The disorganized and inefficient tumor vasculature is a major obstacle to the delivery and efficacy of antineoplastic treatments. Antiangiogenic agents can normalize the tumor vessels, improving vessel function and boosting the distribution and activity of chemotherapy. The type III repeats (T3R) domain of thrombospondin-1 contains different potential antiangiogenic sequences. We therefore hypothesized that it might affect the tumor vasculature. Ectopic expression of the T3R domain by the tumor cells or by the host, or administration of recombinant T3R, delayed the in vivo growth of experimental tumors. Tumors presented marked reorganization of the vasculature, with abundant but smaller vessels, associated with substantially less necrosis. Mechanistically, the use of truncated forms of the domain, containing different active sequences, pointed to the FGF2/FGFR/ERK axis as a target for T3R activity. Along with reduced necrosis, the expression of T3R promoted tumor distribution of chemotherapy (paclitaxel), with a higher drug concentration and more homogeneous distribution, as assessed by HPLC and MALDI imaging mass spectrometry. T3R-expressing tumors were more responsive to paclitaxel and cisplatin. This study shows that together with its known role as a canonical inhibitor of angiogenesis, thrombospondin-1 can also remodel tumor blood vessels, affecting the morphological and functional properties of the tumor vasculature. The ability of T3R to reduce tumor growth and improve the response to chemotherapy opens new perspectives for therapeutic strategies based on T3R to be used in combination therapies.

杂乱无章且效率低下的肿瘤脉管系统是抗肿瘤治疗的传递和疗效的主要障碍。抗血管生成剂可以使肿瘤血管正常化，改善血管功能并增强化疗的分布和活性。血小板反应蛋白-1 的 III 型重复 (T3R) 结构域包含不同的潜在抗血管生成序列。因此，我们假设它可能会影响肿瘤脉管系统。肿瘤细胞或宿主对 T3R 结构域的异位表达，或重组 T3R 的施用，延迟了体内实验性肿瘤的生长。肿瘤呈现显着的脉管系统重组，血管丰富但更小，坏死明显减少。从机制上讲，使用包含不同活性序列的截断形式的结构域指向 FGF2/FGFR/ERK 轴作为 T3R 活性的目标。通过 HPLC 和 MALDI 成像质谱评估，随着坏死减少，T3R 的表达促进了化疗（紫杉醇）的肿瘤分布，具有更高的药物浓度和更均匀的分布。表达 T3R 的肿瘤对紫杉醇和顺铂更敏感。这项研究表明，连同其作为血管生成的经典抑制剂的已知作用，血小板反应蛋白-1 还可以重塑肿瘤血管，影响肿瘤脉管系统的形态和功能特性。T3R 减少肿瘤生长和改善对化疗反应的能力为基于 T3R 的治疗策略用于联合治疗开辟了新的前景。