Campos Ximena, Muñoz Yenny, Selman Alberto, Yazigi Roberto, Moyano Leonor, Weinstein-Oppenheimer Caroline, Lara Hernán E, Romero Carmen
Laboratorio de Endocrinología y Biología Reproductiva, Hospital Clinico Universidad de Chile, Chile.
Gynecol Oncol. 2007 Jan;104(1):168-75. doi: 10.1016/j.ygyno.2006.07.007. Epub 2006 Aug 28.
To compare the expression of nerve growth factor (NGF) and its high-affinity receptor trkA in normal ovaries and in epithelial ovarian carcinomas. Given NGF acts as an angiogenic factor through a vascular endothelial growth factor (VEGF)-mediated mechanism in several types of tissues, we examined whether NGF regulates the expression of VEGF isoforms in epithelial ovarian cancer (EOC).
The expression and localization of NGF and tyrosine kinase receptor A (trkA) in normal ovarian samples and in ovarian cancer samples were analyzed by RT-PCR and immunohistochemistry. NGF regulates the expression of three VEGF isoforms (VEGF(121), VEGF(165) and VEGF(189)); these were examined using RT-PCR in explants of EOC and ELISA in culture media.
TrkA mRNA levels were over-expressed in ovarian cancer compared to normal ovarian samples, whereas NGF mRNA levels remained unchanged. NGF and trkA proteins were absent or found in very low levels in normal ovarian surface epithelium (OSE), whereas they were highly expressed in epithelial cells of EOC. Additionally, NGF stimulated the expression of VEGF isoforms in cancer explants. The effect was dose-dependent and inhibited by a NGF antibody and by K(252a), a trk receptor inhibitor.
The abundance of NGF and trkA receptors in epithelial cells of EOC, together with the ability of NGF to increase VEGF expression strongly suggests an autocrine role of NGF in EOC. These findings suggest that blocking neurotrophin action could be a therapeutic target in treating ovarian cancer.
比较神经生长因子（NGF）及其高亲和力受体trkA在正常卵巢组织和上皮性卵巢癌组织中的表达情况。鉴于NGF在多种组织中通过血管内皮生长因子（VEGF）介导的机制发挥血管生成因子的作用，我们研究了NGF是否调节上皮性卵巢癌（EOC）中VEGF亚型的表达。
采用逆转录聚合酶链反应（RT-PCR）和免疫组织化学方法分析正常卵巢样本和卵巢癌样本中NGF及酪氨酸激酶受体A（trkA）的表达和定位。NGF调节三种VEGF亚型（VEGF(121)、VEGF(165)和VEGF(189)）的表达；采用RT-PCR检测EOC外植体中这些亚型，并采用酶联免疫吸附测定（ELISA）检测培养基中的表达情况。
与正常卵巢样本相比，trkA mRNA水平在卵巢癌中过表达，而NGF mRNA水平保持不变。正常卵巢表面上皮（OSE）中不存在NGF和trkA蛋白或其水平极低，而在EOC的上皮细胞中它们高表达。此外，NGF刺激癌外植体中VEGF亚型的表达。该效应呈剂量依赖性，并被NGF抗体和trk受体抑制剂K(252a)抑制。
EOC上皮细胞中NGF和trkA受体的丰度，以及NGF增加VEGF表达的能力，强烈提示NGF在EOC中具有自分泌作用。这些发现表明，阻断神经营养因子的作用可能是治疗卵巢癌的一个治疗靶点。
