TY - JOUR
T1 - Tumor vascular remodeling by thrombospondin-1 enhances drug delivery and antineoplastic activity
AU - Pinessi, Denise
AU - Resovi, Andrea
AU - Sangalli, Fabio
AU - Morosi, Lavinia
AU - Zentilin, Lorena
AU - Borsotti, Patrizia
AU - Carlessi, Elena
AU - Passoni, Alice
AU - Davoli, Enrico
AU - Belotti, Dorina
AU - Giavazzi, Raffaella
AU - Giacca, Mauro
AU - Valbusa, Giovanni
AU - Berndt, Alexander
AU - Zucchetti, Massimo
AU - Taraboletti, Giulia
N1 - Funding Information:
Funding : Supported by AIRC, project IG 2018-21359 to GT. DP is recipient of the AIRC fellowship “Lina e Giovanni Giasini”
Publisher Copyright:
© 2021 Elsevier B.V.
PY - 2021/10/12
Y1 - 2021/10/12
N2 - 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.
AB - 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.
KW - Angiogenesis
KW - Drug distribution
KW - Matricellular proteins
KW - Tumor microenvironment
UR - http://www.scopus.com/inward/record.url?scp=85117387681&partnerID=8YFLogxK
U2 - 10.1016/j.matbio.2021.10.001
DO - 10.1016/j.matbio.2021.10.001
M3 - Article
AN - SCOPUS:85117387681
SN - 0945-053X
VL - 103-104
SP - 22
EP - 36
JO - Matrix Biology
JF - Matrix Biology
ER -