title: Globo-H ceramide shed from cancer cells triggers translin-associated factor X-dependent angiogenesis.
abstract: Tumor angiogenesis is a critical element of cancer progression, and strategies for its selective blockade are still sought. Here, we examine the angiogenic effects of Globo-H ceramide (GHCer), the most prevalent glycolipid in a majority of epithelial cancers and one that acts as an immune checkpoint. Here, we report that GHCer becomes incorporated into endothelial cells through the absorption of microvesicles shed from tumor cells. In endothelial cells, GHCer addition induces migration, tube formation, and intracellular Ca(2+) mobilization in vitro and angiogenesis in vivo. Breast cancer cells expressing high levels of GHCer displayed relatively greater tumorigenicity and angiogenesis compared with cells expressing low levels of Globo-H. Clincally, GHCer(+) breast cancer specimens contained higher vessel density than GHCer(-) breast cancer specimens. Mechanistic investigations linked the angiogenic effects of GHCer to its endocytosis and binding to TRAX, with consequent release of PLCβ1 from TRAX to trigger Ca(2+) mobilization. Together, our findings highlight the importance of GHC as a target for cancer therapy by providing new information on its key role in tumor angiogenesis.
authors.affiliation: Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan. Institute of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
authors.forename: Jing-Yan
authors.initials: JY
authors.lastname: Cheng
authors.affiliation: Institute of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
authors.forename: Sheng-Hung
authors.initials: SH
authors.lastname: Wang
authors.affiliation: Institute of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
authors.forename: Juway
authors.initials: J
authors.lastname: Lin
authors.affiliation: Institute of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
authors.forename: Yi-Chien
authors.initials: YC
authors.lastname: Tsai
authors.affiliation: Institute of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
authors.forename: John
authors.initials: J
authors.lastname: Yu
authors.affiliation: Institute of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
authors.forename: Jen-Chine
authors.initials: JC
authors.lastname: Wu
authors.affiliation: Institute of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
authors.forename: Jung-Tung
authors.initials: JT
authors.lastname: Hung
authors.affiliation: Genomics Research Center, Academia Sinica, Taipei, Taiwan.
authors.forename: Jin-Jin
authors.initials: JJ
authors.lastname: Lin
authors.affiliation: Department of Pathology, Taipei City Hospital Ren Ai Branch, Taipei, Taiwan.
authors.forename: Yih-Yiing
authors.initials: YY
authors.lastname: Wu
authors.affiliation: Department of Surgical Pathology, Changhua Christian Hospital, Changhua, Taiwan.
authors.forename: Kun-Tu
authors.initials: KT
authors.lastname: Yeh
authors.affiliation: Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan. Institute of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital, Taoyuan, Taiwan. aliceyu@ucsd.edu.
authors.forename: Alice L
authors.initials: AL
authors.lastname: Yu
mesh_terms: D000818:Animals; D015295:Antigens, Tumor-Associated, Carbohydrate / Q000378:metabolism*; D001943:Breast Neoplasms / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology; D002118:Calcium / Q000378:metabolism; D063646:Carcinogenesis / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D002518:Ceramides / Q000378:metabolism*; D022162:Cytoplasmic Vesicles / Q000378:metabolism / Q000473:pathology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004705:Endocytosis / Q000502:physiology; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology
chemical_list: D015295:Antigens, Tumor-Associated, Carbohydrate; D002518:Ceramides; D004268:DNA-Binding Proteins; C472765:Globo-H; D002118:Calcium