarcinoma: From Molecules towards Drugs of Clinical Relevance

SIMPLE SUMMARY: A few types of cancers are currently as challenging and difficult to defeat as pancreatic ductal adenocarcinoma. Several reasons contribute to the complexity of this disease and are extensively studied in the attempt to beat this unassailable condition. Among those factors, the invasion of nerves by cancer cells, or perineural invasion, has been discovered to be a common feature of this cancer helping the tumour in its progression, facilitating relapses and causing considerable pain for patients. For these reasons, more effective therapies directed at inhibiting nerve invasion promoted by pancreatic ductal adenocarcinoma are strongly advocated. This review discusses the current understanding of perineural invasion in pancreatic ductal adenocarcinoma and the state of the art regarding pharmacological progress in this field. ABSTRACT: Pancreatic ductal adenocarcinoma is one of the most threatening solid malignancies. Molecular and cellular mediators that activate paracrine signalling also regulate the dynamic interaction between pancreatic cancer cells and nerves. This reciprocal interface leads to perineural invasion (PNI), defined as the ability of cancer cells to invade nerves, similar to vascular and lymphatic metastatic cascade. Targeting PNI in pancreatic cancer might help ameliorate prognosis and pain relief. In this review, the modern knowledge of PNI in pancreatic cancer has been analysed and critically presented. We focused on molecular pathways promoting cancer progression, with particular emphasis on neuropathic pain generation, and we reviewed the current knowledge of pharmacological inhibitors of the PNI axis. PNI represents a common hallmark of PDAC and correlates with recurrence, poor prognosis and pain in pancreatic cancer patients. The interaction among pancreatic cancer cells, immune cells and nerves is biologically relevant in each stage of the disease and stimulates great interest, but the real impact of the administration of novel agents in clinical practice is limited. It is still early days for PNI-targeted treatments, and further advanced studies are needed to understand whether they could be effective tools in the clinical setting.