Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Higher sensitivity of Adamts12-deficient mice to tumor growth and angiogenesis

Abstract

ADAMTS (a disintegrin and metalloproteinase domain with thrombospondin motifs) constitute a family of endopeptidases related to matrix metalloproteinases. These proteases have been largely implicated in tissue remodeling and angiogenesis associated with physiological and pathological processes. To elucidate the in vivo functions of ADAMTS-12, we have generated a knockout mouse strain (Adamts12−/−) in which Adamts12 gene was deleted. The mutant mice had normal gestations and no apparent defects in growth, life span and fertility. By applying three different in vivo models of angiogenesis (malignant keratinocyte transplantation, Matrigel plug and aortic ring assays) to Adamts12−/− mice, we provide evidence for a protective effect of this host enzyme toward angiogenesis and cancer progression. In the absence of Adamts-12, both the angiogenic response and tumor invasion into host tissue were increased. Complementing results were obtained by using medium conditioned by cells overexpressing human ADAMTS-12, which inhibited vessel outgrowth in the aortic ring assay. This angioinhibitory effect of ADAMTS-12 was independent of its enzymatic activity as a mutated inactive form of the enzyme was similarly efficient in inhibiting endothelial cell sprouting in the aortic ring assay than the wild-type form. Altogether, our results show that ADAMTS-12 displays antiangiogenic properties and protect the host toward tumor progression.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  • Bai XH, Wang DW, Luan Y, Yu XP, Liu CJ . (2009). Regulation of chondrocyte differentiation by ADAMTS-12 metalloproteinase depends on its enzymatic activity. Cell Mol Life Sci 66: 667–680.

    Article  CAS  Google Scholar 

  • Balbin M, Fueyo A, Tester AM, Pendas AM, Pitiot AS, Astudillo A et al. (2003). Loss of collagenase-2 confers increased skin tumor susceptibility to male mice. Nat Genet 35: 252–257.

    Article  CAS  Google Scholar 

  • Berndt S, Bruyere F, Jost M, Edwards DR, Noel A . (2008). In vitro and in vivo models of angiogenesis to dissect MMP functions. In Edwards DR, Hoyer-Hansen G, Blasi F, Sloane BF (eds). The Cancer Degradome: Proteases and Cancer Biology. Springer: New-York, 305–325.

    Chapter  Google Scholar 

  • Berndt S, Perrier DS, Blacher S, Pequeux C, Lorquet S, Munaut C et al. (2006). Angiogenic activity of human chorionic gonadotropin through LH receptor activation on endothelial and epithelial cells of the endometrium. FASEB J 20: 2630–2632.

    Article  CAS  Google Scholar 

  • Blacher S, Jost M, Melen-Lamalle L, Lund LR, Romer J, Foidart JM et al. (2008). Quantification of in vivo tumor invasion and vascularization by computerized image analysis. Microvasc Res 75: 169–178.

    Article  CAS  Google Scholar 

  • Cal S, Arguelles JM, Fernandez PL, Lopez-Otin C . (2001). Identification, characterization, and intracellular processing of ADAM-TS12, a novel human disintegrin with a complex structural organization involving multiple thrombospondin-1 repeats. J Biol Chem 276: 17932–17940.

    Article  CAS  Google Scholar 

  • Cauwe B, Van den Steen PE, Opdenakker G . (2007). The biochemical, biological, and pathological kaleidoscope of cell surface substrates processed by matrix metalloproteinases. Crit Rev Biochem Mol Biol 42: 113–185.

    Article  CAS  Google Scholar 

  • Dunn JR, Reed JE, du Plessis DG, Shaw EJ, Reeves P, Gee AL et al. (2006). Expression of ADAMTS-8, a secreted protease with antiangiogenic properties, is downregulated in brain tumours. Br J Cancer 94: 1186–1193.

    Article  CAS  Google Scholar 

  • Egeblad M, Werb Z . (2002). New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer 2: 161–174.

    Article  CAS  Google Scholar 

  • Fusenig NE, Breitkreutz D, Dzarlieva RT, Boukamp P, Bohnert A, Tilgen W . (1983). Growth and differentiation characteristics of transformed keratinocytes from mouse and human skin in vitro and in vivo. J Invest Dermatol 81: 168s–175s.

    Article  CAS  Google Scholar 

  • Iruela-Arispe ML, Carpizo D, Luque A . (2003). ADAMTS1: a matrix metalloprotease with angioinhibitory properties. Ann N Y Acad Sci 995: 183–190.

    Article  CAS  Google Scholar 

  • Jost M, Folgueras AR, Frerart F, Pendas A, Blacher S, Houard X et al. (2006). Earlier onset of tumoral angiogenesis in matrix metalloproteinase-19-deficient mice. Cancer Res 66: 5234–5241.

    Article  CAS  Google Scholar 

  • Jost M, Maillard C, Lecomte J, Lambert V, Tjwa M, Blaise P et al. (2007). Tumoral and choroidal vascularization: differential cellular mechanisms involving plasminogen activator inhibitor type I. Am J Pathol 171: 1369–1380.

    Article  CAS  Google Scholar 

  • Jost M, Vosseler S, Blacher S, Fusenig NE, Mueller MM, Noel A . (2008). The surface transplantation model to study the tumor-host interface. In Edwards DR, Hoyer-Hansen G, Blasi F, Sloane BF (eds). The Cancer Degradome: Proteases and Cancer Biology. Springer: New York, pp 327–342.

    Chapter  Google Scholar 

  • Kurz T, Hoffjan S, Hayes MG, Schneider D, Nicolae R, Heinzmann A et al. (2006). Fine mapping and positional candidate studies on chromosome 5p13 identify multiple asthma susceptibility loci. J Allergy Clin Immunol 118: 396–402.

    Article  CAS  Google Scholar 

  • Lambert V, Wielockx B, Munaut C, Galopin C, Jost M, Itoh T et al. (2003). MMP-2 and MMP-9 synergize in promoting choroidal neovascularization. FASEB J 17: 2290–2292.

    Article  CAS  Google Scholar 

  • Liu YJ, Xu Y, Yu Q . (2006). Full-length ADAMTS-1 and the ADAMTS-1 fragments display pro- and antimetastatic activity, respectively. Oncogene 25: 2452–2467.

    Article  CAS  Google Scholar 

  • Llamazares M, Obaya AJ, Moncada-Pazos A, Heljasvaara R, Espada J, Lopez-Otin C et al. (2007). The ADAMTS12 metalloproteinase exhibits anti-tumorigenic properties through modulation of the Ras-dependent ERK signalling pathway. J Cell Sci 120: 3544–3552.

    Article  CAS  Google Scholar 

  • Lopez-Otin C, Matrisian LM . (2007). Emerging roles of proteases in tumour suppression. Nat Rev Cancer 7: 800–808.

    Article  CAS  Google Scholar 

  • Luque A, Carpizo DR, Iruela-Arispe ML . (2003). ADAMTS1/METH1 inhibits endothelial cell proliferation by direct binding and sequestration of VEGF165. J Biol Chem 278: 23656–23665.

    Article  CAS  Google Scholar 

  • Masson VV, Devy L, Grignet-Debrus C, Bernt S, Bajou K, Blacher S et al. (2002). Mouse aortic ring assay: a new approach of the molecular genetics of angiogenesis. Biol Proced Online 4: 24–31.

    Article  CAS  Google Scholar 

  • Moncada-Pazos A, Obaya AJ, Fraga MF, Viloria CG, Capella G, Gausachs M et al. (2009). The ADAMTS12 metalloprotease gene is epigenetically silenced in tumor cells and transcriptionally activated in the stroma during progression of colon cancer. J Cell Sci 122: 2906–2913.

    Article  CAS  Google Scholar 

  • Mueller MM, Fusenig NE . (2004). Friends or foes—bipolar effects of the tumour stroma in cancer. Nat Rev Cancer 4: 839–849.

    Article  CAS  Google Scholar 

  • Noel A, Jost M, Maquoi E . (2008). Matrix metalloproteinases at cancer tumor-host interface. Semin Cell Dev Biol 19: 52–60.

    Article  CAS  Google Scholar 

  • Nyberg P, Salo T, Kalluri R . (2008). Tumor microenvironment and angiogenesis. Front Biosci 13: 6537–6553.

    Article  CAS  Google Scholar 

  • Overall CM, Blobel CP . (2007). In search of partners: linking extracellular proteases to substrates. Nat Rev Mol Cell Biol 8: 245–257.

    Article  CAS  Google Scholar 

  • Porter S, Clark IM, Kevorkian L, Edwards DR . (2005). The ADAMTS metalloproteinases. Biochem J 386: 15–27.

    Article  CAS  Google Scholar 

  • Porter S, Scott SD, Sassoon EM, Williams MR, Jones JL, Girling AC et al. (2004). Dysregulated expression of adamalysin-thrombospondin genes in human breast carcinoma. Clin Cancer Res 10: 2429–2440.

    Article  CAS  Google Scholar 

  • Rocks N, Paulissen G, El Hour M, Quesada F, Crahay C, Gueders M et al. (2008). Emerging roles of ADAM and ADAMTS metalloproteinases in cancer. Biochimie 90: 369–379.

    Article  CAS  Google Scholar 

  • Vazquez F, Hastings G, Ortega MA, Lane TF, Oikemus S, Lombardo M et al. (1999). METH-1, a human ortholog of ADAMTS-1, and METH-2 are members of a new family of proteins with angio-inhibitory activity. J Biol Chem 274: 23349–23357.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors acknowledge F Olivier, G Roland and L Volders for their excellent technical assistance. This work was supported by grants from Ministerio de Ciencia e Innovación, Fundación M. Botin (Spain), the FP7-HEALTH-2007-A—Project No. 201279 ‘MICROENVIMET’, the Fonds de la Recherche Scientifique-FNRS (FRS-FNRS, Belgium), the Foundation against Cancer (foundation of public interest, Belgium), the DGTRE from the SPW (Région Wallonne, Belgium), the Interuniversity Attraction Poles Programme—Belgian Science Policy (Brussels, Belgium). MEH, AM, JD, LH and FE are recipients of grants from the Fonds de la Recherche Scientifique (FRS-FNRS, Belgium).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to A Noel.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

El Hour, M., Moncada-Pazos, A., Blacher, S. et al. Higher sensitivity of Adamts12-deficient mice to tumor growth and angiogenesis. Oncogene 29, 3025–3032 (2010). https://doi.org/10.1038/onc.2010.49

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2010.49

Keywords

This article is cited by

Search

Quick links