Department of Pathobiology, University of Guelph, Guelph, ON, N1G 2W1, Canada.
Department of Biomedical Sciences, University of Guelph, Guelph, ON, N1G 2W1, Canada.
Cancer Gene Ther. 2020 May;27(5):356-367. doi: 10.1038/s41417-019-0108-8. Epub 2019 Jun 4.
An integral step in the development of solid tumors is the recruitment of blood vessels to fuel tumor growth. Antiangiogenic therapies can inhibit this process and control solid tumor growth. Thrombospondin-1 is an antiangiogenic protein possessing three type I repeats (3TSR) near the center of the protein and a CD47-binding peptide (CD47) in its C-terminus. Previously, we showed that treatment with recombinant 3TSR induces tumor regression, normalizes tumor vasculature, and improves uptake of chemotherapy drugs in an orthotopic, syngeneic mouse model of advanced stage epithelial ovarian cancer (EOC). While effective, this intervention required daily intraperitoneal injections. To circumvent this, here we employ adeno-associated virus (AAV) gene therapy vectors to express 3TSR alone or in combination with the CD47-binding peptide of TSP-1 and evaluate the impact on tumor development and survival in a mouse model of EOC. A single intraperitoneal injection of 1 × 10 vg of AAV expressing 3TSR, CD47-binding peptide, or 3TSR + CD47 effectively suppressed primary tumor growth; however, only AAV-3TSR was able to inhibit development of secondary lesions at 90-days post-tumor implantation and significantly improve survival. Taken together, AAV-mediated expression of 3TSR appears safe and effective at inhibiting tumor development and represents a novel, less invasive approach for treating ovarian carcinoma.
实体瘤发展的一个重要步骤是招募血管为肿瘤生长提供营养。抗血管生成疗法可以抑制这一过程并控制实体瘤的生长。血小板反应蛋白-1 是一种具有三个 I 型重复序列（3TSR）的抗血管生成蛋白，位于蛋白质中心附近，其 C 末端具有 CD47 结合肽（CD47）。之前，我们表明，用重组 3TSR 治疗可诱导肿瘤消退，使肿瘤血管正常化，并改善在同源、同基因的晚期上皮性卵巢癌（EOC）小鼠模型中化疗药物的摄取。虽然有效，但这种干预需要每天进行腹腔内注射。为了避免这种情况，我们在这里使用腺相关病毒（AAV）基因治疗载体来单独表达 3TSR 或与 TSP-1 的 CD47 结合肽组合，并评估其对 EOC 小鼠模型中肿瘤发展和存活的影响。单次腹腔内注射 1×10vg 的表达 3TSR、CD47 结合肽或 3TSR+CD47 的 AAV 可有效抑制原发性肿瘤生长；然而，只有 AAV-3TSR 能够抑制肿瘤植入后 90 天的继发性病变的发展，并显著提高存活率。综上所述，AAV 介导的 3TSR 表达在抑制肿瘤发展方面是安全有效的，代表了一种治疗卵巢癌的新型、微创方法。
