TY - JOUR
T1 - Neurotrophin Receptors TrkA, p75NTR, and Sortilin Are Increased and Targetable in Thyroid Cancer
AU - Faulkner, Sam
AU - Jobling, Philip
AU - Rowe, Christopher W.
AU - Rodrigues Oliveira, S. M.
AU - Roselli, Severine
AU - Thorne, Rick F.
AU - Oldmeadow, Christopher
AU - Attia, John
AU - Jiang, Chen Chen
AU - Zhang, Xu Dong
AU - Walker, Marjorie M.
AU - Hondermarck, Hubert
N1 - Publisher Copyright:
© 2018 American Society for Investigative Pathology
PY - 2018/1
Y1 - 2018/1
N2 - Neurotrophin receptors are emerging targets in oncology, but their clinicopathologic significance in thyroid cancer is unclear. In this study, the neurotrophin tyrosine receptor kinase TrkA (also called NTRK1), the common neurotrophin receptor p75NTR, and the proneurotrophin receptor sortilin were analyzed with 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 histologic subtypes but associated with lymph node metastasis (P = 0.0148), suggesting the involvement of TrkA in tumor invasiveness. Nerves in the tumor microenvironment were positive for TrkA. p75NTR was overexpressed in anaplastic thyroid cancers compared with papillary and follicular subtypes (P < 0.0001). Sortilin was overexpressed in thyroid cancers compared with 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 found that siRNA against TrkA, p75NTR, and sortilin decreased cell survival and cell migration through decreased SRC and ERK activation. Together, these data reveal TrkA, p75NTR, and sortilin as potential therapeutic targets in thyroid cancer.
AB - Neurotrophin receptors are emerging targets in oncology, but their clinicopathologic significance in thyroid cancer is unclear. In this study, the neurotrophin tyrosine receptor kinase TrkA (also called NTRK1), the common neurotrophin receptor p75NTR, and the proneurotrophin receptor sortilin were analyzed with 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 histologic subtypes but associated with lymph node metastasis (P = 0.0148), suggesting the involvement of TrkA in tumor invasiveness. Nerves in the tumor microenvironment were positive for TrkA. p75NTR was overexpressed in anaplastic thyroid cancers compared with papillary and follicular subtypes (P < 0.0001). Sortilin was overexpressed in thyroid cancers compared with 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 found that siRNA against TrkA, p75NTR, and sortilin decreased cell survival and cell migration through decreased SRC and ERK activation. Together, these data reveal TrkA, p75NTR, and sortilin as potential therapeutic targets in thyroid cancer.
UR - http://www.scopus.com/inward/record.url?scp=85037702043&partnerID=8YFLogxK
U2 - 10.1016/j.ajpath.2017.09.008
DO - 10.1016/j.ajpath.2017.09.008
M3 - Article
C2 - 29037860
SN - 0002-9440
VL - 188
SP - 229
EP - 241
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 1
ER -