Zhang Yong, Dang Chengxue, Ma Qingyong, Shimahara Yasuyuki
Department of Surgery and Clinical Oncology, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
Oncol Rep. 2005 Jul;14(1):161-71.
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.
神经生长因子(NGF)是生长因子神经营养素家族的原型成员,根据肿瘤类型,它对神经元和某些非神经元肿瘤具有刺激和抑制作用。据报道,两种类型的NGF受体,即高亲和力受体TrkA和低亲和力受体p75NGFR,在这一过程中发挥着重要作用。此外,还检测到TrkA高表达对乳腺癌患者的总生存预后更有利,但在胰腺癌患者中,根据预后情况,这两种受体之间的关系尚不清楚。我们使用实时定量逆转录聚合酶链反应,研究了56例人原发性胰腺癌中NGF受体(NGFRs:TrkA和p75NGFR)mRNA的表达。此外,使用胰腺癌细胞系来验证NGF对胰腺癌细胞生长的影响是否取决于TrkA和P75受体的表达水平及平衡。在所有肿瘤标本和细胞系中均发现了NGFRs。在胰腺癌细胞中,NGF的生长效应似乎取决于TrkA和p75NGFR的表达水平及比例。TrkA和p75NGFR呈负相关,且均与腹痛或背痛以及神经周围浸润有关。就此而言,TrkA高表达水平表现出更频繁的神经周围浸润和更高程度的疼痛,而p75NGFR的结果则相反。在总生存研究的Cox单因素分析中,p75NGFR高表达与更长的总生存期相关,而TrkA则表现出相反的作用,且包括疼痛的影响。HPG、肿瘤大小、淋巴结受累情况和神经周围浸润不是预后因素。在Cox多因素分析中,TrkA和p75NGFR均为预后参数。总之,我们的研究发现胰腺癌中TrkA的表达是肿瘤侵袭性的标志物。相反,我们还发现p75NGFR表达升高与良好的预后相关;我们证明了NGF对胰腺癌具有刺激和抑制作用,其作用基于TrkA和p75NGFR的表达水平及比例。