Neurotrophin Pathway Receptors NGFR and TrkA Control Perineural Invasion, Metastasis, and Pain in Oral Cancer

Abstract

Oral squamous cell carcinoma (OSCC) patients suffer from poor survival due to metastasis or locoregional recurrence, processes that are both facilitated by perineural invasion (PNI). OSCC has higher rates of PNI than other cancer subtypes, with PNI present in 80% of tumors. Despite the impact of PNI on oral cancer prognosis and pain, little is known about the genes that drive PNI, which in turn drive pain, invasion, and metastasis. In this study, clinical data, preclinical, and in vitro models are leveraged to elucidate the role of neurotrophins in OSCC metastasis, PNI, and pain. The expression data in OSCC patients with metastasis, PNI, or pain demonstrate dysregulation of neurotrophin genes. TrkA and nerve growth factor receptor (NGFR) are focused, two receptors that are activated by NGF, a neurotrophin expressed at high levels in OSCC. It is demonstrated that targeted knockdown of these two receptors inhibits proliferation and invasion in an in vitro and preclinical model of OSCC, and metastasis, PNI, and pain. It is further determined that TrkA knockdown alone inhibits thermal hyperalgesia, whereas NGFR knockdown alone inhibits mechanical allodynia. Collectively the results highlight the ability of OSCC to co-opt different components of the neurotrophin pathway in metastasis, PNI, and pain.

Molecular pathway of pancreatic cancer‐associated neuropathic pain

“…[55,56] Expression of NGFs and its receptor tropomyosin receptor kinase A (TrkA), might increase the perineural invasion, which can be referred to as neurotrophic effects. [57,58] Neurotrophins compose of NGF, brain-derived neurotrophic factors (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4/5 (NT-4/5) which are derived during neural remodeling in tumor microenvironment. [59] Receptor families F I G U R E 1 Tumor microenvironment shows the growth of cancer cells and metastasis to the nearby components such as normal cells, blood vessels, and nerves.…”

CD51 Intracellular Domain Promotes Cancer Cell Neurotropism through Interacting with Transcription Factor NR4A3 in Colorectal Cancer

“…A ChIP-seq assay using anti-FLAG antibody was employed. We searched for PNI-related genes with specific ChIP-enriched peaks located in the promoter regions of the public database and found several potential genes reported previously, including NTRK1 [38], NTRK3 [39], and SEMA3E [40] (Figure 5D). As shown in Figure 5E, the direct binding of NR4A3 to the promoters of these genes was further validated by a ChIP-qPCR assay using primers designed against the binding site.…”

Crosstalk between cancer cells and the nervous system

“…Several factors have been identified, such as neurotrophins like the NGF family, GDNF family, midkine family, their receptors, and axon guidance molecules, such as semaphorin 3D (SEMA3D), that can mediate the PNI process in pancreatic cancer and head and neck cancer [58,68,[72][73][74][75][76]. Notably, GDNF, released by neurons, can promote PNI by binding to the RET receptor isoform, RET51 [74,77].…”