Tumor innervation and clinical outcome in pancreatic cancer

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.

Neurobiology of Cancer: Introduction of New Drugs in the Treatment and Prevention of Cancer

“…It has been suggested that the innervation of cancer tissue is a new hallmark of cancer [ 114 ]. In support of this, it has been demonstrated that increased nerve size and density represents a negative prognostic marker of cancer disease [ 7 , 115 , 116 , 117 , 118 ].…”

“…Neurotransmitters released from nerves innervating cancer exert complex effects on cancer progression and the development of metastases [ 122 ]. These effects depend on the type of nerves [ 105 ] and their density in cancer tissue [ 7 , 115 , 116 , 117 , 118 ]. For example, norepinephrine released from sympathetic nerves plays an important role in the initial phases of prostate cancer development, while acetylcholine released from parasympathetic nerves potentiates the progression of prostate cancer and development of metastases [ 7 ].…”

Nerve density in cancer: Less is better

“…It also showed a significant association between the presence of nerves and poor survival for patients < 50 years of age. However, the small sample size of 11 patients did not allow for definitive conclusions 54 .…”

“…Another factor to consider when evaluating nerves in a tumor is the variability in morphological appearance of the nerve segments. Some studies showed that nerves within tumors are larger than nerves in normal tissues 40,53,54 . Another study showed that nerve size is comparable between chronic pancreatitis and pancreatic cancer, and that nerves are reduced in size when tumor stroma is desmoplastic 44 .…”

“…Using a TMA with 99 pancreatic cancer and 71 normal pancreas patient samples, investigators assessed presence or absence of nerves in the samples considering all three markers, S100, PGP9.5, and GAP43, in consecutive sections 54 . Only 10% of pancreatic cancers and 13% of normal pancreas samples had nerves in the TMA sections.…”