The BMP pathway either enhances or inhibits the Wnt pathway depending on the SMAD4 and p53 status in CRC.
BACKGROUND
Constitutive Wnt activation is essential for colorectal cancer (CRC) initiation but also underlies the cancer stem cell phenotype, metastasis and chemosensitivity. Importantly Wnt activity is still modulated as evidenced by higher Wnt activity at the invasive front of clonal tumours termed the β-catenin paradox. SMAD4 and p53 mutation status and the bone morphogenetic protein (BMP) pathway are known to affect Wnt activity. The combination of SMAD4 loss, p53 mutations and BMP signalling may integrate to influence Wnt signalling and explain the β-catenin paradox.


METHODS
We analysed the expression patterns of SMAD4, p53 and β-catenin at the invasive front of CRCs using immunohistochemistry. We activated BMP signalling in CRC cells in vitro and measured BMP/Wnt activity using luciferase reporters. MTT assays were performed to study the effect of BMP signalling on CRC chemosensitivity.


RESULTS
Eighty-four percent of CRCs with high nuclear β-catenin staining are SMAD4 negative and/or p53 aberrant. BMP signalling inhibits Wnt signalling in CRC only when p53 and SMAD4 are unaffected. In the absence of SMAD4, BMP signalling activates Wnt signalling. When p53 is lost or mutated, BMP signalling no longer influences Wnt signalling. The cytotoxic effects of 5-FU are influenced in a similar manner.


CONCLUSIONS
The BMP signalling pathway differentially modulates Wnt signalling dependent on the SMAD4 and p53 status. The use of BMPs in cancer therapy, as has been proposed by previous studies, should be targeted to individual cancers based on the mutational status of p53 and SMAD4.
Department of Gastroenterology and Hepatology, Leiden University Medical Center, Albinusdreef 2, 2300RC Leiden, The Netherlands.
P W
PW
Voorneveld
Department of Gastroenterology and Hepatology, Leiden University Medical Center, Albinusdreef 2, 2300RC Leiden, The Netherlands.
L L
LL
Kodach
Department of Gastroenterology and Hepatology, Leiden University Medical Center, Albinusdreef 2, 2300RC Leiden, The Netherlands.
R J
RJ
Jacobs
Department of Pathology, Academic Medical Center, Amsterdam, The Netherlands.
C J M
CJ
van Noesel
Department of Gastroenterology and Hepatology, Erasmus MC, Erasmus University Rotterdam, Rotterdam, The Netherlands.
M P
MP
Peppelenbosch
Department of Gastroenterology and Hepatology, Leiden University Medical Center, Albinusdreef 2, 2300RC Leiden, The Netherlands.
K S
KS
Korkmaz
Department of Gastroenterology and Hepatology, Leiden University Medical Center, Albinusdreef 2, 2300RC Leiden, The Netherlands.
I
I
Molendijk
Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands.
E
E
Dekker
Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
H
H
Morreau
Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands.
G W
GW
van Pelt
Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands.
R A E M
RA
Tollenaar
Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands.
W
W
Mesker
1] Department of Gastroenterology and Hepatology, Leiden University Medical Center, Albinusdreef 2, 2300RC Leiden, The Netherlands [2] Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands.
L J A C
LJ
Hawinkels
Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands.
M
M
Paauwe
Department of Gastroenterology and Hepatology, Leiden University Medical Center, Albinusdreef 2, 2300RC Leiden, The Netherlands.
H W
HW
Verspaget
DDL Diagnostic Laboratory, Rijswijk, The Netherlands.
D T
DT
Geraets
1] Department of Gastroenterology and Hepatology, Leiden University Medical Center, Albinusdreef 2, 2300RC Leiden, The Netherlands [2] Center for Inflammatory Bowel Diseases, University of California Los Angeles Medical Center, Santa Monica, CA, USA.
D W
DW
Hommes
Department of Pathology, Utrecht Medical Center, Utrecht, The Netherlands.
G J A
GJ
Offerhaus
1] Department of Gastroenterology and Hepatology, Leiden University Medical Center, Albinusdreef 2, 2300RC Leiden, The Netherlands [2] Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands [3] Tytgat Institute for Liver & Intestinal Research, Academic Medical Center, Amsterdam, The Netherlands.
G R
GR
van den Brink
Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands.
P
P
Ten Dijke
Department of Gastroenterology and Hepatology, Leiden University Medical Center, Albinusdreef 2, 2300RC Leiden, The Netherlands.
J C H
JC
Hardwick
D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045325:HCT116 Cells; D057809:HEK293 Cells; D019073:HT29 Cells; D006801:Humans; D015398:Signal Transduction; D051901:Smad4 Protein / Q000378:metabolism*; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
D019485:Bone Morphogenetic Proteins; C495270:CTNNB1 protein, human; C497796:SMAD4 protein, human; D051901:Smad4 Protein; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D051176:beta Catenin