Open AccessSpatiotemporal heterogeneity of tumor vasculature during tumor growth and antiangiogenic treatment: MRI assessment using permeability and blood volume parameters
Author(s) -
Kim Cherry,
Suh JiYeon,
Heo Changhoe,
Lee Chang Kyung,
Shim Woo Hyun,
Park Bum Woo,
Cho Gyunggoo,
Lee DoWan,
Woo DongCheol,
Kim SangYeob,
Kim Yun Jae,
Bae DongJun,
Kim Jeong Kon
Publication year - 2018
Publication title -
cancer medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.403
H-Index - 53
ISSN - 2045-7634
DOI - 10.1002/cam4.1624
Subject(s) - vascular permeability , phenotype , pathology , medicine , tumor progression , cancer research , chemistry , cancer , biochemistry , gene
Tumor heterogeneity is an important concept when assessing intratumoral variety in vascular phenotypes and responses to antiangiogenic treatment. This study explored spatiotemporal heterogeneity of vascular alterations in C6 glioma mice during tumor growth and antiangiogenic treatment on serial MR examinations (days 0, 4, and 7 from initiation of vehicle or multireceptor tyrosine kinase inhibitor administration). Transvascular permeability ( TP ) was quantified on dynamic‐contrast‐enhanced MRI (DCE‐MRI) using extravascular extracellular agent (Gd‐ DOTA ); blood volume ( BV ) was estimated using intravascular T 2 agent ( SPION ). With regard to region‐dependent variability in vascular phenotypes, the control group demonstrated higher TP in the tumor center than in the periphery, and greater BV in the tumor periphery than in the center. This distribution pattern became more apparent with tumor growth. Antiangiogenic treatment effect was regionally heterogeneous: in the tumor center, treatment significantly suppressed the increase in TP and decrease in BV (ie, typical temporal change in the control group); in the tumor periphery, treatment‐induced vascular alterations were insignificant and BV remained high. On histopathological examination, the control group showed greater CD 31, VEGFR 2, Ki67, and NG 2 expression in the tumor periphery than in the center. After treatment, CD 31 and Ki67 expression was significantly suppressed only in the tumor center, whereas VEGFR 2 and α‐caspase 3 expression was decreased and NG 2 expression was increased in the entire tumor. These results demonstrate that MRI can reliably depict spatial heterogeneity in tumor vascular phenotypes and antiangiogenic treatment effects. Preserved angiogenic activity (high BV on MRI and high CD 31) and proliferation (high Ki67) in the tumor periphery after treatment may provide insights into the mechanism of tumor resistance to antiangiogenic treatment.