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

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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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Accession codes

Accessions

GenBank/EMBL/DDBJ

Abbreviations

MAPK:

mitogen-activated protein kinase

MMP-9:

matrix metalloproteinase-9

TGF-β:

transforming growth factor beta

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Acknowledgements

We thank J-M Gauthier, J Massague, A Bhattacharya, and J Bromberg for providing reagents; Heinz Baumann, Ivan Still, and Elizabeth Repasky for critical reading of the paper; Mary M Vaughan and Karoly Toth for assistance with the immunohistochemistry and histopathology; Patricia Masso-Welch and Ming-Qiang Ren for help in some animal experiments. This work was supported by PHS Grant R01 CA95263 and USAMRMC Grant DAMD17-02-01-0602 (to AVB) and in part by the Roswell Park Cancer Institute Cancer Center Support Grant CA 16056.

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  1. Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY, USA

    A Safina, E Vandette & A V Bakin

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  1. A Safina
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Correspondence to A V Bakin.

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Safina, A., Vandette, E. & Bakin, A. ALK5 promotes tumor angiogenesis by upregulating matrix metalloproteinase-9 in tumor cells. Oncogene 26, 2407–2422 (2007). https://doi.org/10.1038/sj.onc.1210046

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