Blocking Nerve Growth Factor Signaling Reduces the Neural Invasion Potential of Pancreatic Cancer Cells

Abstract

Perineural invasion (PNI) is thought to be one of the factors responsible for the high rate of tumor recurrence after surgery and the pain generation associated with pancreatic cancer. Signaling via the nerve growth factor (NGF) pathway between pancreatic cancer cells and the surrounding nerves has been implicated in PNI, and increased levels of these proteins have been correlated to poor prognosis. In this study, we examine the molecular mechanism of the NGF signaling pathway in PNI in pancreatic cancer. We show that knocking down NGF or its receptors, TRKA and p75NTR, or treatment with GW441756, a TRKA kinase inhibitor, reduces the proliferation and migration of pancreatic cancer cells in vitro. Furthermore, pancreatic cancer cells migrate towards dorsal root ganglia (DRG) in a co-culture assay, indicating a paracrine NGF signaling between the DRGs and pancreatic cancer cells. Knocking down the expression of NGF pathway proteins or inhibiting the activity of TRKA by GW441756 reduced the migratory ability of Mia PaCa2 towards the DRGs. Finally, blocking NGF signaling by NGF neutralizing antibodies or GW441756 inhibited the neurite formation in PC-12 cells in response to conditioned media from pancreatic cancer cells, indicating a reciprocal signaling pathway between the pancreatic cancer cells and nerves. Our results indicate that NGF signaling pathway provides a potential target for developing molecularly targeted therapies to decrease PNI and reduce pain generation. Since there are several TRKA antagonists currently in early clinical trials they could now be tested in the clinical situation of pancreatic cancer induced pain.

β2 Adrenergic-Neurotrophin Feedforward Loop Promotes Pancreatic Cancer

“…Tumor cells have been shown to attract nerves, presumably by secreting neurotrophins (NT) such as NGF, BDNF, NT3, and NT4. NTs are a family of growth factors that stimulate nerve growth and mediate axonal guidance, synaptic plasticity and protection of nerves from injury, but can also act as autocrine growth factors and potentiate tumor cell invasion (Bapat et al, 2016). In this respect, it is important to note that intra- and extra-pancreatic perineural invasion by cancer cells is present in 71%–100% of PDAC resection specimens, and associated with worse patient survival (Liebl et al, 2014).…”

Nerve‐tumour interaction enhances the aggressiveness of oral squamous cell carcinoma

“…Nerve‐tumour interaction has been a widely accepted theory of the pathogenesis of PNI. It has been reported that autocrine or paracrine phenomena involving soluble factors and their receptors such as neurotrophic factors, chemokines and neuropeptides play important roles in the crosstalk between nerves and tumours. In addition to neurone and cancer cells, other cell types have also been demonstrated to be involved, including supporting cells, Schwann cells and endoneurial macrophages .…”

“…such as neurotrophic factors, [15][16][17][18] chemokines 19,20 and neuropeptides 21,22 play important roles in the crosstalk between nerves and tumours. In addition to neurone and cancer cells, other cell types have also been demonstrated to be involved, including supporting cells, Schwann cells and endoneurial macrophages.…”

Functions of the multi‐interacting protein KIDINS220/ARMS in cancer and other pathologies

“…Increased expression of NGFR or both NGFR and Trks was also shown in ovarian cancer, neuroblastoma, renal cell carcinoma and Schwannomas, whereas NGFR expression has been shown to be decreased in both gastric cancer and hepatocellular carcinomas . In addition, the possibility to target neurotrophin receptors was shown in several of the cited here over as well as for melanomas and pancreatic cancer cells . The potential role of KIDINS220 was not evaluated in any of these studies on neurotrophin‐receptors and cancer, but due to its central position in neurotrophin signalling, we imagine that it's involved as well.…”

“…78 In addition, the possibility to target neurotrophin receptors was shown in several of the cited here over as well as for melanomas 79 and pancreatic cancer cells. 80 The potential role of KIDINS220 was not evaluated in any of these studies on neurotrophin-receptors and cancer, but due to its central position in neurotrophin signalling, we imagine that it's involved as…”