Tumor innervation and clinical outcome in pancreatic cancer

Aysha Ferdoushi,Nathan Griffin,Hubert Hondermarck,Chen Chen Jiang,Sam Faulkner,Hui Liu,Fangfang Gao,Phillip Jobling,Xiaoyue Xu,Dirk F Van Helden,James W Denham,Simon J King,Mark Marsland

doi:10.1038/s41598-021-86831-w

Abstract

Pancreatic cancer is a highly aggressive malignancy characterized by poor survival, recurrence after surgery and resistance to therapy. Nerves infiltrate the microenvironment of pancreatic cancers and contribute to tumor progression, however the clinicopathological significance of tumor innervation is unclear. In this study, the presence of nerves and their cross-sectional size were quantified by immunohistochemistry for the neuronal markers S-100, PGP9.5 and GAP-43 in a series of 99 pancreatic cancer cases versus 71 normal adjacent pancreatic tissues. A trend was observed between the presence of nerves in the tumor microenvironment of pancreatic cancer and worse overall patient survival (HR = 1.8, 95% CI 0.77–4.28, p = 0.08). The size of nerves, as measured by cross-sectional area, were significantly higher in pancreatic cancer than in the normal adjacent tissue (p = 0.002) and larger nerves were directly associated with worse patient survival (HR = 0.41, 95% CI 0.19–0.87, p = 0.04). In conclusion, this study suggests that the presence and size of nerves within the pancreatic cancer microenvironment are associated with tumor aggressiveness.

Highlights

Pancreatic cancer is a highly aggressive malignancy characterized by poor survival, recurrence after surgery and resistance to therapy
In animal models of prostate[2] and gastric[3,4] cancer, it has been shown that the infiltration of new nerves in the tumor microenvironment is necessary to cancer growth and metastasis and that denervation strongly inhibits tumor progression
Typical morphological features corresponding to nerves were observed by IHC staining for the neuronal markers S-100, PGP9.5 and GAP-43 (Fig. 1)

Summary

Introduction

Pancreatic cancer is a highly aggressive malignancy characterized by poor survival, recurrence after surgery and resistance to therapy. Nerves infiltrate the microenvironment of pancreatic cancers and contribute to tumor progression, the clinicopathological significance of tumor innervation is unclear. The size of nerves, as measured by cross-sectional area, were significantly higher in pancreatic cancer than in the normal adjacent tissue (p = 0.002) and larger nerves were directly associated with worse patient survival (HR = 0.41, 95% CI 0.19–0.87, p = 0.04). The invasion of nerves by cancer cells, termed perineural invasion (PNI), has been extensively described in PC and is generally associated with increased tumor aggressiveness[16] It is unclear if the increased PNI in PC is primarily due to increased invasiveness of PC cells or to the increased infiltration of new nerves in the tumor microenvironment

Methods

Results

Conclusion