This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Andarawewa, K. L. Articles by Rio, M.-C. Search for Related Content PubMed PubMed Citation Articles by Andarawewa, K. L. Articles by Rio, M.-C.

Dual Stromelysin-3 Function during Natural Mouse Mammary Tumor Virus-ras Tumor Progression

Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique/Institut National de la Santé et de la Recherche Médicale U184/ULP BP 163, 67404 Illkirch, Cedex, C.U. de Strasbourg [K. L. A., A. B., R. M., C. M., I. S., C. T., M-C. R.], and Service d’Anatomie Pathologique Générale, Centre Hospitalier Universitaire de Hautepierre, 67098 Strasbourg, Cedex [M-P. C., M. G., J-P. B.], France

In human carcinomas, stromelysin-3/matrix metalloproteinase 11 (ST3, MMP11) expression by nonmalignant fibroblastic cells located in the immediate vicinity of cancer cells is a bad prognostic factor. Using mouse models of primary tumors, it has been demonstrated that ST3 is a key player during local invasion, favoring cancer cell survival in connective tissue through an antiapoptotic function. To investigate the ST3 impact on additional phases of cancer cell invasion, we developed mammary gland cancer prone MMTV-ras transgenic mice in wild-type (ras+/+;ST3+/+) or ST3-deficient (ras+/+;ST3-/-) genotype and studied their whole natural cancer history. The tumor-free survival and delay between the first ras oncogenic hit and primary tumor appearance increased in ras+/+;ST3-/- mice (P < 0.000001 and <0.0000007, respectively). A systematic search for occult primary tumors and metastases revealed, in addition to a lower total number and size of primary tumors (P < 0.02), an unexpected higher number of metastases (P < 0.01) in ras+/+;ST3-/- mice. Moreover, for a similar number and size of primary invasive tumors, ras+/+;ST3-/- mice developed more metastases, indicating that the cancer cells evolving in ST3-deficient stroma have an increased potential to hematogenous dissemination. We conclude that the ST3 microenvironment is a consistently active partner of invading cancer cells but that its function differs throughout cancer progression, being tumor enhancer or repressor in processes leading to local or distal invasion. Such a dual effect for an MMP might shed light, at least partially, for the absence of survival benefit for patients included in anti-MMP clinical trials.

This article has been cited by other articles:

				D. Peruzzi, F. Mori, A. Conforti, D. Lazzaro, E. De Rinaldis, G. Ciliberto, N. La Monica, and L. Aurisicchio MMP11: A Novel Target Antigen for Cancer Immunotherapy Clin. Cancer Res., June 15, 2009; 15(12): 4104 - 4113. [Abstract] [Full Text] [PDF]

				K. Almholt, A. Juncker-Jensen, O. D. Laerum, K. Dano, M. Johnsen, L. R. Lund, and J. Romer Metastasis is strongly reduced by the matrix metalloproteinase inhibitor Galardin in the MMTV-PymT transgenic breast cancer model Mol. Cancer Ther., September 1, 2008; 7(9): 2758 - 2767. [Abstract] [Full Text] [PDF]

				Y.-H. Yang, H. Deng, W.-M. Li, Q.-Y. Zhang, X.-T. Hu, B. Xiao, H.-H. Zhu, P.-L. Geng, and Y.-Y. Lu Identification of Matrix Metalloproteinase 11 as a Predictive Tumor Marker in Serum Based on Gene Expression Profiling Clin. Cancer Res., January 1, 2008; 14(1): 74 - 81. [Abstract] [Full Text] [PDF]

				J. J. Partridge, M. A. Madsen, V. C. Ardi, T. Papagiannakopoulos, T. A. Kupriyanova, J. P. Quigley, and E. I. Deryugina Functional Analysis of Matrix Metalloproteinases and Tissue Inhibitors of Metalloproteinases Differentially Expressed by Variants of Human HT-1080 Fibrosarcoma Exhibiting High and Low Levels of Intravasation and Metastasis J. Biol. Chem., December 7, 2007; 282(49): 35964 - 35977. [Abstract] [Full Text] [PDF]

				H.-I. Kwak, T. Gustafson, R. P. Metz, B. Laffin, P. Schedin, and W. W. Porter Inhibition of breast cancer growth and invasion by single-minded 2s Carcinogenesis, February 1, 2007; 28(2): 259 - 266. [Abstract] [Full Text] [PDF]

				Y. Pan, L. Zhao, J. Liang, J. Liu, Y. Shi, N. Liu, G. Zhang, H. Jin, J. Gao, H. Xie, et al. Cellular prion protein promotes invasion and metastasis of gastric cancer FASEB J, September 1, 2006; 20(11): 1886 - 1888. [Abstract] [Full Text] [PDF]

				M. Jost, A. R. Folgueras, F. Frerart, A. M. Pendas, S. Blacher, X. Houard, S. Berndt, C. Munaut, D. Cataldo, J. Alvarez, et al. Earlier onset of tumoral angiogenesis in matrix metalloproteinase-19-deficient mice. Cancer Res., May 15, 2006; 66(10): 5234 - 5241. [Abstract] [Full Text] [PDF]

				K. L. Andarawewa, E. R. Motrescu, M.-P. Chenard, A. Gansmuller, I. Stoll, C. Tomasetto, and M.-C. Rio Stromelysin-3 Is a Potent Negative Regulator of Adipogenesis Participating to Cancer Cell-Adipocyte Interaction/Crosstalk at the Tumor Invasive Front Cancer Res., December 1, 2005; 65(23): 10862 - 10871. [Abstract] [Full Text] [PDF]

				S. Arora, J. Kaur, C. Sharma, M. Mathur, S. Bahadur, N. K. Shukla, S. V.S. Deo, and R. Ralhan Stromelysin 3, Ets-1, and Vascular Endothelial Growth Factor Expression in Oral Precancerous and Cancerous Lesions: Correlation with Microvessel Density, Progression, and Prognosis Clin. Cancer Res., March 15, 2005; 11(6): 2272 - 2284. [Abstract] [Full Text] [PDF]

				K. Louis, N. Guerineau, O. Fromigue, V. Defamie, A. Collazos, P. Anglard, M. A. Shipp, P. Auberger, D. Joubert, and B. Mari Tumor Cell-mediated Induction of the Stromal Factor Stromelysin-3 Requires Heterotypic Cell Contact-dependent Activation of Specific Protein Kinase C Isoforms J. Biol. Chem., January 14, 2005; 280(2): 1272 - 1283. [Abstract] [Full Text] [PDF]