TY - JOUR
T1 - Bone morphogenetic protein antagonist gremlin-1 regulates colon cancer progression
AU - Karagiannis, George S.
AU - Musrap, Natasha
AU - Saraon, Punit
AU - Treacy, Ann
AU - Schaeffer, David F.
AU - Kirsch, Richard
AU - Riddell, Robert H.
AU - Diamandis, Eleftherios P.
N1 - Publisher Copyright:
© 2015 by De Gruyter 2015.
PY - 2015/2/1
Y1 - 2015/2/1
N2 - Bone morphogenetic proteins (BMP) are phylogenetically conserved signaling molecules of the transforming growth factor-beta (TGF-beta) superfamily of proteins, involved in developmental and (patho)physiological processes, including cancer. BMP signaling has been regarded as tumor-suppressive in colorectal cancer (CRC) by reducing cancer cell proliferation and invasion, and by impairing epithelial-to-mesenchymal transition (EMT). Here, we mined existing proteomic repositories to explore the expression of BMPs in CRC. We found that the BMP antagonist gremlin-1 (GREM1) is secreted from heterotypic tumor-host cell interactions. We then sought to investigate whether GREM1 is contextually and mechanistically associated with EMT in CRC. Using immunohistochemistry, we showed that GREM1-expressing stromal cells harbor prominent features of myofibroblasts (i.e., cancer-associated fibroblasts), such as expression of α-smooth muscle actin and laminin-beta-1, and were in contextual proximity to invasion fronts with loss of the tight junction protein occludin and parallel nuclear accumulation of β-catenin, two prominent EMT hallmarks. Furthermore, in vitro assays demonstrated that GREM1-dependent suppression of BMP signaling results in EMT induction, characterized by cadherin switching (loss of E-cadherin-upregulation of N-cadherin) and overexpression of Snail. Collectively, our data support that GREM1 promotes the loss of cancer cell differentiation at the cancer invasion front, a mechanism that may facilitate tumor progression.
AB - Bone morphogenetic proteins (BMP) are phylogenetically conserved signaling molecules of the transforming growth factor-beta (TGF-beta) superfamily of proteins, involved in developmental and (patho)physiological processes, including cancer. BMP signaling has been regarded as tumor-suppressive in colorectal cancer (CRC) by reducing cancer cell proliferation and invasion, and by impairing epithelial-to-mesenchymal transition (EMT). Here, we mined existing proteomic repositories to explore the expression of BMPs in CRC. We found that the BMP antagonist gremlin-1 (GREM1) is secreted from heterotypic tumor-host cell interactions. We then sought to investigate whether GREM1 is contextually and mechanistically associated with EMT in CRC. Using immunohistochemistry, we showed that GREM1-expressing stromal cells harbor prominent features of myofibroblasts (i.e., cancer-associated fibroblasts), such as expression of α-smooth muscle actin and laminin-beta-1, and were in contextual proximity to invasion fronts with loss of the tight junction protein occludin and parallel nuclear accumulation of β-catenin, two prominent EMT hallmarks. Furthermore, in vitro assays demonstrated that GREM1-dependent suppression of BMP signaling results in EMT induction, characterized by cadherin switching (loss of E-cadherin-upregulation of N-cadherin) and overexpression of Snail. Collectively, our data support that GREM1 promotes the loss of cancer cell differentiation at the cancer invasion front, a mechanism that may facilitate tumor progression.
KW - Angiogenesis
KW - bone morphogenetic protein
KW - cancer-associated fibroblasts
KW - colorectal cancer
KW - epithelial-to-mesenchymal transition
KW - gremlin-1
KW - stroma
KW - tumor microenvironment
UR - http://www.scopus.com/inward/record.url?scp=84921369233&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84921369233&partnerID=8YFLogxK
U2 - 10.1515/hsz-2014-0221
DO - 10.1515/hsz-2014-0221
M3 - Article
C2 - 25153376
AN - SCOPUS:84921369233
SN - 1431-6730
VL - 396
SP - 163
EP - 183
JO - Biological Chemistry
JF - Biological Chemistry
IS - 2
ER -