Tumor-specific interendothelial adhesion mediated by FLRT2 facilitates cancer aggressiveness
Tomofumi Ando, Ikue Tai-Nagara, Yuki Sugiura, Dai Kusumoto, Koji Okabayashi, Yasuaki Kido, Kohji Sato, Hideyuki Saya, Sutip Navankasattusas, Dean Y. Li, Makoto Suematsu, Yuko Kitagawa, Elena Seiradake, Satoru Yamagishi, Yoshiaki Kubota
Tomofumi Ando, Ikue Tai-Nagara, Yuki Sugiura, Dai Kusumoto, Koji Okabayashi, Yasuaki Kido, Kohji Sato, Hideyuki Saya, Sutip Navankasattusas, Dean Y. Li, Makoto Suematsu, Yuko Kitagawa, Elena Seiradake, Satoru Yamagishi, Yoshiaki Kubota
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Research Article Angiogenesis Vascular biology

Tumor-specific interendothelial adhesion mediated by FLRT2 facilitates cancer aggressiveness

Abstract

Blood vessel abnormalization alters cancer cell metabolism and promotes cancer dissemination and metastasis. However, the biological features of the abnormalized blood vessels that facilitate cancer progression and whether they can be targeted therapeutically have not been fully investigated. Here, we found that an axon guidance molecule, fibronectin leucine-rich transmembrane protein 2 (FLRT2), is expressed preferentially in abnormalized vessels of advanced colorectal cancers in humans and that its expression correlates negatively with long-term survival. Endothelial cell–specific deletion of Flrt2 in mice selectively pruned abnormalized vessels, resulting in a unique metabolic state termed “oxygen-glucose uncoupling,” which suppressed tumor metastasis. Moreover, Flrt2 deletion caused an increase in the number of mature vessels, resulting in a significant increase in the antitumor effects of immune checkpoint blockers. Mechanistically, we found that FLRT2 forms noncanonical interendothelial adhesions that safeguard against oxidative stress through homophilic binding. Together, our results demonstrated the existence of tumor-specific interendothelial adhesions that enable abnormalized vessels to facilitate cancer aggressiveness. Targeting this type of adhesion complex could be a safe and effective therapeutic option to suppress cancer progression.

Authors

Tomofumi Ando, Ikue Tai-Nagara, Yuki Sugiura, Dai Kusumoto, Koji Okabayashi, Yasuaki Kido, Kohji Sato, Hideyuki Saya, Sutip Navankasattusas, Dean Y. Li, Makoto Suematsu, Yuko Kitagawa, Elena Seiradake, Satoru Yamagishi, Yoshiaki Kubota

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Figure 1

Endothelial expression of FLRT2 in advanced human colorectal cancers.

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Endothelial expression of FLRT2 in advanced human colorectal cancers. (A...
(A) Schematic diagram depicting the location of the progressive and superficial areas in human colorectal cancer. (B–G) Immunohistochemical analysis of FLRT2 and CD34 expression in serial sections of paraffin-embedded samples cut from resected tumors from stage IV cases. Endothelial cells in the progressive area (closed arrowheads), but not those in the superficial area (open arrowheads), express FLRT2. (H–K) Immunohistochemical analysis of FLRT2 expression in the progressive area of tumors from individuals with various stages of colorectal cancer. Endothelial cells in tumors at advanced stages show FLRT2 expression (arrowheads). (L) Quantification of FLRT2 expression, as measured by the IHC score (n = 46 each). (M) Quantification of FLRT2 expression in the progressive area of tumors at various stages (n = 13 [stage I], 23 [stage II/III], 10 [stage IV]). The red line represents regression. (N) Kaplan-Meier curve showing recurrence-free survival of patients with stage II or III colorectal cancer, stratified according to FLRT2 expression (high- and low-scoring tumors). The log-rank test was used to compare differences between groups (n = 66). (O) Relative expression of FLRT2 and FLRT3 under various culture conditions (n = 4 each). (P–U) Immunocytochemistry analysis of HUVECs. Localization of FLRT2 proteins at the intracellular junctions (arrowheads) increased markedly after oxidative stress induced by KU55933. Representative images for 3 independent experiments are shown. Scale bars: 500 μm (B and C); 50 μm (D–K and P–U). Data are presented as the mean ± SD. Comparisons between mean values of 2 groups were evaluated using a 2-tailed Student’s t test. Comparisons among multiple groups (M and O) were evaluated using 2-way ANOVA followed by Bonferroni’s multiple-comparison test. Kaplan-Meier curves and the log-rank test were used to compare survival among the groups.