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.