Ciafrè S A, Barillari G, Bongiorno-Borbone L, Wannenes F, Izquierdo M, Farace M G
Department of Experimental Medicine and Biochemical Sciences, University of Rome, 'Tor Vergata', Rome, Italy.
Gene Ther. 2002 Feb;9(4):297-302. doi: 10.1038/sj.gt.3301652.
Angiogenesis, the formation of new blood vessels out of pre-existing capillaries, is essential for tumor progression. Many factors have been identified that are able to inhibit angiogenesis. Here, we report the construction of a tricistronic retroviral vector encoding two inhibitors of angiogenesis expressed in mammals: the N-terminal fragment of rat prolactin (16KrPRL) and a secreted form of human platelet factor 4 (sPF4). When transduced by this retroviral vector, a rat glioblastoma cell line loses its ability of promoting endothelial cell locomotion, the initial step of angiogenesis, and the formation of an endothelial cell tube network. In spite of this encouraging in vitro result, however, the anti-angiogenic vector cannot block glioblastoma progression in animal models. These results suggest that therapeutic strategies aiming to block tumor progression through the inhibition of tumor-associated angiogenesis, should not only provide large numbers of angiogenesis inhibitors, but also target the angiogenic factors produced by tumor cells. Moreover, the data described herein may confirm recent findings from other groups which indicate that in order to successfully counteract tumor progression, drugs inhibiting new blood vessel formation should be employed in combination with traditional anti-tumor strategies, such as chemotherapy or radiotherapy.
血管生成是指从已有的毛细血管中形成新的血管，这对于肿瘤进展至关重要。现已发现许多能够抑制血管生成的因子。在此，我们报道了一种三顺反子逆转录病毒载体的构建，该载体编码两种在哺乳动物中表达的血管生成抑制剂：大鼠催乳素的N端片段（16KrPRL）和人血小板因子4的分泌形式（sPF4）。当用这种逆转录病毒载体转导时，一种大鼠胶质母细胞瘤细胞系失去了促进内皮细胞运动（血管生成的起始步骤）以及形成内皮细胞管网络的能力。然而，尽管有这一令人鼓舞的体外实验结果，但该抗血管生成载体在动物模型中并不能阻止胶质母细胞瘤的进展。这些结果表明，旨在通过抑制肿瘤相关血管生成来阻止肿瘤进展的治疗策略，不仅应提供大量的血管生成抑制剂，还应靶向肿瘤细胞产生的血管生成因子。此外，本文所述数据可能证实了其他研究小组最近的发现，即要成功对抗肿瘤进展，抑制新血管形成的药物应与传统的抗肿瘤策略（如化疗或放疗）联合使用。
