Bone morphogenetic protein antagonist gremlin-1 regulates colon cancer progression

George S. Karagiannis, Natasha Musrap, Punit Saraon, Ann Treacy, David F. Schaeffer, Richard Kirsch, Robert H. Riddell, Eleftherios P. Diamandis

Research output: Contribution to journalArticlepeer-review

41 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)163-183
Number of pages21
JournalBiological Chemistry
Volume396
Issue number2
DOIs
StatePublished - Feb 1 2015
Externally publishedYes

Keywords

  • Angiogenesis
  • bone morphogenetic protein
  • cancer-associated fibroblasts
  • colorectal cancer
  • epithelial-to-mesenchymal transition
  • gremlin-1
  • stroma
  • tumor microenvironment

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Clinical Biochemistry

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