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 5

Deletion of Flrt2 prevents tumor metastases and spontaneous tumor formation.

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Deletion of Flrt2 prevents tumor metastases and spontaneous tumor format...
(A) Protocol for 4OHT injections and tumor inoculation. (B) Measurement of tumor volume in mice 28 days after transplantation of AXT cells into the back skin (arrowheads) (n = 12 [control], 7 [Flrt2iΔEC]). (C) Kaplan-Meier survival analysis of mice inoculated subcutaneously with AXT cells (n = 13 [control], 17 [Flrt2iΔEC]). (D–L) Immunohistochemical analysis of primary tumors, lungs, or livers from mice 28 days after transplantation of AXT cells into the back skin (n = 4 [control primary], 4 [control lung], 12 [control liver], 7 [Flrt2iΔEC primary], 12 [Flrt2iΔEC lung], 7 [Flrt2iΔEC liver]). Intravasation of tumor cells (open arrowheads) in primary tumors and their metastasis to distant organs (closed arrowheads) are less pronounced in Flrt2iΔEC mice. (M) Protocol for tamoxifen injection into APCMin/+ model mice. (N–T) Representative images showing the macroscopic appearance of the colon, along with the sectioned colon and small intestine specimens stained with H&E (n = 6 [control], 5 [Flrt2iΔEC]). APCMin/+Flrt2iΔEC mice have fewer and smaller tumors (arrowheads) in both the colon and small intestine than APCMin/+ mice. Scale bars: 1 cm (B); 2 mm (F–I, N, and O); 50 μm (D and E). Data are presented as the mean ± SD. Comparisons between mean values of 2 groups were evaluated using a 2-tailed Student’s t test. Kaplan-Meier curves and the log-rank test were used to compare survival among the groups.