Department of Biochemistry and Molecular Genetics, School of Medicine, University of Limoges, Limoges, France.
Breast Cancer Res Treat. 2012 Jul;134(1):31-40. doi: 10.1007/s10549-011-1903-6. Epub 2011 Dec 9.
Most of the antiangiogenic strategies used in oncology principally target endothelial cells through the vascular endothelial growth factor (VEGF) pathway. Multiple kinase inhibitors can secondarily reduce mural cell stabilization of the vessels by blocking platelet-derived growth factor receptor (PDGFR) activity. However, sphingosine-1-phosphate (S1P), which is also implicated in mural cell recruitment, has yet to be targeted in clinical practice. We therefore investigated the potential of a simultaneous blockade of the PDGF and S1P pathways on the chemotactic responses of vascular smooth muscle cells (VSMCs) and the resulting effects of this blockade on breast tumor growth. Due to crosstalk between the S1P and PDGF pathways, we used AG1296 and/or VPC-23019 to inhibit PDGFR-β and S1PR1/S1PR3 receptors, respectively. We showed that S1PR1 and S1PR3 are the principal receptors that mediate the S1P chemotactic signal on rat VSMCs and that they act synergistically with PDGFR-β during PDGF-B signaling. We also showed that simultaneous blockade of the PDGFR-β and S1PR1/S1PR3 signals had a synergistic effect, decreasing VSMC migration velocity toward endothelial cell and breast carcinoma cell-secreted cytokines by 65-90%. This blockade also strongly decreased the ability of VSMCs to form a three-dimensional cell network. Similar results were obtained with the combination of sunitinib malate (a VEGFR/PDGFR kinase inhibitor) and fingolimod (an S1P analog). Sunitinib malate is a clinically approved cancer treatment, whereas fingolimod is currently indicated only for treatment of multiple sclerosis. Orally administered, the combination of these drugs greatly decreased rat breast tumor growth in a syngeneic cancer model (Walker 256). This bi-therapy did not exert cumulative toxicity and histological analysis of the tumors revealed normalization of the tumor vasculature. The simultaneous blockade of these signaling pathways with sunitinib malate and fingolimod may provide an effective means of reducing tumor angiogenesis, and may improve the delivery of other chemotherapies.
大多数用于肿瘤学的抗血管生成策略主要通过血管内皮生长因子 (VEGF) 途径靶向内皮细胞。多种激酶抑制剂通过阻断血小板衍生生长因子受体 (PDGFR) 活性，可间接减少血管壁细胞的稳定。然而，鞘氨醇-1-磷酸 (S1P) 也参与了壁细胞的募集，但尚未在临床实践中靶向 S1P。因此，我们研究了同时阻断 PDGF 和 S1P 途径对血管平滑肌细胞 (VSMC) 趋化反应的潜力，以及这种阻断对乳腺癌生长的影响。由于 S1P 和 PDGF 途径之间存在串扰，我们分别使用 AG1296 和/或 VPC-23019 抑制 PDGFR-β 和 S1PR1/S1PR3 受体。我们表明，S1PR1 和 S1PR3 是介导 S1P 趋化信号在大鼠 VSMC 上的主要受体，它们在 PDGF-B 信号传导过程中与 PDGFR-β 协同作用。我们还表明，同时阻断 PDGFR-β 和 S1PR1/S1PR3 信号具有协同作用，使 VSMC 向内皮细胞和乳腺癌细胞分泌细胞因子的迁移速度降低 65-90%。这种阻断还强烈降低了 VSMC 形成三维细胞网络的能力。使用舒尼替尼马来酸盐（一种 VEGFR/PDGFR 激酶抑制剂）和 fingolimod（一种 S1P 类似物）的组合也得到了类似的结果。舒尼替尼马来酸盐是一种临床批准的癌症治疗药物，而 fingolimod 目前仅用于多发性硬化症的治疗。口服给予这些药物的组合在同种异体癌症模型（Walker 256）中大大降低了大鼠乳腺癌的生长。这种双治疗没有产生累积毒性，肿瘤的组织学分析显示肿瘤血管正常化。舒尼替尼马来酸盐和 fingolimod 同时阻断这些信号通路可能为减少肿瘤血管生成提供一种有效的方法，并可能改善其他化疗药物的递送。
