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Matrix metalloproteinase-11/stromelysin-3 exhibits collagenolytic function against collagen VI under normal and malignant conditions

Oncogene volume 27, pages 6347–6355 (2008)Cite this article

Abstract

The substrate of matrix metalloproteinase 11 (MMP11) remains unknown. We have recently shown that MMP11 is a negative regulator of adipogenesis, able to reduce and even to revert mature adipocyte differentiation. Here, we have used mouse 3T3L1 cells and human U87MG and SaOS cells to show that MMP11 cleaves the native α3 chain of collagen VI, which is an adipocyte-related extracellular matrix component. It is known that extracellular proteolytic processing of this chain is required for correct collagen VI folding. Interestingly, MMP11-deficient fat tissue is less cohesive and exhibits collagen VI alteration, dramatic adipocyte plasma and basement membrane abnormalities and lipid leakage. MMP11 is thus required for correct collagen VI folding and therefore for fat tissue cohesion and adipocyte function. Both MMP11 and collagen VI favor tumor progression. Similar spatio-temporal overexpression at the adipocyte–cancer cell interface has been reported for the two proteins. MMP11-dependent collagen VI processing might therefore be expected to occur during malignancy. Accordingly, collagen VI no longer delineates adipocytes located at the invasive front of breast carcinomas. In conclusion, the native α3 chain of collagen VI constitutes a specific MMP11 substrate. This MMP11 collagenolytic activity is functional in fat tissue ontogenesis as well as during cancer invasive steps.

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References

  • Aigner T, Hambach L, Soder S, Schlotzer-Schrehardt U, Poschl E . (2002). The C5 domain of Col6A3 is cleaved off from the Col6 fibrils immediately after secretion. Biochem Biophys Res Commun 290: 743–748.

    Article  CAS  PubMed  Google Scholar 

  • Andarawewa KL, Motrescu ER, Chenard MP, Gansmuller A, Stoll I, Tomasetto C et al. (2005). Stromelysin-3 is a potent negative regulator of adipogenesis participating to cancer cell-adipocyte interaction/crosstalk at the tumor invasive front. Cancer Res 65: 10862–10871.

    Article  CAS  PubMed  Google Scholar 

  • Basset P, Bellocq JP, Wolf C, Stoll I, Hutin P, Limacher JM et al. (1990). A novel metalloproteinase gene specifically expressed in stromal cells of breast carcinomas. Nature 348: 699–704.

    Article  CAS  PubMed  Google Scholar 

  • Basset P, Okada A, Chenard MP, Kannan R, Stoll I, Anglard P et al. (1997). Matrix metalloproteinases as stromal effectors of human carcinoma progression: therapeutic implications. Matrix Biol 15: 535–541.

    Article  CAS  PubMed  Google Scholar 

  • Bernlohr DA, Angus CW, Lane MD, Bolanowski MA, Kelly Jr TJ . (1984). Expression of specific mRNAs during adipose differentiation: identification of an mRNA encoding a homologue of myelin P2 protein. Proc Natl Acad Sci USA 81: 5468–5472.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Boulay A, Masson R, Chenard MP, El Fahime M, Cassard L, Bellocq JP et al. (2001). High cancer cell death in syngeneic tumors developed in host mice deficient for the stromelysin-3 matrix metalloproteinase. Cancer Res 61: 2189–2193.

    CAS  PubMed  Google Scholar 

  • Celis JE, Moreira JM, Cabezon T, Gromov P, Friis E, Rank F et al. (2005). Identification of extracellular and intracellular signaling components of the mammary adipose tissue and its interstitial fluid in high risk breast cancer patients: toward dissecting the molecular circuitry of epithelial-adipocyte stromal cell interactions. Mol Cell Proteomics 4: 492–522.

    Article  CAS  PubMed  Google Scholar 

  • Dieudonne MN, Bussiere M, Dos Santos E, Leneveu MC, Giudicelli Y, Pecquery R . (2006). Adiponectin mediates antiproliferative and apoptotic responses in human MCF7 breast cancer cells. Biochem Biophys Res Commun 345: 271–279.

    Article  CAS  PubMed  Google Scholar 

  • Gregoire FM . (2001). Adipocyte differentiation: from fibroblast to endocrine cell. Exp Biol Med (Maywood) 226: 997–1002.

    Article  CAS  Google Scholar 

  • Han J, Daniel JC . (1995). Biosynthesis of type VI collagen by glioblastoma cells and possible function in cell invasion of three-dimensional matrices. Connect Tissue Res 31: 161–170.

    Article  CAS  PubMed  Google Scholar 

  • Iyengar P, Combs TP, Shah SJ, Gouon-Evans V, Pollard JW, Albanese C et al. (2003). Adipocyte-secreted factors synergistically promote mammary tumorigenesis through induction of anti-apoptotic transcriptional programs and proto-oncogene stabilization. Oncogene 22: 6408–6423.

    Article  CAS  PubMed  Google Scholar 

  • Iyengar P, Espina V, Williams TW, Lin Y, Berry D, Jelicks LA et al. (2005). Adipocyte-derived collagen VI affects early mammary tumor progression in vivo, demonstrating a critical interaction in the tumor/stroma microenvironment. J Clin Invest 115: 1163–1176.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kannan R, Ruff M, Kochins JG, Manly SP, Stoll I, El Fahime M et al. (1999). Purification of active matrix metalloproteinase catalytic domains and its use for screening of specific stromelysin-3 inhibitors. Protein Expr Purif 16: 76–83.

    Article  CAS  PubMed  Google Scholar 

  • Kielty CM, Lees M, Shuttleworth CA, Woolley D . (1993). Catabolism of intact type VI collagen microfibrils: susceptibility to degradation by serine proteinases. Biochem Biophys Res Commun 191: 1230–1236.

    Article  CAS  PubMed  Google Scholar 

  • Kuo HJ, Maslen CL, Keene DR, Glanville RW . (1997). Type VI collagen anchors endothelial basement membranes by interacting with type IV collagen. J Biol Chem 272: 26522–26529.

    Article  CAS  PubMed  Google Scholar 

  • Lamande SR, Morgelin M, Adams NE, Selan C, Allen JM . (2006). The C5 domain of the collagen VI alpha3(VI) chain is critical for extracellular microfibril formation and is present in the extracellular matrix of cultured cells. J Biol Chem 281: 16607–16614.

    Article  CAS  PubMed  Google Scholar 

  • Manabe Y, Toda S, Miyazaki K, Sugihara H . (2003). Mature adipocytes, but not preadipocytes, promote the growth of breast carcinoma cells in collagen gel matrix culture through cancer-stromal cell interactions. J Pathol 201: 221–228.

    Article  PubMed  Google Scholar 

  • Masson R, Lefebvre O, Noel A, Fahime ME, Chenard MP, Wendling C et al. (1998). In vivo evidence that the stromelysin-3 metalloproteinase contributes in a paracrine manner to epithelial cell malignancy. J Cell Biol 140: 1535–1541.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • McCawley LJ, Matrisian LM . (2001). Matrix metalloproteinases: they’re not just for matrix anymore. Curr Opin Cell Biol 13: 534–540.

    Article  CAS  PubMed  Google Scholar 

  • Motrescu ER, Rio MC . (2008). Cancer cells, adipocytes and matrix metalloproteinase 11: a vicious tumor progression cycle. Biol Chem 389.

  • Myint E, Brown DJ, Ljubimov AV, Kyaw M, Kenney MC . (1996). Cleavage of human corneal type VI collagen alpha 3 chain by matrix metalloproteinase-2. Cornea 15: 490–496.

    Article  CAS  PubMed  Google Scholar 

  • Nakajima I, Muroya S, Tanabe R, Chikuni K . (2002). Positive effect of collagen V and VI on triglyceride accumulation during differentiation in cultures of bovine intramuscular adipocytes. Differentiation 70: 84–91.

    Article  CAS  PubMed  Google Scholar 

  • Noel A, Boulay A, Kebers F, Kannan R, Hajitou A, Calberg-Bacq CM et al. (2000). Demonstration in vivo that stromelysin-3 functions through its proteolytic activity. Oncogene 19: 1605–1612.

    Article  CAS  PubMed  Google Scholar 

  • Noel A, Santavicca M, Stoll I, L’Hoir C, Staub A, Murphy G et al. (1995). Identification of structural determinants controlling human and mouse stromelysin-3 proteolytic activities. J Biol Chem 270: 22866–22872.

    Article  CAS  PubMed  Google Scholar 

  • Pei D, Majmudar G, Weiss SJ . (1994). Hydrolytic inactivation of a breast carcinoma cell-derived serpin by human stromelysin-3. J Biol Chem 269: 25849–25855.

    CAS  PubMed  Google Scholar 

  • Pei D, Weiss SJ . (1995). Furin-dependent intracellular activation of the human stromelysin-3 zymogen. Nature 375: 244–247.

    Article  CAS  PubMed  Google Scholar 

  • Rio MC . (2002). Stromelysin-3, a Particular Member of the Matrix Metalloproteinase Family, kluwer academic edn. Kluwer Academic Publisher: Dordrecht.

    Google Scholar 

  • Ruhl M, Johannsen M, Atkinson J, Manski D, Sahin E, Somasundaram R et al. (1999). Soluble collagen VI induces tyrosine phosphorylation of paxillin and focal adhesion kinase and activates the MAP kinase erk2 in fibroblasts. Exp Cell Res 250: 548–557.

    Article  CAS  PubMed  Google Scholar 

  • Schaffler A, Scholmerich J, Buechler C . (2007). Mechanisms of disease: adipokines and breast cancer—endocrine and paracrine mechanisms that connect adiposity and breast cancer. Nat Clin Pract Endocrinol Metab 3: 345–354.

    Article  PubMed  Google Scholar 

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Acknowledgements

We thank Takako Sasaki from the Max-Planck-Institute for Biochemistry, Munich, Germany for his help. This study was supported by funds from the Institut National de la Santé et de la Recherche Médicale, the Centre National de la Recherche Scientifique, the Hôpital Universitaire de Strasbourg, the Association pour la Recherche sur le Cancer, the Ligue Nationale Française contre le Cancer and the Comités du Haut-Rhin et du Bas-Rhin (équipe labellisée), the European Commission (FP6 LSHC-CT-2003-503297; Cancer Degradome Project), the Institut National du Cancer, Fond National pour la Santé ACI 2004 Cancéropôle Grand-Est and the ‘Ruban Rose’ prize. EM was a recipient of an EU fellowship.

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  1. Departement de Biologie du Cancer, Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS UMR 7104, INSERM U596, Université Louis Pasteur, Illkirch Cedex, France

    E R Motrescu, S Blaise, N Etique, N Messaddeq, I Stoll, C Tomasetto & M-C Rio

  2. Service d’Anatomie Pathologique Générale, Centre Hospitalier Universitaire de Hautepierre, Strasbourg Cedex, France

    M-P Chenard

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  1. E R Motrescu
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Correspondence to M-C Rio.

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Motrescu, E., Blaise, S., Etique, N. et al. Matrix metalloproteinase-11/stromelysin-3 exhibits collagenolytic function against collagen VI under normal and malignant conditions. Oncogene 27, 6347–6355 (2008). https://doi.org/10.1038/onc.2008.218

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