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ALK5 promotes tumor angiogenesis by upregulating matrix metalloproteinase-9 in tumor cells.

Abstract
Transforming growth factor beta 1 (TGF-beta1) is a potent tumor suppressor but, paradoxically, TGF-beta1 enhances tumor growth and metastasis in the late stages of cancer progression. This study investigated the role of TGF-beta type I receptor, ALK5, and three mitogen-activated protein kinases (MAPKs) in metastasis by breast cancer cell line MDA-MB-231. We show that autocrine TGF-beta signaling in MDA-MB-231 cells is required for tumor cell invasion and tumor angiogenesis. Expression of kinase-inactive ALK5 reduces tumor invasion and formation of new blood vessels within the tumor orthotopic xenografts in severe combined immunodeficiency (SCID) mice. In contrast, constitutively active ALK5-T204D enhances tumor invasion and angiogenesis by stimulating expression of matrix metalloproteinase MMP-9/gelatinase-B. Ablation of MMP-9 in ALK5-T204D cells by RNA interference (RNAi) reduces tumor invasion and tumor growth. Importantly, RNAi-MMP-9 reduces tumor neovasculature and increases tumor cell death. Induction of MMP-9 by TGF-beta-ALK5 signaling requires MEK-ERK but not JNK, p38 MAPK or Smad4. Dominant-negative MEK blocks and constitutively active MEK1 enhances MMP-9 expression. However, all three MAPK cascades (ERK, JNK and p38 MAPK) are required for TGF-beta-mediated cell migration. Collectively, our results show that TGF-beta-ALK5-MAPK signaling in tumor cells promotes tumor angiogenesis and MMP-9 is an important component of this program.
AuthorsA Safina, E Vandette, A V Bakin
JournalOncogene (Oncogene) Vol. 26 Issue 17 Pg. 2407-22 (Apr 12 2007) ISSN: 0950-9232 [Print] England
PMID17072348 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
Chemical References
  • Receptors, Transforming Growth Factor beta
  • Transforming Growth Factor beta1
  • Protein Serine-Threonine Kinases
  • Activin Receptors, Type I
  • Receptor, Transforming Growth Factor-beta Type I
  • TGFBR1 protein, human
  • Tgfbr1 protein, mouse
  • Matrix Metalloproteinase 9
Topics
  • Activin Receptors, Type I (physiology)
  • Animals
  • Breast Neoplasms (blood supply, enzymology, pathology)
  • Enzyme Activation (physiology)
  • Female
  • Humans
  • Matrix Metalloproteinase 9 (biosynthesis, genetics)
  • Mice
  • Mice, SCID
  • Neoplasm Invasiveness
  • Neovascularization, Pathologic (enzymology)
  • Protein Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type I
  • Receptors, Transforming Growth Factor beta (physiology)
  • Signal Transduction (physiology)
  • Transforming Growth Factor beta1 (physiology)
  • Up-Regulation (physiology)

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