Down-regulation of the homeodomain factor Cdx2 in colorectal cancer by collagen type I: an active role for the tumor environment in malignant tumor progression.
The homeobox transcription factor Cdx2 specifies intestinal development and homeostasis and is considered a tumor suppressor in colorectal carcinogenesis. However, Cdx2 mutations are rarely found. Invasion of colorectal cancer is characterized by a transient loss of differentiation and nuclear accumulation of the oncoprotein beta-catenin in budding tumor cells. Strikingly, this is reversed in growing metastases, indicating that tumor progression is a dynamic process that is not only driven by genetic alterations but also regulated by the tumor environment. Here we describe a transient loss of Cdx2 in budding tumor cells at the tumor host interface, and reexpression of Cdx2 in metastases. Cell culture experiments show that collagen type I, through beta(1) integrin signaling, triggers a transient transcriptional down-regulation of Cdx2 and its intestine-specific target gene sucrase isomaltase, associated with a loss of differentiation. These data indicate an active role for the tumor environment in malignant tumor progression.
Department of Pathology, University of Erlangen-Nürnberg, Erlangen, Germany. thomas.brabletz@patho.imed.uni-erlangen.de
Thomas
T
Brabletz
Simone
S
Spaderna
Jochen
J
Kolb
Falk
F
Hlubek
Gerhard
G
Faller
Christiane J
CJ
Bruns
Andreas
A
Jung
Jens
J
Nentwich
Isabelle
I
Duluc
Claire
C
Domon-Dell
Thomas
T
Kirchner
Jean-Noel
JN
Freund
D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D000818:Animals; D030161:Avian Proteins; D024042:Collagen Type I / Q000502:physiology*; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D003598:Cytoskeletal Proteins / Q000096:biosynthesis / Q000235:genetics; D018450:Disease Progression; D015536:Down-Regulation; D018398:Homeodomain Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D019012:Integrin beta1 / Q000502:physiology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D015398:Signal Transduction / Q000502:physiology; D015534:Trans-Activators / Q000096:biosynthesis / Q000235:genetics; D051176:beta Catenin
D030161:Avian Proteins; C495267:CTNNB1 protein, mouse; D024042:Collagen Type I; D003598:Cytoskeletal Proteins; D018398:Homeodomain Proteins; D019012:Integrin beta1; D015534:Trans-Activators; D051176:beta Catenin