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Bone Morphogenetic Protein Antagonist Gremlin-1 Regulates Colon Cancer Progression

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Bone Morphogenetic Protein Antagonist Gremlin-1 Regulates Colon Cancer Progression Biol. Chem. 2015; 396(2): 163–183 George S. Karagiannis, Natasha Musrap, Punit Saraon, Ann Treacy, David F. Schaeffer, Richard Kirsch, Robert H. Riddell and Eleftherios P. Diamandis* Bone morphogenetic protein antagonist gremlin-1 regulates colon cancer progression Abstract: Bone morphogenetic proteins (BMP) are phylo- E-cadherin-upregulation of N-cadherin) and overexpres- genetically conserved signaling molecules of the trans- sion of Snail. Collectively, our data support that GREM1 forming growth factor-beta (TGF-beta) superfamily of promotes the loss of cancer cell differentiation at the can- proteins, involved in developmental and (patho)physi- cer invasion front, a mechanism that may facilitate tumor ological processes, including cancer. BMP signaling has progression. been regarded as tumor-suppressive in colorectal cancer (CRC) by reducing cancer cell proliferation and invasion, Keywords: angiogenesis; bone morphogenetic protein; and by impairing epithelial-to-mesenchymal transition cancer-associated fibroblasts; colorectal cancer; epithe- (EMT). Here, we mined existing proteomic repositories lial-to-mesenchymal transition; gremlin-1; stroma; tumor to explore the expression of BMPs in CRC. We found that microenvironment. the BMP antagonist gremlin-1 (GREM1) is secreted from heterotypic tumor-host cell interactions. We then sought DOI 10.1515/hsz-2014-0221 to investigate whether GREM1 is contextually and mecha- Received June 26, 2014; accepted August 1, 2014; previously nistically associated with EMT in CRC. Using immunohis- published online August 6, 2014 tochemistry, 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 Introduction contextual proximity to invasion fronts with loss of the Bone morphogenetic proteins (BMPs) are a group of phylo- tight junction protein occludin and parallel nuclear accu- genetically conserved signaling molecules, which belong mulation of β-catenin, two prominent EMT hallmarks. to the transforming growth factor-β (TGF-β) superfamily Furthermore, in vitro assays demonstrated that GREM1- of proteins, and were initially shown to induce endochon- dependent suppression of BMP signaling results in EMT dral bone formation (Chen et al., 2004). During embryonic induction, characterized by cadherin switching (loss of life, BMPs are responsible for neurogenesis, hematopoie- sis, reduction of limb bud outgrowth and formation of *Corresponding author: Eleftherios P. Diamandis, Department osteoblast and chondrocyte precursors (Kishigami and of Laboratory Medicine and Pathobiology, University of Toronto, Mishina, 2005). After birth, BMPs are involved in skeletal Toronto, Ontario, Canada; Department of Pathology and Laboratory homeostasis, mainly by promoting the maintenance of Medicine, Mount Sinai Hospital, Joseph and Wolf Lebovic Ctr., 60 Murray St., Toronto M5T 3L9, Ontario, Canada; and Department of bone mass (Miyazono et al., 2005). BMP signaling is medi- Clinical Biochemistry, University Health Network, Toronto, Ontario, ated through type I and type II serine/threonine kinase Canada, e-mail: ediamandis@mtsinai.on.ca receptors. Upon ligand binding, the type II receptor forms George S. Karagiannis, Natasha Musrap and Punit Saraon: a heterodimer with type I receptor and the constitutive Department of Laboratory Medicine and Pathobiology, University kinase of the type II receptor activates the type I receptor. of Toronto, Toronto, Ontario, Canada; and Department of Pathology Such activation may initiate signal transduction through and Laboratory Medicine, Mount Sinai Hospital, Joseph and Wolf Lebovic Ctr., 60 Murray St., Toronto M5T 3L9, Ontario, Canada phosphorylation of downstream factors [i.e., mothers Ann Treacy: MC Pathology, the Laboratory, Charlemont Clinic, against decapentaplegic (Smads)], which further causes Charlemont Mall, Dublin 2, Ireland their translocation into the nucleus, where they inhibit David F. Schaeffer: Department of Pathology and Laboratory or activate transcription of target genes (Miyazono et al., Medicine, University of British Columbia, Vancouver V5Z 1M9, 2005). British Columbia, Canada Richard Kirsch and Robert H. Riddell: Department of Pathology and In the normal colon, BMPs are primarily produced Laboratory Medicine, Mount Sinai Hospital, Joseph and Wolf Lebovic by epithelial cells to sustain epithelial phenotype and Ctr., 60 Murray St., Toronto M5T 3L9, Ontario, Canada polarity at the level of the colonic crypt (Hardwick et al., Brought to you by | Carnegie Mellon University Authenticated Download Date | 1/23/15 10:48 PM 164 G.S. Karagiannis et al.: GREM1 regulates EMT in colon cancer 2004). However, this pathway has been considered as a 2008), we had previously delineated secretome pro- major barrier to the development of intestinal cancer, files from 13 CRC cell lines (Karagiannis et al., 2014b). and various mechanisms, including genetic, epigenetic We retrieved these data, to examine in vitro secretion of and/or extracellular ones, seem to be conscientious for its BMP2, BMP4 and BMP7 in CRC. BMP2 was absent in all impairment (Hardwick et al., 2008). The most important 13 CRC secretomes, BMP4 was identified in all but the hallmark acquired from BMP-suppression seems to be the RKO secretome and BMP7 was identified in five out of disruption of the epithelial phenotype, possibly through the 13 CRC secretomes, namely the SW1116, SW480, the deployment of epithelial-to-mesenchymal transition SW620, LS174T and Colo205 ones (Figure 1A). In each (EMT) (Hardwick et al., 2004; Karagiannis et al., 2012b), case, the mean spectral counts of both BMP4 and BMP7 an event that is quite critical for the effective propaga- were higher in the SW1116 cell line, the earliest (Duke’s tion of the metastatic cascade (Kalluri, 2009; Kalluri and Stage A) stage among the 13 cell lines (Figure 1A). Notably, Weinberg, 2009; Hanahan and Weinberg, 2011). Despite BMP4 and BMP7 secretion displayed a significant reduc- an inhibitory effect of BMPs on the Wnt pathway that has tion (p < 0.025; Holms-corrected, Jonckheere-Terpstra test) been previously documented (He et al., 2004; Bertrand across the increasing Duke’s-based staging of the CRC cell et al., 2012), the exact contribution of BMPs and their lines (Figure 1B), and this occurred in a replication error antagonists in CRC progression, and especially EMT, are (RER) status-independent (p > 0.025, Holms-corrected only poorly understood. Mann-Whitney U-test) fashion (Figure 1C). Further, we Currently, high-throughput proteomics coupled to investigated BMP2, BMP4 and BMP7 gene-expression pro- mass spectrometry and bioinformatics play key roles in files in a cDNA array consisting of 24 CRC patients matched the identification, quantification and characterization with normal colonic mucosal tissue adjacent to the tumor of proteins in complex biological samples (Kulasingam (Figure S3A–C). Consistently, BMP2 showed a significant and Diamandis, 2008; Karagiannis et al., 2010), and their (p < 0.007; Holms-corrected Wilcoxon test) ∼4.5-fold down- emergence has benefited cancer research (i.e., oncopro- regulation in cancer compared to normal tissues, while teomics) with a plethora of opportunities for rationalized BMP4 and BMP7 were significantly (p < 0.007; Holms-cor- diagnosis and management (Jain, 2008; Karagiannis rected Wilcoxon test) upregulated (∼1.4-fold and ∼12-fold, et al., 2010). Using proteomics, we previously defined respectively) (Figure 1D). We verified gene-expression of protein expression signatures with potential involvement the BMP receptors type IA (BMPR1A), IB (BMPR1B) and II in tumor-host cell interactions (Karagiannis et al., 2012a), (BMPR2) in this patient array, but none of these receptors and subsequently targeted the BMP pathway as potential showed differential expression (Figure 1D; Figure S3D–F). mediator of cancer progression (Karagiannis et al., 2013; Given that BMP pathway suppression is strongly doc- Karagiannis et al., 2014c). Here, we perform meta-mining umented in sporadic CRC (Kodach et al., 2008), we consid- of these proteomic repositories to explore the expression ered that the aberrant secretion of BMPs by colon cancer levels of BMPs and their regulators and show that the BMP cells both in vitro and in patient tissues was paradoxical. antagonist gremlin-1 (GREM1) is strongly expressed in CRC Thus, we initially sought to verify in silico that progression desmoplastic invasion fronts. Further, we provide prelimi- of CRC is characterized by significant overexpression of nary evidence that GREM1 is not only contextually cor- BMPs and further examined the translational impact of related with cancer cells undergoing EMT in tissues with these expressional perturbations in advanced CRC. First, invasive colorectal carcinomas, but that it also mediates we performed gene-expression meta-analysis (Geneves- EMT by specifically disrupting the BMP7-dependent pro- tigator) and found ∼3.1-fold increase in the expression motion of epithelial phenotype in vitro. of both BMP4 and BMP7, and ∼2.2-fold decrease in the expression of BMP2 in colon adenocarcinoma/carcinoma compared to control tissues (Figure 1D). Representative heatmaps from studies showing discriminatory differences Results in BMP2, BMP4 and BMP7 gene-expression between colon cancer and healthy control tissues are shown (Figure S4). Proteomic and in silico investigations of the Second, we incorporated survival data from
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