Metalloproteinase-Dependent and -Independent processes contribute to inhibition of breast cancer cell migration, angiogenesis and liver metastasis by a disintegrin and metalloproteinase with thrombospondin motifs-15

Richard Kelwick, Laura Wagstaff, Julie Decock, Christian Roghi, Lindsay S. Cooley, Stephen D. Robinson, Hugh Arnold, Jelena Gavrilovic, Diane M. Jaworski, Kazuhiro Yamamoto, Hideaki Nagase, Bastian Seubert, Achim Krüger, Dylan R. Edwards

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

The ADAMTS proteinases are a family of secreted, matrix-Associated enzymes that have diverse roles in the regulation of tissue organization and vascular homeostasis. Several of the 19 human family members have been identified as having either tumor promoting or suppressing roles. We previously demonstrated that decreased ADAMTS15 expression correlated with a worse clinical outcome in mammary carcinoma (e.g., Porter et al., Int J Cancer 2006;118:1241-7). We have explored the effects of A Disintegrin and Metalloproteinase with Thrombospondin motifs-15 (ADAMTS-15) on the behavior of MDA-MB-231 and MCF-7 breast cancer cells by stable expression of either a wild-type (wt) or metalloproteinase-inactive (E362A) protein. No effects on mammary cancer cell proliferation or apoptosis were observed for either form of ADAMTS-15. However, both forms reduced cell migration on fibronectin or laminin matrices, though motility on a Type I collagen matrix was unimpaired. Knockdown of syndecan-4 attenuated the inhibitory effects of ADAMTS-15 on cell migration. In contrast to its effects on cell migration, wt ADAMTS-15 but not the E362A inactive mutant inhibited endothelial tubulogenesis in 3D collagen gels and angiogenesis in the aortic ring assay. In experimental metastasis assays in nude mice, MDA-MB-231 cells expressing either form of ADAMTS-15 showed reduced spread to the liver, though lung colonization was enhanced for cells expressing wt ADAMTS-15. These studies indicate that extracellular ADAMTS-15 has multiple actions on tumor pathophysiology. Via modulation of cell-ECM interactions, which likely involve syndecan-4, it attenuates mammary cancer cell migration independent of its metalloproteinase activity; however, its antiangiogenic action requires catalytic functionality, and its effects on metastasis in vivo are tissue niche-dependent.

Original languageEnglish
Pages (from-to)E14-E26
JournalInternational Journal of Cancer
Volume136
Issue number4
DOIs
Publication statusPublished - 1 Jan 2014
Externally publishedYes

Fingerprint

Thrombospondins
Disintegrins
Metalloproteases
Cell Movement
Breast Neoplasms
Neoplasm Metastasis
Liver
Syndecan-4
Inhibition (Psychology)
Neoplasms
Laminin
Collagen Type I
Fibronectins
Nude Mice
Cell Communication
Blood Vessels
Homeostasis
Collagen
Gels
Cell Proliferation

Keywords

  • ADAMTS
  • Angiogenesis
  • Mammary cancer
  • Metalloproteinase
  • Metastasis
  • Migration

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Metalloproteinase-Dependent and -Independent processes contribute to inhibition of breast cancer cell migration, angiogenesis and liver metastasis by a disintegrin and metalloproteinase with thrombospondin motifs-15. / Kelwick, Richard; Wagstaff, Laura; Decock, Julie; Roghi, Christian; Cooley, Lindsay S.; Robinson, Stephen D.; Arnold, Hugh; Gavrilovic, Jelena; Jaworski, Diane M.; Yamamoto, Kazuhiro; Nagase, Hideaki; Seubert, Bastian; Krüger, Achim; Edwards, Dylan R.

In: International Journal of Cancer, Vol. 136, No. 4, 01.01.2014, p. E14-E26.

Research output: Contribution to journalArticle

Kelwick, R, Wagstaff, L, Decock, J, Roghi, C, Cooley, LS, Robinson, SD, Arnold, H, Gavrilovic, J, Jaworski, DM, Yamamoto, K, Nagase, H, Seubert, B, Krüger, A & Edwards, DR 2014, 'Metalloproteinase-Dependent and -Independent processes contribute to inhibition of breast cancer cell migration, angiogenesis and liver metastasis by a disintegrin and metalloproteinase with thrombospondin motifs-15', International Journal of Cancer, vol. 136, no. 4, pp. E14-E26. https://doi.org/10.1002/ijc.29129
Kelwick, Richard ; Wagstaff, Laura ; Decock, Julie ; Roghi, Christian ; Cooley, Lindsay S. ; Robinson, Stephen D. ; Arnold, Hugh ; Gavrilovic, Jelena ; Jaworski, Diane M. ; Yamamoto, Kazuhiro ; Nagase, Hideaki ; Seubert, Bastian ; Krüger, Achim ; Edwards, Dylan R. / Metalloproteinase-Dependent and -Independent processes contribute to inhibition of breast cancer cell migration, angiogenesis and liver metastasis by a disintegrin and metalloproteinase with thrombospondin motifs-15. In: International Journal of Cancer. 2014 ; Vol. 136, No. 4. pp. E14-E26.
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abstract = "The ADAMTS proteinases are a family of secreted, matrix-Associated enzymes that have diverse roles in the regulation of tissue organization and vascular homeostasis. Several of the 19 human family members have been identified as having either tumor promoting or suppressing roles. We previously demonstrated that decreased ADAMTS15 expression correlated with a worse clinical outcome in mammary carcinoma (e.g., Porter et al., Int J Cancer 2006;118:1241-7). We have explored the effects of A Disintegrin and Metalloproteinase with Thrombospondin motifs-15 (ADAMTS-15) on the behavior of MDA-MB-231 and MCF-7 breast cancer cells by stable expression of either a wild-type (wt) or metalloproteinase-inactive (E362A) protein. No effects on mammary cancer cell proliferation or apoptosis were observed for either form of ADAMTS-15. However, both forms reduced cell migration on fibronectin or laminin matrices, though motility on a Type I collagen matrix was unimpaired. Knockdown of syndecan-4 attenuated the inhibitory effects of ADAMTS-15 on cell migration. In contrast to its effects on cell migration, wt ADAMTS-15 but not the E362A inactive mutant inhibited endothelial tubulogenesis in 3D collagen gels and angiogenesis in the aortic ring assay. In experimental metastasis assays in nude mice, MDA-MB-231 cells expressing either form of ADAMTS-15 showed reduced spread to the liver, though lung colonization was enhanced for cells expressing wt ADAMTS-15. These studies indicate that extracellular ADAMTS-15 has multiple actions on tumor pathophysiology. Via modulation of cell-ECM interactions, which likely involve syndecan-4, it attenuates mammary cancer cell migration independent of its metalloproteinase activity; however, its antiangiogenic action requires catalytic functionality, and its effects on metastasis in vivo are tissue niche-dependent.",
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