Bone morphogenetic proteins induce pancreatic cancer cell invasiveness through a Smad1-dependent mechanism that involves matrix metalloproteinase-2.

Bone morphogenetic proteins (BMPs) have an emerging role in human cancers. Here we demonstrate that the BMP-signaling pathway is intact and functional in human pancreatic cancer cells, with several BMP signaling components and transcriptional targets upregulated in human pancreatic cancer specimens compared with normal pancreatic tissue. Functionally, multiple BMP family members, including BMP-2, BMP-4 and BMP-7, induce an epithelial to mesenchymal transition (EMT) in the human pancreatic cancer cell line Panc-1, as demonstrated by morphological alterations and loss of E-cadherin expression. BMP-mediated EMT results in an increase in invasiveness of Panc-1 cells, in part through increased expression and activity of matrix metalloproteinase (MMP)-2, a known mediator of pancreatic cancer cell invasiveness. Accompanying EMT, BMP reduces expression of the transforming growth factor (TGF)-beta superfamily receptor, transforming growth factor-beta type III receptor (TbetaRIII), for which we have previously demonstrated loss of expression during pancreatic cancer progression. Maintaining TbetaRIII expression inhibits BMP-mediated invasion and suppresses Smad1 activation. Further, Smad1 is required for BMP-induced invasiveness and partially responsible for BMP-mediated increases in MMP-2 activity. These data suggest that BMP signaling, through Smad1 induction and upregulation of MMP-2, is an important mediator of pancreatic cancer invasiveness and a potential therapeutic target for treating this deadly disease.

[1]  F. Bozzo,et al.  Redox mechanisms switch on hypoxia-dependent epithelial-mesenchymal transition in cancer cells. , 2008, Carcinogenesis.

[2]  C. Wood,et al.  Expression of the type III TGF-beta receptor is negatively regulated by TGF-beta. , 2008, Carcinogenesis.

[3]  G. Blobe,et al.  Bone Morphogenetic Proteins Signal through the Transforming Growth Factor-β Type III Receptor* , 2008, Journal of Biological Chemistry.

[4]  G. Blobe,et al.  TbetaRIII suppresses non-small cell lung cancer invasiveness and tumorigenicity. , 2008, Carcinogenesis.

[5]  G. Blobe,et al.  Loss of type III transforming growth factor beta receptor expression increases motility and invasiveness associated with epithelial to mesenchymal transition during pancreatic cancer progression. , 2008, Carcinogenesis.

[6]  R. Trembath,et al.  Regulation of bone morphogenetic protein signalling in human pulmonary vascular development , 2008, The Journal of pathology.

[7]  A. Masamune,et al.  Bone morphogenetic protein 4 induces epithelial‐mesenchymal transition through MSX2 induction on pancreatic cancer cell line , 2007, Journal of cellular physiology.

[8]  H. Buhr,et al.  Epithelial to Mesenchymal Transition: Expression of the Regulators Snail, Slug, and Twist in Pancreatic Cancer , 2007, Clinical Cancer Research.

[9]  M. Nachtigal,et al.  BMP4 induces EMT and Rho GTPase activation in human ovarian cancer cells. , 2007, Carcinogenesis.

[10]  S. Murphy,et al.  Loss of betaglycan expression in ovarian cancer: role in motility and invasion. , 2007, Cancer research.

[11]  P. Dijke,et al.  Transforming Growth Factor-β Receptor Type I-dependent Fibrogenic Gene Program Is Mediated via Activation of Smad1 and ERK1/2 Pathways* , 2007, Journal of Biological Chemistry.

[12]  T. Ravikumar,et al.  Bone morphogenetic protein-4 is overexpressed in colonic adenocarcinomas and promotes migration and invasion of HCT116 cells. , 2007, Experimental cell research.

[13]  Y. Mishina,et al.  BMP4-BMPR1A signaling in beta cells is required for and augments glucose-stimulated insulin secretion. , 2007, Cell metabolism.

[14]  Malte Buchholz,et al.  Sp1 is required for transforming growth factor-beta-induced mesenchymal transition and migration in pancreatic cancer cells. , 2007, Cancer research.

[15]  T. Barrette,et al.  Oncomine 3.0: genes, pathways, and networks in a collection of 18,000 cancer gene expression profiles. , 2007, Neoplasia.

[16]  G. Blobe,et al.  The type III transforming growth factor-beta receptor as a novel tumor suppressor gene in prostate cancer. , 2007, Cancer research.

[17]  B. Moeller,et al.  The type III TGF-β receptor suppresses breast cancer progression , 2007 .

[18]  A. Bosserhoff,et al.  Functional implication of BMP4 expression on angiogenesis in malignant melanoma , 2006, Oncogene.

[19]  J. Marks,et al.  The type III TGF-beta receptor suppresses breast cancer progression. , 2007, The Journal of clinical investigation.

[20]  T. Gress,et al.  Sp 1 Is Required for Transforming Growth Factor-B – Induced Mesenchymal Transition and Migration in Pancreatic Cancer Cells , 2007 .

[21]  Gerald C. Chu,et al.  Smad4 is dispensable for normal pancreas development yet critical in progression and tumor biology of pancreas cancer. , 2006, Genes & development.

[22]  N. Sarvetnick,et al.  BMP4 Regulates Pancreatic Progenitor Cell Expansion through Id2* , 2006, Journal of Biological Chemistry.

[23]  E. Langenfeld,et al.  Bone morphogenetic protein 2 stimulation of tumor growth involves the activation of Smad-1/5 , 2006, Oncogene.

[24]  J. Thiery,et al.  Complex networks orchestrate epithelial–mesenchymal transitions , 2006, Nature Reviews Molecular Cell Biology.

[25]  R. Schwartz,et al.  Bmp2 is essential for cardiac cushion epithelial-mesenchymal transition and myocardial patterning , 2005, Development.

[26]  K. Sangkuhl,et al.  Identification of Receptors and Signaling Pathways for Orphan Bone Morphogenetic Protein/Growth Differentiation Factor Ligands Based on Genomic Analyses* , 2005, Journal of Biological Chemistry.

[27]  B. Frenkel,et al.  Diverse biological effect and Smad signaling of bone morphogenetic protein 7 in prostate tumor cells. , 2005, Cancer research.

[28]  K. Miyazono,et al.  BMP receptor signaling: transcriptional targets, regulation of signals, and signaling cross-talk. , 2005, Cytokine & growth factor reviews.

[29]  Yi Tang,et al.  SCFβ-TrCP1 Controls Smad4 Protein Stability in Pancreatic Cancer Cells , 2005 .

[30]  Yi Tang,et al.  SCF(beta-TrCP1) controls Smad4 protein stability in pancreatic cancer cells. , 2005, American Journal of Pathology.

[31]  M. Zou,et al.  Microarray analysis of metastasis-associated gene expression profiling in a murine model of thyroid carcinoma pulmonary metastasis: identification of S100A4 (Mts1) gene overexpression as a poor prognostic marker for thyroid carcinoma. , 2004, The Journal of clinical endocrinology and metabolism.

[32]  M. Imamura,et al.  N-Cadherin Expression and Epithelial-Mesenchymal Transition in Pancreatic Carcinoma , 2004, Clinical Cancer Research.

[33]  B. Davidson,et al.  Laminin-Induced Signaling in Tumor Cells , 2004, Cancer Research.

[34]  Y. Itahana,et al.  Id-1 as a molecular target in therapy for breast cancer cell invasion and metastasis , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[35]  T. Aigner,et al.  Bone Morphogenetic Protein‐Mediating Receptor‐Associated Smads as well as Common Smad Are Expressed in Human Articular Chondrocytes but not Up‐Regulated or Down‐Regulated in Osteoarthritic Cartilage , 2002, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[36]  R. DePinho,et al.  Pancreatic cancer biology and genetics , 2002, Nature Reviews Cancer.

[37]  Seung K. Kim,et al.  Signaling and transcriptional control of pancreatic organogenesis. , 2002, Current opinion in genetics & development.

[38]  Z. Werb,et al.  New functions for the matrix metalloproteinases in cancer progression , 2002, Nature Reviews Cancer.

[39]  G. Xu,et al.  Expression of TGF-beta signaling genes in the normal, premalignant, and malignant human trophoblast: loss of smad3 in choriocarcinoma cells. , 2001, Biochemical and biophysical research communications.

[40]  T. Gress,et al.  TGF‐β–induced invasiveness of pancreatic cancer cells is mediated by matrix metalloproteinase‐2 and the urokinase plasminogen activator system , 2001, International journal of cancer.

[41]  T. Seufferlein,et al.  Transforming growth factor beta1 treatment leads to an epithelial-mesenchymal transdifferentiation of pancreatic cancer cells requiring extracellular signal-regulated kinase 2 activation. , 2001, Cancer research.

[42]  M. Skinner,et al.  Hormonal regulation and differential actions of the helix-loop-helix transcriptional inhibitors of differentiation (Id1, Id2, Id3, and Id4) in Sertoli cells. , 2001, Endocrinology.

[43]  N. Kamata,et al.  Reverse correlation of E-cadherin and snail expression in oral squamous cell carcinoma cells in vitro. , 2001, Oral oncology.

[44]  J. Burke,et al.  Expression of E-cadherin by human retinal pigment epithelium: delayed expression in vitro. , 1999, Investigative ophthalmology & visual science.

[45]  H. Friess,et al.  Bone morphogenetic protein 2 exerts diverse effects on cell growth in vitro and is expressed in human pancreatic cancer in vivo. , 1999, Gastroenterology.

[46]  J. Massagué,et al.  Betaglycan presents ligand to the TGFβ signaling receptor , 1993, Cell.

[47]  J. Massagué,et al.  Betaglycan presents ligand to the TGF beta signaling receptor. , 1993, Cell.

[48]  T. Akagi,et al.  ESTABLISHMENT and CHARACTERISTICS OF A HUMAN PANCREATIC CANCER CELL LINE (HGC‐25) , 1977, Acta pathologica japonica.

[49]  Haiyun Denga,et al.  Bone morphogenetic protein-4 is overexpressed in colonic adenocarcinomas and promotes migration and invasion of HCT 116 cells , 2022 .