Innervation of papillary thyroid cancer and its association with extra-thyroidal invasion

Abstract

Nerves are emerging regulators of cancer progression and in several malignancies innervation of the tumour microenvironment is associated with tumour aggressiveness. However, the innervation of thyroid cancer is unclear. Here, we investigated the presence of nerves in thyroid cancers and the potential associations with clinicopathological parameters. Nerves were detected by immunohistochemistry using the pan-neuronal marker PGP9.5 in whole-slide sections of papillary thyroid cancer (ptc) (n = 75), compared to follicular thyroid cancer (FTC) (n = 13), and benign thyroid tissues (n = 26). Nerves were detected in most normal thyroid tissues and thyroid cancers, but nerve density was increased in PTC (12 nerves/cm 2 [IQR 7-21]) compared to benign thyroid (6 nerves/cm 2 [IQR: 3-10]) (p = 0.001). In contrast, no increase in nerve density was observed in FTC. In multivariate analysis, nerve density correlated positively with extrathyroidal invasion (p < 0.001), and inversely with tumour size (p < 0.001). The majority of nerves were adrenergic, although cholinergic and peptidergic innervation was detected. Perineural invasion was present in 35% of PTC, and was independently associated with extrathyroidal invasion (p = 0.008). This is the first report of infiltration of nerves into the tumour microenvironment of thyroid cancer and its association with tumour aggressiveness. The role of nerves in thyroid cancer pathogenesis should be further investigated.

Tumor-induced neurogenesis and immune evasion as targets of innovative anti-cancer therapies

“…207 This suggests that during cancer, the molecules that promote angiogenesis could also induce axonogenesis/ neurogenesis mechanisms and vice versa. In fact, tumors are innervated mainly by sympathetic fibers, 208 this correlates with the high parallelism of sympathetic nerves and body vasculature.…”

“…219 Tumors are innervated by sensorial fibers, in papillary thyroid cancer are detected peptidergic (sensorial fibers) and cholinergic (parasympathetic fibers) innervations, although most nerves are commonly adrenergic (sympathetic fibers). 208 Direct communication between sensorial afferent fibers and cancer cells stimulates proliferation and invasion of transformed cells. In breast cancer cells, NK1 receptors, stimulated by SP, activate secretory pathways that increase extracellular activity of metalloproteinases (MMPs); turning on HER2 growth factor receptor transactivation which, via Src, elicits proliferative and invasive processes.…”

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

“…Rowe et al 49 investigated the clinical relevance of nerves in thyroid cancer. A meticulous assessment of nerve density was performed in papillary and follicular thyroid cancers, and in normal thyroid tissue from unrelated patients.…”