title: A class of extracellular vesicles from breast cancer cells activates VEGF receptors and tumour angiogenesis.
abstract: Non-classical secretory vesicles, collectively referred to as extracellular vesicles (EVs), have been implicated in different aspects of cancer cell survival and metastasis. Here, we describe how a specific class of EVs, called microvesicles (MVs), activates VEGF receptors and tumour angiogenesis through a unique 90 kDa form of VEGF (VEGF90K). We show that VEGF90Kis generated by the crosslinking of VEGF165, catalysed by the enzyme tissue transglutaminase, and associates with MVs through its interaction with the chaperone Hsp90. We further demonstrate that MV-associated VEGF90Khas a weakened affinity for Bevacizumab, causing Bevacizumab to be ineffective in blocking MV-dependent VEGF receptor activation. However, treatment with an Hsp90 inhibitor releases VEGF90Kfrom MVs, restoring the sensitivity of VEGF90Kto Bevacizumab. These findings reveal a novel mechanism by which cancer cell-derived MVs influence the tumour microenvironment and highlight the importance of recognizing their unique properties when considering drug treatment strategies.
authors.affiliation: Department of Molecular Medicine, Cornell University, Ithaca, New York 14853, USA.
authors.forename: Qiyu
authors.initials: Q
authors.lastname: Feng
authors.affiliation: Department of Molecular Medicine, Cornell University, Ithaca, New York 14853, USA.
authors.forename: Chengliang
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah 84112, USA.
authors.forename: David
authors.initials: D
authors.lastname: Lum
authors.affiliation: Department of Molecular Medicine, Cornell University, Ithaca, New York 14853, USA.
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Druso
authors.affiliation: Department of Biomedical Sciences, Cornell University, Ithaca, New York 14853, USA.
authors.forename: Bryant
authors.initials: B
authors.lastname: Blank
authors.affiliation: Department of Molecular Medicine, Cornell University, Ithaca, New York 14853, USA.
authors.forename: Kristin F
authors.initials: KF
authors.lastname: Wilson
authors.affiliation: Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah 84112, USA.
authors.forename: Alana
authors.initials: A
authors.lastname: Welm
authors.affiliation: Department of Molecular Medicine, Cornell University, Ithaca, New York 14853, USA.
authors.forename: Marc A
authors.initials: MA
authors.lastname: Antonyak
authors.affiliation: Department of Molecular Medicine, Cornell University, Ithaca, New York 14853, USA.|Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York 14853, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Cerione
mesh_terms: D043925:Angiogenesis Inducing Agents / Q000378:metabolism; D000818:Animals; D016227:Benzoquinones / Q000378:metabolism / Q000494:pharmacology*; D000068258:Bevacizumab / Q000378:metabolism / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor / Q000187:drug effects / Q000378:metabolism; D055252:Cell-Derived Microparticles / Q000145:classification / Q000378:metabolism; D004195:Disease Models, Animal; D004338:Drug Combinations; D000067128:Extracellular Vesicles / Q000145:classification* / Q000378:metabolism*; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000187:drug effects / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D047029:Lactams, Macrocyclic / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D009389:Neovascularization, Pathologic / Q000378:metabolism* / Q000473:pathology; D040262:Receptors, Vascular Endothelial Growth Factor / Q000378:metabolism*; D022142:Secretory Vesicles; D015398:Signal Transduction; D011503:Transglutaminases; D014183:Transplantation, Heterologous; D059016:Tumor Microenvironment; D042461:Vascular Endothelial Growth Factor A / Q000187:drug effects / Q000378:metabolism
chemical_list: D043925:Angiogenesis Inducing Agents; D016227:Benzoquinones; D004338:Drug Combinations; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab; C112765:tanespimycin; D011503:Transglutaminases; D040262:Receptors, Vascular Endothelial Growth Factor