Pinessi Denise, Resovi Andrea, Sangalli Fabio, Morosi Lavinia, Zentilin Lorena, Borsotti Patrizia, Carlessi Elena, Passoni Alice, Davoli Enrico, Belotti Dorina, Giavazzi Raffaella, Giacca Mauro, Valbusa Giovanni, Berndt Alexander, Zucchetti Massimo, Taraboletti Giulia
Laboratory of Tumor Microenvironment, Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, 24126 Bergamo, Italy.
Laboratory of Renal Biophysics, Department of Biomedical Engineering, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, 24126 Bergamo, Italy.
Matrix Biol. 2021 Sep;103-104:22-36. doi: 10.1016/j.matbio.2021.10.001. Epub 2021 Oct 12.
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.
紊乱且低效的肿瘤脉管系统是抗肿瘤治疗的递送及疗效的主要障碍。抗血管生成药物可使肿瘤血管正常化，改善血管功能并增强化疗药物的分布及活性。血小板反应蛋白-1的III型重复序列（T3R）结构域含有不同的潜在抗血管生成序列。因此，我们推测它可能会影响肿瘤脉管系统。肿瘤细胞或宿主异位表达T3R结构域，或给予重组T3R，均可延缓实验性肿瘤在体内的生长。肿瘤呈现出脉管系统的显著重组，血管丰富但更细小，坏死明显减少。从机制上讲，使用含有不同活性序列的该结构域截短形式表明，FGF2/FGFR/ERK轴是T3R活性的靶点。与坏死减少同时，T3R的表达促进了化疗药物（紫杉醇）在肿瘤中的分布，通过高效液相色谱法和基质辅助激光解吸电离成像质谱法评估，药物浓度更高且分布更均匀。表达T3R的肿瘤对紫杉醇和顺铂更敏感。本研究表明，血小板反应蛋白-1除了作为经典的血管生成抑制剂发挥已知作用外，还可重塑肿瘤血管，影响肿瘤脉管系统的形态和功能特性。T3R降低肿瘤生长并改善化疗反应的能力为基于T3R的联合治疗策略开辟了新的前景。
