Dual role of carcinoembryonic antigen-related cell adhesion molecule 1 in angiogenesis and invasion of human urinary bladder cancer.
Here, we show that carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is expressed in umbrella cells of bladder urothelium but is down-regulated in superficial bladder cancer, such as histologic tumor stage a (pTa) and transitional cell carcinoma in situ (pTis). Concurrently, CEACAM1 is up-regulated in the endothelia of adjacent angiogenic blood vessels. Mimicking the CEACAM1 down-regulation in the urothelium, CEACAM1 was silenced in bladder cancer cell lines 486p and RT4 using the small interfering RNA technique. CEACAM1 down-regulation was confirmed at the protein level by Western blot analyses. CEACAM1 silencing leads to a significant up-regulation of vascular endothelial growth factor (VEGF)-C and VEGF-D in quantitative reverse transcription-PCR. Correspondingly, supernatants from the CEACAM1-overexpressing bladder cancer cell lines reduce, but those from CEACAM1 silencing induce endothelial tube formation and potentiate the morphogenetic effects of VEGF. These data suggest that the epithelial down-regulation of CEACAM1 induces angiogenesis via increased expression of VEGF-C and VEGF-D. Inversely, CEACAM1 is up-regulated in endothelial cells of angiogenic blood vessels. This in turn is involved in the switch from noninvasive and nonvascularized to invasive and vascularized bladder cancer. CEACAM1 appears to be a promising endothelial target for bladder cancer therapy.
Oliveira-Ferrer
Leticia
L
Institute of Anatomy I and Department of Urology, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
Tilki
Derya
D
Ziegeler
Gudrun
G
Hauschild
Jessica
J
Loges
Sonja
S
Irmak
Ster
S
Kilic
Ergin
E
Huland
Hartwig
H
Friedrich
Martin
M
Ergün
Süleyman
S
D015703:Antigens, CD / Q000096:biosynthesis* / Q000235:genetics; D000943:Antigens, Differentiation / Q000096:biosynthesis* / Q000235:genetics; D015815:Cell Adhesion Molecules; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D001743:Urinary Bladder / Q000378:metabolism / Q000502:physiology; D001749:Urinary Bladder Neoplasms / Q000098:blood supply* / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D042582:Vascular Endothelial Growth Factor C / Q000096:biosynthesis / Q000235:genetics; D042643:Vascular Endothelial Growth Factor D / Q000096:biosynthesis / Q000235:genetics
D015703:Antigens, CD; D000943:Antigens, Differentiation; C069847:CD66 antigens; D015815:Cell Adhesion Molecules; D042582:Vascular Endothelial Growth Factor C; D042643:Vascular Endothelial Growth Factor D