Dysregulation of the vascular endothelial growth factor and semaphorin ligand-receptor families in prostate cancer metastasis.
Dysregulation of the vascular endothelial growth factor and semaphorin ligand-receptor families in prostate cancer metastasis.
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DOI：
10.1186/s12918-015-0201-z
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发表时间：
2015-09-04
影响因子：
--
通讯作者：
Mac Gabhann F
中科院分区：
文献类型：
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作者：
Bender RJ;Mac Gabhann F
血管内皮生长因子（VEGF）家族是癌症血管生成的核心。然而，靶向VEGF作为抗癌治疗方法已经显示出对某些肿瘤类型的成功，但对其他肿瘤类型则没有成功。在这里，我们研究了扩展的VEGF家族在前列腺癌中的表达，包括与VEGF竞争神经纤毛蛋白结合的脑信号蛋白（Sema）家族成员，它们本身可以具有促或抗血管生成活性。首先，我们使用多变量统计方法，包括偏最小二乘法和聚类，在以前发表的前列腺癌微阵列数据集中检查VEGF/Sema基因表达的变异性。我们表明，与某些癌症，如肾癌，原发性前列腺癌的特点是下调促血管生成的VEGF家族成员和下调抗血管生成的Sema家族成员。我们发现了促淋巴管生成的特征，包括编码VEGFC和VEGFD的基因，与最终变得具有侵袭性的原发性肿瘤相关。与原发性前列腺肿瘤相比，前列腺癌转移显示关键促血管生成VEGF家族成员的表达增加，并进一步抑制抗血管生成III类Sema家族成员。鉴于迄今为止VEGF靶向分子在前列腺癌中缺乏成功，这表明抗血管生成Sema信号传导的减少可能增强VEGF信号传导，甚至促进对VEGF靶向治疗的抗性。抑制VEGF“加速器”可能需要伴随促进Sema“制动器”以阻断癌症血管生成。为了利用我们对机制的理解，并将多基因表达变化与结果联系起来，我们在许多肿瘤样本中进行了竞争性VEGF和Sema受体结合的个性化计算模拟。模拟表明，Sema表达的损失通过降低丛蛋白信号而不是通过经由竞争的松弛增强VEGF信号来促进血管生成。生物信息学数据与配体-受体相互作用的计算建模的组合分析表明，前列腺癌转移中血管生成的增强可能通过两种不同的途径发生：VEGFA的升高和3类脑信号蛋白的减少。在转移性前列腺癌中治疗性抑制血管生成应该是这两种途径的原因。本文的在线版本（doi：10.1186/s12918-015-0201-z）包含补充材料，可供授权用户使用。
The vascular endothelial growth factor (VEGF) family is central to cancer angiogenesis. However, targeting VEGF as an anti-cancer therapeutic approach has shown success for some tumor types but not others. Here we examine the expression of the expanded VEGF family in prostate cancer, including the Semaphorin (Sema) family members that compete with VEGFs for Neuropilin binding and can themselves have pro- or anti-angiogenic activity. First, we used multivariate statistical methods, including partial least squares and clustering, to examine VEGF/Sema gene expression variability in previously published prostate cancer microarray datasets. We show that unlike some cancers, such as kidney cancer, primary prostate cancer is characterized by both a down-regulation of the pro-angiogenic members of the VEGF family and a down-regulation of anti-angiogenic members of the Sema family. We found pro-lymphangiogenic signatures, including the genes encoding VEGFC and VEGFD, associated with primary tumors that ultimately became aggressive. In contrast to primary prostate tumors, prostate cancer metastases showed increased expression of key pro-angiogenic VEGF family members and further repression of anti-angiogenic class III Sema family members. Given the lack of success of VEGF-targeting molecules so far in prostate cancer, this suggests that the reduction in anti-angiogenic Sema signaling may potentiate VEGF signaling and even promote resistance to VEGF-targeting therapies. Inhibition of the VEGF ‘accelerator’ may need to be accompanied by promotion of the Sema ‘brake’ to block cancer angiogenesis. To leverage our mechanistic understanding, and to link multigene expression changes to outcomes, we performed individualized computational simulations of competitive VEGF and Sema receptor binding across many tumor samples. The simulations suggest that loss of Sema expression promotes angiogenesis by lowering plexin signaling, not by potentiating VEGF signaling via relaxation of competition. The combined analysis of bioinformatic data with computational modeling of ligand-receptor interactions demonstrated that enhancement of angiogenesis in prostate cancer metastases may occur through two different routes: elevation of VEGFA and reduction of class 3 Semaphorins. Therapeutic inhibition of angiogenesis in metastatic prostate cancer should account for both of these routes. The online version of this article (doi:10.1186/s12918-015-0201-z) contains supplementary material, which is available to authorized users.