Expression of nerve growth factor receptors and their prognostic value in human pancreatic cancer.

Abstract

Nerve growth factor (NGF), the prototypic member of the neurotrophin family of growth factors, exerts both stimulatory and inhibitory effects on neuronal and certain non-neuronal tumors, depending on the type of tumor. It has been reported that two types of NGF receptors, high-affinity receptor, TrkA, and low-affinity receptor, p75NGFR, play important roles in this process. Moreover, it has also been detected that high levels of TrkA expression have a more favorable overall survival prognosis in breast cancer patients, but the relationships between the two receptors according to the prognosis in pancreatic cancer patients are unknown. We investigated the expression of NGF receptors (NGFRs: TrkA and p75NGFR) mRNA in 56 human primary pancreatic cancers, using real-time quantitative reverse transcription-PCR. Moreover, pancreatic cancer cell lines were used to validate if the effects of NGF on pancreatic cancer cell growth are dependent on the expression levels and the balance of TrkA and P75 receptors. NGFRs were found in all of the tumor specimens and cell lines. It appears that in pancreatic cancer cells the growth effects of NGF depend on the expression levels and the ratio of TrkA and p75NGFR. TrkA and p75NGFR negatively correlated and were both associated with abdominal or back pain and perineural invasion. Regarding this, high TrkA expression levels exhibited more frequent perineural invasion and a higher degree of pain, whereas the results of p75NGFR are on the contrary. For Cox univariate analyses in the OS study, high expression of p75NGFR was associated with longer overall survival yet TrkA exhibited opposite effects and included the effect of pain. HPG, tumor size, node involvement, and perineural invasion were not prognostic factors. In Cox multivariate analyses, TrkA and p75NGFR were both prognostic para-meters. In conclusion, our study found that the expression of TrkA in pancreatic cancer is a marker of tumor aggressiveness. Conversely, we also found that elevated p75NGFR expression is associated with a favorable prognosis; we demonstrated that NGF exerts both stimulatory and inhibitory effects on pancreatic cancers with the effect based on the expression levels and the ratio of TrkA and p75NGFR.