CXCR2 and RET Single Nucleotide Polymorphisms in Pancreatic Cancer
CXCR2 and RET Single Nucleotide Polymorphisms in Pancreatic Cancer
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DOI：
10.1007/s00268-008-9826-z
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发表时间：
2009-04-01
影响因子：
2.6
通讯作者：
Hines, O. Joe
中科院分区：
文献类型：
--
作者：
Donahue, Timothy R.;Hines, O. Joe
血管生成增强和神经侵袭是胰腺癌患者预后不良的标志。胰腺癌的系统治疗在很大程度上是无效的，因此需要改进的靶向治疗。单核苷酸多态(SNP)是导致疾病易感性和对疾病反应的巨大多样性的DNA序列变异。CXCR2是CXC趋化因子诱导血管生成的重要介质，在胰腺癌中表达上调。在一项临床前角膜微囊试验中，用抗CXCR2抗体治疗表达CXCR2的胰腺癌细胞株抑制了血管生成。到目前为止，还没有任何CXCR2 SNP与胰腺癌相关，但CXCR2 SNP被认为与系统性硬化症的血管生成有关。RET基因编码的受体酪氨酸激酶及其配体胶质源性神经营养因子(GDNF)在胰腺癌中上调。用抗RET抗体或RET siRNA体外治疗表达RET的胰腺癌细胞株抑制GDNF诱导的侵袭力。G691S RET SNP此前已被证明与胰腺癌侵袭性增强有关。我们建议，对每个患者肿瘤的G691S RET SNP、潜在的CXCR2 SNP以及其他与胰腺癌相关的尚未确定的SNP进行分子图谱分析，将有助于改善对个体预后的了解，并允许使用更个性化、更有针对性的辅助治疗。
Enhanced angiogenesis and perineural invasion are markers of poor prognosis in patients with pancreatic cancer. Systemic therapies for pancreatic cancer have been largely ineffective, and thus improved, targeted therapies are needed. Single nucleotide polymorphisms (SNP) are DNA sequence variations that result in vast diversity of disease susceptibility and response to disease. CXCR2 is an important mediator of CXC chemokine-induced angiogenesis and is upregulated in pancreatic cancer. In a preclinical corneal micropocket assay, treatment of pancreatic cancer cell lines that express CXCR2 with anti-CXCR2 antibody inhibited angiogenesis. To date, there have not been any CXCR2 SNP associated with pancreatic cancer, but CXCR2 SNP has been postulated to be associated with angiogenesis in systemic sclerosis. The receptor tyrosine kinase encoded by the RET gene and its ligand glial derived neurotrophic factor (GDNF) are upregulated in pancreatic cancer. In vitro treatment of pancreatic cancer cell lines that express RET with anti-RET antibody or RET siRNA-inhibited GDNF-induced invasiveness. G691S RET SNP has been previously shown to be associated with enhanced pancreatic cancer invasiveness. We suggest that molecular profiling of each patient's tumor for G691S RET SNP, potentially CXCR2 SNP, and also other yet-to-be identified SNP associated with pancreatic cancer will allow for both improved understanding of individual prognosis and allow for utilization of more personalized, targeted adjuvant therapies.