Nerve growth factor (
NGF) and its receptors are increasingly implicated in
cancer progression, but their expression in
cervical cancer is unclear. The objective of this study was to define the
protein expression of
NGF, its precursor (proNGF), as well as their receptors, the
tyrosine kinase receptor TrkA, the common
neurotrophin receptor p75NTR and the pro-
neurotrophin receptor sortilin in
cervical cancer. Immunohistochemistry was performed in a cohort of
cervical cancers (n = 287), including the two major subtypes of the disease:
squamous cell carcinomas (SCC) and
adenocarcinomas (AC). Normal cervical tissues (n = 28) were also analyzed.
Protein expression was determined by computer-based digital quantification of staining intensity and comparative statistical analyses were made with clinicopathological parameters including histological subtype, age, grade,
tumor size, lymph node invasion, and stage. The expression of
NGF, proNGF, TrkA, p75NTR, and
sortilin was higher in
cervical cancer compared to normal cervical tissues.
NGF and TrkA were found overexpressed in SCC compared to AC (P = .0006 and P < .0001, respectively). The expression of
NGF (P = .0053), proNGF (P = .0022), and p75NTR (P = .0002), but not that of TrkA or
sortilin, was associated with increasing grade in SCC. In addition, nerve infiltration into the tumor microenvironment was assessed using the pan-neuronal marker PGP9.5. Infiltrating nerves were detected in 27% of cervical
tumors and expressed TrkA. Functional investigations using the HELA
cervical cancer cell line indicated that the Trk
tyrosine kinase inhibitor GNF-5837 reduced cell viability through decreased ERK1/2 activation. Together, these data reveal the overexpression of
NGF and TrkA in cervical SCC, suggesting a potential therapeutic value of targeting the
NGF-TrkA signaling pathway in this subtype of
cervical cancer.