Sennino Barbara, Kuhnert Frank, Tabruyn Sebastien P, Mancuso Michael R, Hu-Lowe Dana D, Kuo Calvin J, McDonald Donald M
Cardiovascular Research Institute, Comprehensive Cancer Center, and Department of Anatomy, University of California, San Francisco, CA 94143-0452, USA.
Cancer Res. 2009 May 15;69(10):4527-36. doi: 10.1158/0008-5472.CAN-08-3779. Epub 2009 Apr 28.
Vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and their receptors are important targets in cancer therapy based on angiogenesis inhibition. However, it is unclear whether inhibition of VEGF and PDGF together is more effective than inhibition of either one alone. Here, we used two contrasting tumor models to compare the effects of inhibiting VEGF or PDGF alone, by adenovirally generated soluble receptors, to the effects of inhibiting both together. In RIP-Tag2 tumors, VEGF and PDGF inhibition together reduced tumor vascularity and abundance of pericytes. However, VEGF inhibition reduced tumor vascularity without decreasing pericyte density, and PDGF inhibition reduced pericytes without reducing tumor vascularity. By contrast, in Lewis lung carcinomas (LLC), inhibition of VEGF or PDGF reduced blood vessels and pericytes to the same extent as did inhibition of both together. Similar results were obtained using tyrosine kinase inhibitors AG-013736 and imatinib. In LLC, VEGF expression was largely restricted to pericytes and PDGF was largely restricted to endothelial cells, but, in RIP-Tag2 tumors, expression of both growth factors was more widespread and significantly greater than in LLC. These findings suggest that inhibition of PDGF in LLC reduced pericytes, and then tumor vessels regressed because pericytes were the main source of VEGF. The vasculature of RIP-Tag2 tumors, in which most VEGF is from tumor cells, was more resistant to PDGF inhibition. The findings emphasize the interdependence of pericytes and endothelial cells in tumors and the importance of tumor phenotype in determining the cellular effects of VEGF and PDGF inhibitors on tumor vessels.
血管内皮生长因子（VEGF）、血小板衍生生长因子（PDGF）及其受体是基于血管生成抑制的癌症治疗中的重要靶点。然而，尚不清楚同时抑制VEGF和PDGF是否比单独抑制其中任何一种更有效。在此，我们使用两种截然不同的肿瘤模型，比较通过腺病毒产生的可溶性受体单独抑制VEGF或PDGF的效果与同时抑制两者的效果。在RIP-Tag2肿瘤中，同时抑制VEGF和PDGF可降低肿瘤血管生成和周细胞数量。然而，抑制VEGF可降低肿瘤血管生成但不降低周细胞密度，而抑制PDGF可减少周细胞但不降低肿瘤血管生成。相比之下，在Lewis肺癌（LLC）中，抑制VEGF或PDGF对血管和周细胞的减少程度与同时抑制两者相同。使用酪氨酸激酶抑制剂AG-013736和伊马替尼也获得了类似结果。在LLC中，VEGF表达主要局限于周细胞，PDGF表达主要局限于内皮细胞，但在RIP-Tag2肿瘤中，两种生长因子的表达更为广泛且显著高于LLC。这些发现表明，在LLC中抑制PDGF可减少周细胞，随后肿瘤血管消退，因为周细胞是VEGF的主要来源。在RIP-Tag2肿瘤中，大多数VEGF来自肿瘤细胞，其脉管系统对PDGF抑制更具抗性。这些发现强调了肿瘤中周细胞和内皮细胞的相互依赖性以及肿瘤表型在确定VEGF和PDGF抑制剂对肿瘤血管的细胞效应方面的重要性。
