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Tumor-specific interendothelial adhesion mediated by FLRT2 facilitates cancer aggressiveness.
Ando, Tomofumi; Tai-Nagara, Ikue; Sugiura, Yuki; Kusumoto, Dai; Okabayashi, Koji; Kido, Yasuaki; Sato, Kohji; Saya, Hideyuki; Navankasattusas, Sutip; Li, Dean Y; Suematsu, Makoto; Kitagawa, Yuko; Seiradake, Elena; Yamagishi, Satoru; Kubota, Yoshiaki.
Affiliation
  • Ando T; Department of Anatomy.
  • Tai-Nagara I; Department of Surgery.
  • Sugiura Y; Department of Anatomy.
  • Kusumoto D; Department of Biochemistry, and.
  • Okabayashi K; Department of Cardiology, Keio University School of Medicine, Tokyo, Japan.
  • Kido Y; Department of Surgery.
  • Sato K; Department of Anatomy.
  • Saya H; Department of Organ & Tissue Anatomy, Hamamatsu University School of Medicine, Hamamatsu, Japan.
  • Navankasattusas S; Division of Gene Regulation, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan.
  • Li DY; Department of Medicine, Program in Molecular Medicine.
  • Suematsu M; Department of Medicine, Program in Molecular Medicine.
  • Kitagawa Y; Department of Oncological Sciences.
  • Seiradake E; Department of Human Genetics.
  • Yamagishi S; ARUP Laboratories.
  • Kubota Y; Division of Cardiovascular Medicine, Department of Medicine, and.
J Clin Invest ; 132(6)2022 03 15.
Article in En | MEDLINE | ID: mdl-35104247
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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Membrane Glycoproteins / Neoplasms Type of study: Guideline Limits: Animals Language: En Journal: J Clin Invest Year: 2022 Document type: Article

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Membrane Glycoproteins / Neoplasms Type of study: Guideline Limits: Animals Language: En Journal: J Clin Invest Year: 2022 Document type: Article