The American journal of pathology 2017 10 13() pii 10.1016/j.ajpath.2017.09.008
Neurotrophin receptors are emerging targets in oncology, but their clinicopathological significance in thyroid cancer is unclear. Here, the neurotrophin tyrosine receptor kinase TrkA (also called NTRK1), the common neurotrophin receptor p75(NTR), and the pro-neurotrophin receptor sortilin were analyzed by immunohistochemistry in a cohort of thyroid cancers (n=128), and compared with adenomas and normal thyroid tissues (n=62). TrkA was detected in 20% of thyroid cancers, compared with none of the benign samples (P = 0.0007). TrkA expression was independent of histological subtypes but associated with lymph node metastasis (P = 0.0148), suggesting the involvement of TrkA in tumor invasiveness. Also, nerves in the tumor microenvironment were positive for TrkA. P75(NTR) was overexpressed in anaplastic thyroid cancers compared to papillary and follicular subtypes (P < 0.0001). Sortilin was overexpressed in thyroid cancers, compared to benign thyroid tissues (P < 0.0001). Neurotrophin receptor expression was confirmed in a panel of thyroid cancer cell lines, at the mRNA and protein levels. Functional investigations using the anaplastic thyroid cancer cell line CAL-62 demonstrated that siRNA against TrkA, p75(NTR), and sortilin decreased cell survival and cell migration through decreased SRC and ERK activation. Similar results were obtained with another anaplastic cell line, 8505c, except for p75(NTR), which was not expressed. Together, these data reveal TrkA, p75(NTR), and sortilin as potential therapeutic targets in thyroid cancer.