Tumor-specific interendothelial adhesion mediated by FLRT2 facilitates cancer aggressiveness
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,...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
American Society for Clinical Investigation
2022
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| _version_ | 1797107926572204032 |
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| author | Ando, T Tai-Nagara, I Sugiura, Y Kusumoto, D Okabayashi, K Kido, Y Sato, K Saya, H Navankasattusas, S Li, DY Suematsu, M Kitagawa, Y Seiradake, E Yamagishi, S Kubota, Y |
| author_facet | Ando, T Tai-Nagara, I Sugiura, Y Kusumoto, D Okabayashi, K Kido, Y Sato, K Saya, H Navankasattusas, S Li, DY Suematsu, M Kitagawa, Y Seiradake, E Yamagishi, S Kubota, Y |
| author_sort | Ando, T |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-07T07:21:02Z |
| format | Journal article |
| id | oxford-uuid:32c1a03d-abfe-4a93-8314-616ef64abbfc |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T07:21:02Z |
| publishDate | 2022 |
| publisher | American Society for Clinical Investigation |
| record_format | dspace |
| spelling | oxford-uuid:32c1a03d-abfe-4a93-8314-616ef64abbfc2022-10-19T06:13:38ZTumor-specific interendothelial adhesion mediated by FLRT2 facilitates cancer aggressivenessJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:32c1a03d-abfe-4a93-8314-616ef64abbfcEnglishSymplectic ElementsAmerican Society for Clinical Investigation2022Ando, TTai-Nagara, ISugiura, YKusumoto, DOkabayashi, KKido, YSato, KSaya, HNavankasattusas, SLi, DYSuematsu, MKitagawa, YSeiradake, EYamagishi, SKubota, YBlood 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. |
| spellingShingle | Ando, T Tai-Nagara, I Sugiura, Y Kusumoto, D Okabayashi, K Kido, Y Sato, K Saya, H Navankasattusas, S Li, DY Suematsu, M Kitagawa, Y Seiradake, E Yamagishi, S Kubota, Y Tumor-specific interendothelial adhesion mediated by FLRT2 facilitates cancer aggressiveness |
| title | Tumor-specific interendothelial adhesion mediated by FLRT2 facilitates cancer aggressiveness |
| title_full | Tumor-specific interendothelial adhesion mediated by FLRT2 facilitates cancer aggressiveness |
| title_fullStr | Tumor-specific interendothelial adhesion mediated by FLRT2 facilitates cancer aggressiveness |
| title_full_unstemmed | Tumor-specific interendothelial adhesion mediated by FLRT2 facilitates cancer aggressiveness |
| title_short | Tumor-specific interendothelial adhesion mediated by FLRT2 facilitates cancer aggressiveness |
| title_sort | tumor specific interendothelial adhesion mediated by flrt2 facilitates cancer aggressiveness |
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