alphaB-crystallin promotes tumor angiogenesis by increasing vascular survival during tube morphogenesis.
Selective targeting of endothelial cells in tumor vessels requires delineation of key molecular events in formation and survival of blood vessels within the tumor microenvironment. To this end, proteins transiently up-regulated during vessel morphogenesis were screened for their potential as targets in antiangiogenic tumor therapy. The molecular chaperone alphaB-crystallin was identified as specifically induced with regard to expression level, modification by serine phosphorylation, and subcellular localization during tubular morphogenesis of endothelial cells. Small interfering RNA-mediated knockdown of alphaB-crystallin expression did not affect endothelial proliferation but led to attenuated tubular morphogenesis, early activation of proapoptotic caspase-3, and increased apoptosis. alphaB-crystallin was expressed in a subset of human tumor vessels but not in normal capillaries. Tumors grown in alphaB-crystallin(-/-) mice were significantly less vascularized than wild-type tumors and displayed increased areas of apoptosis/necrosis. Importantly, tumor vessels in alphaB-crystallin(-/-) mice were leaky and showed signs of caspase-3 activation and extensive apoptosis. Ultrastructural analyses showed defective vessels partially devoid of endothelial lining. These data strongly implicate alphaB-crystallin as an important regulator of tubular morphogenesis and survival of endothelial cell during tumor angiogenesis. Hereby we identify the small heat shock protein family as a novel class of angiogenic modulators.
Dimberg
Anna
A
Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden. Anna.Dimberg@genpat.uu.se
Rylova
Svetlana
S
Dieterich
Lothar C
LC
Olsson
Anna-Karin
AK
Schiller
Petter
P
Wikner
Charlotte
C
Bohman
Svante
S
Botling
Johan
J
Lukinius
Agneta
A
Wawrousek
Eric F
EF
Claesson-Welsh
Lena
L
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002196:Capillaries / Q000187:drug effects / Q000502:physiology*; D053148:Caspase 3 / Q000378:metabolism; D002417:Cattle; D002470:Cell Survival / Q000187:drug effects*; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000473:pathology*; D017353:Gene Deletion; D006801:Humans; D008833:Microcirculation / Q000187:drug effects / Q000502:physiology; D009024:Morphogenesis; D009389:Neovascularization, Pathologic / Q000473:pathology*; D034741:RNA, Small Interfering / Q000235:genetics; D014162:Transfection; D038203:alpha-Crystallin B Chain / Q000235:genetics / Q000502:physiology*
D034741:RNA, Small Interfering; D038203:alpha-Crystallin B Chain; D053148:Caspase 3