The precursor for nerve growth factor and innervation in thyroid cancer

The precursor for nerve growth factor (proNGF) has recently been shown to be expressed in thyroid cancer, suggesting that neurotrophins and nerves may contribute to thyroid malignancy. Nerves and neurotrophins are emerging as important mediators of cancer initiation and progression, and may represent new biomarkers or therapeutic targets. It was first hypothesized that proNGF may be a diagnostic biomarker for thyroid cancer, either in serum or solubilised thyroid-biopsy material, in patients with benign and malignant nodular thyroid disease. ProNGF was detected in a minority of specimens, but there was no correlation with thyroid malignancy. However, serum proNGF correlated with hyperthyroidism, a relationship that is supported by animal data. It was then considered whether proNGF could have a functional role in thyroid cancer, examining first the evidence for innervation of thyroid cancer. Nerve density in papillary thyroid cancers was found to be twofold higher than in benign thyroid (12 nerves/cm2 [IQR 7-21] vs 6 nerves/cm2 [IQR: 3-10], p=0.001). Most nerves were of the adrenergic subtype. Nerve density in papillary thyroid cancers was positively associated with extrathyroidal invasion (p<0.001). Nerves in the thyroid cancer microenvironment expressed the neurotrophin receptor TrkA, as did a subset of primary thyroid cancers. Whilst proNGF expression in thyroid cancer was again demonstrated, it was not shown to be associated with neo-innervation (p=0.07), although this relationship warrants further exploration in light of the near-significant result. ProNGF was shown to be expressed in thyroid cancer nodal metastases, which correlated with expression in paired primary tumours, although it did not correlate with markers of aggressiveness or high risk features. The key finding of increased nerve density in the papillary subtype of thyroid cancer suggests that nerves may have biological relevance in thyroid cancer and invites further study. The presence of neurotrophin receptors in thyroid cancer raises the possibility that nerve-cancer crosstalk may be mediated by neurotrophins, however this relationship remains incompletely understood. This work establishes that proNGF is not a diagnostic biomarker for thyroid cancer in serum or biopsy material.