Effects of overexpression of ephrin-B2 on tumour growth in human colorectal cancer.
Eph receptor tyrosine kinases (RTKs) and their membrane-bound ligands, the ephrins, are essential for embryonic vascular development. Recently, it has been demonstrated that overexpression of specific Ephs and ephrins is associated with a poor prognosis in human tumours. Our group has shown that EphB and the ephrin-B subfamilies are coexpressed in human colorectal cancer, and ephrin-B2 is expressed at higher levels in human colorectal cancer than in adjacent normal mucosa. As the Eph/ephrin system is involved in embryologic vasculogenesis and ephrin-B2 is expressed ubiquitously in all colon cancers studied in our laboratory, we hypothesised that overexpression of ephrin-B2 in colon cancer cells may induce tumour angiogenesis and increase tumour growth. To investigate this hypothesis, we stably transfected KM12L4 human colon cancer cells with ephrin-B2 to study its effect on tumour growth in vivo. We found that overexpression of ephrin-B2 markedly decreased tumour growth in a mouse xenograft model. Immunohistochemical staining showed that ephrin-B2 transfectants produced higher tumour microvessel density and lower tumour cell proliferation than did parental or vector-transfected control cells. Using (51)Cr-labelled red blood cells (RBCs) to determine the functional blood volume in tumours, we demonstrated that tumours from ephrin-B2-transfected cells had significantly decreased blood volume compared with tumours from parental or vector-transfected control cells. Evaluation of in vitro parameters of cell cycle mediators demonstrated no alteration in the cell cycle. Although ephrin-B2 transfection increased tumour vessel density, the decrease in blood perfusion suggests that these vessels may be 'dysfunctional'. We conclude that overexpression of ephrin-B2 suppresses tumour cell growth and vascular function in this in vivo colon cancer model.
Liu
W
W
Department of Cancer Biology, The University of Texas M D Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030-4009, USA.
Jung
Y D
YD
Ahmad
S A
SA
McCarty
M F
MF
Stoeltzing
O
O
Reinmuth
N
N
Fan
F
F
Ellis
L M
LM
D000818:Animals; D015152:Blotting, Northern; D002453:Cell Cycle; D002455:Cell Division; D003110:Colonic Neoplasms / Q000235:genetics* / Q000473:pathology*; D036388:Ephrin-B2 / Q000032:analysis / Q000096:biosynthesis*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D008024:Ligands; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental; D009389:Neovascularization, Pathologic; D011505:Protein-Tyrosine Kinases / Q000494:pharmacology; D014162:Transfection; D014407:Tumor Cells, Cultured
D036388:Ephrin-B2; D008024:Ligands; D011505:Protein-Tyrosine Kinases