EphB-ephrin-B interactions suppress colorectal cancer progression by compartmentalizing tumor cells.
The genes encoding tyrosine kinase receptors EphB2 and EphB3 are beta-catenin and Tcf4 target genes in colorectal cancer (CRC) and in normal intestinal cells. In the intestinal epithelium, EphB signaling controls the positioning of cell types along the crypt-villus axis. In CRC, EphB activity suppresses tumor progression beyond the earliest stages. Here we show that EphB receptors compartmentalize the expansion of CRC cells through a mechanism dependent on E-cadherin-mediated adhesion. We demonstrate that EphB-mediated compartmentalization restricts the spreading of EphB-expressing tumor cells into ephrin-B1-positive territories in vitro and in vivo. Our results indicate that CRC cells must silence EphB expression to avoid repulsive interactions imposed by normal ephrin-B1-expressing intestinal cells at the onset of tumorigenesis.
Cortina
Carme
C
Oncology Programme, Institute for Research in Biomedicine (IRB), Josep Samitier 1-5, 08028 Barcelona. Spain.
Palomo-Ponce
Sergio
S
Iglesias
Mar
M
Fernández-Masip
Juan Luis
JL
Vivancos
Ana
A
Whissell
Gavin
G
Humà
Mireia
M
Peiró
Nerea
N
Gallego
Lourdes
L
Jonkheer
Suzanne
S
Davy
Alice
A
Lloreta
Josep
J
Sancho
Elena
E
Batlle
Eduard
E
D000236:Adenoma / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D000818:Animals; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D018450:Disease Progression; D036387:Ephrin-B1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D017491:Genes, APC / Q000502:physiology; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology; D007414:Intestinal Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D036081:Receptors, Eph Family / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013347:Subcellular Fractions; D051820:TCF Transcription Factors / Q000378:metabolism; D058118:Transcription Factor 7-Like 2 Protein; D051176:beta Catenin / Q000378:metabolism
D036387:Ephrin-B1; D012333:RNA, Messenger; D051820:TCF Transcription Factors; C544894:TCF7L2 protein, human; C544895:Tcf7l2 protein, mouse; D058118:Transcription Factor 7-Like 2 Protein; D051176:beta Catenin; D036081:Receptors, Eph Family