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

A Safina, E Vandette, AV Bakin - Oncogene, 2007 - nature.com
A Safina, E Vandette, AV Bakin
Oncogene, 2007nature.com
Transforming growth factor beta 1 (TGF-β1) is a potent tumor suppressor but, paradoxically,
TGF-β1 enhances tumor growth and metastasis in the late stages of cancer progression.
This study investigated the role of TGF-β 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-β signaling in MDA-MB-231 cells is required for tumor cell invasion and
tumor angiogenesis. Expression of kinase-inactive ALK5 reduces tumor invasion and …
Abstract
Transforming growth factor beta 1 (TGF-β1) is a potent tumor suppressor but, paradoxically, TGF-β1 enhances tumor growth and metastasis in the late stages of cancer progression. This study investigated the role of TGF-β 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-β 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-β-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-β-mediated cell migration. Collectively, our results show that TGF-β-ALK5-MAPK signaling in tumor cells promotes tumor angiogenesis and MMP-9 is an important component of this program.
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