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

Abstract

Transforming growth factor beta 1 (TGF-b1) is a potent tumor suppressor but, paradoxically, TGF-b1 enhances tumor growth and metastasis in the late stages of cancer progression. This study investigated the role of TGF-b 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-b signaling in MDA-MB-231 cells is required for tumor cell invasion and tumor angiogenesis. Expression of kinaseinactive 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-b-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-b-mediated cell migration. Collectively, our results show that TGF-b-ALK5-MAPK signaling in tumor cells promotes tumor angiogenesis and MMP-9 is an important component of this program.

Downregulation of microRNAs directs the EMT and invasive potential of anaplastic thyroid carcinomas

“…In extension to previous analyses, our results furthermore indicate that the microRNAmodulated role of TGFb signaling in directing EMT/ MET and invasion of ATCs also involves the control of TGFBR1 expression by the miR-200 family. These results are supported by previous analyses in other tumors and tumor-derived cells, in which it was shown that TGFBR1 acting through SMAD2/SMAD3 promotes metastasis and angiogenesis by modulating gene expression, for instance, the upregulation of metalloproteinase-9 and/or vascular endothelial growth factor (Cui et al, 1996;Piek et al, 1999;Guzinska-Ustymowicz and Kemona, 2005;Safina et al, 2007;Shao et al, 2009). Notably, recent evidence indicates that altered TGFb signaling also modulates microRNA maturation by RSMADs, as shown for the proinvasive miR-21 (Davis et al, 2008).…”

TAK1 is required for TGF-β1-mediated regulation of matrix metalloproteinase-9 and metastasis

“…MMP-9 contributes to tumor angiogenesis by promoting recruitment of endothelial cells (Bergers et al, 2000) and pericytes (Chantrain et al, 2004). Indeed, TGF-b1-mediated tumor angiogenesis is significantly reduced when MMP-9 is suppressed by RNA interference (short interfering RNA, siRNA) (Safina et al, 2007). The molecular mechanism of MMP-9 regulation by TGF-b1 is still not well understood.…”

“…Early studies with kinase inhibitors have implicated p38MAPK in MMP-9 regulation by TGF-b1 in breast cancer cells (Farina et al, 1998;Suarez-Cuervo et al, 2004). Recent studies with dominant-negative (dn) mutants of MAPKs have shown that p38MAPK is dispensable, whereas MEK-ERK contributes to TGF-b1 regulation of MMP-9 (Safina et al, 2007). Ras-ERK signaling has been also implicated in regulation of MMP-9 in fibroblasts and epithelial cell lines (Gum et al, 1996;Himelstein et al, 1997;Iyer et al, 2005).…”

“…Invasion and metastasis of cancer cells have been associated with TGF-b1-mediated upregulation of MMP-9/gelatinase-B (Farina et al, 1998;Suarez-Cuervo et al, 2004;Safina et al, 2007). MMP-9 contributes to tumor angiogenesis by promoting recruitment of endothelial cells (Bergers et al, 2000) and pericytes (Chantrain et al, 2004).…”

TGF-β-activated Kinase-1: A Potential Prognostic Marker for Clear Cell Renal Cell Carcinoma

“…TAK1 was proved to be a critical regulator of matrix-metalloproteinase-9 (MMP-9) expression (Safina et al, 2008). MMP-9/gelatinase-B contributes to the invasive and metastatic potential of cancer cells (Farina et al, 1998;Suarez et al, 2004;Safina et al, 2007), as well as to tumor angiogenesis, by promoting recruitment of endothelial cells (Bergers et al, 2000) and pericytes (Chantrain et al, 2004).…”