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Cell and Tumor Biology |
1 Institute of Molecular Pathology, University of Copenhagen; 2 Department of Pathology, Rigshospitalet University Hospital, Copenhagen, Denmark; 3 Department of Pathology, Turku University, Turku, Finland; and 4 Beth Israel Deaconess Center, Harvard Medical School, Boston, Massachusetts
Requests for reprints: Ulla M. Wewer, Institute of Molecular Pathology, University of Copenhagen, Frederik V's vej 11, 2100 Copenhagen, Denmark. Phone: 45-3532-6056; Fax: 45-3532-6081; E-mail: ullaw{at}pai.ku.dk.
As in developmental and regenerative processes, cell survival is of fundamental importance in cancer. Thus, a tremendous effort has been devoted to dissecting the molecular mechanisms involved in understanding the resistance of tumor cells to programmed cell death. Recently, the importance of stromal fibroblasts in tumor initiation and progression has been elucidated. Here, we show that stromal cell apoptosis occurs in human breast carcinoma but is only rarely seen in nonmalignant breast lesions. Furthermore, we show that ADAM12, a disintegrin and metalloprotease up-regulated in human breast cancer, accelerates tumor progression in a mouse breast cancer model. ADAM12 does not influence tumor cell proliferation but rather confers both decreased tumor cell apoptosis and increased stromal cell apoptosis. This dual role of ADAM12 in governing cell survival is underscored by the finding that ADAM12 increases the apoptotic sensitivity of nonneoplastic cells in vitro while rendering tumor cells more resistant to apoptosis. Together, these results show that the ability of ADAM12 to influence apoptosis may contribute to tumor progression.
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  H. P. Sorensen, R. R. Vives, C. Manetopoulos, R. Albrechtsen, M. C. Lydolph, J. Jacobsen, J. R. Couchman, and U. M. Wewer Heparan Sulfate Regulates ADAM12 through a Molecular Switch Mechanism J. Biol. Chem., November 14, 2008; 283(46): 31920 - 31932. [Abstract] [Full Text] [PDF]
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K. Bourd-Boittin, H. Le Pabic, D. Bonnier, A. L'Helgoualc'h, and N. Theret RACK1, a New ADAM12 Interacting Protein: CONTRIBUTION TO LIVER FIBROGENESIS J. Biol. Chem., September 19, 2008; 283(38): 26000 - 26009. [Abstract] [Full Text] [PDF]
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 N. Kawaguchi, K. Horiuchi, J. D. Becherer, Y. Toyama, P. Besmer, and C. P. Blobel Different ADAMs have distinct influences on Kit ligand processing: phorbol-ester-stimulated ectodomain shedding of Kitl1 by ADAM17 is reduced by ADAM19 J. Cell Sci., March 15, 2007; 120(6): 943 - 952. [Abstract] [Full Text] [PDF]
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 K. Horiuchi, S. Le Gall, M. Schulte, T. Yamaguchi, K. Reiss, G. Murphy, Y. Toyama, D. Hartmann, P. Saftig, and C. P. Blobel Substrate Selectivity of Epidermal Growth Factor-Receptor Ligand Sheddases and their Regulation by Phorbol Esters and Calcium Influx Mol. Biol. Cell, January 1, 2007; 18(1): 176 - 188. [Abstract] [Full Text] [PDF]
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 C. Frohlich, R. Albrechtsen, L. Dyrskjot, L. Rudkjaer, T. F. Orntoft, and U. M. Wewer Molecular Profiling of ADAM12 in Human Bladder Cancer Clin. Cancer Res., December 15, 2006; 12(24): 7359 - 7368. [Abstract] [Full Text] [PDF]
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 Y. Mitsui, S. Mochizuki, T. Kodama, M. Shimoda, T. Ohtsuka, T. Shiomi, M. Chijiiwa, T. Ikeda, M. Kitajima, and Y. Okada ADAM28 Is Overexpressed in Human Breast Carcinomas: Implications for Carcinoma Cell Proliferation through Cleavage of Insulin-like Growth Factor Binding Protein-3. Cancer Res., October 15, 2006; 66(20): 9913 - 9920. [Abstract] [Full Text] [PDF]
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U. M. Wewer, M. Morgelin, P. Holck, J. Jacobsen, M. C. Lydolph, A. H. Johnsen, M. Kveiborg, and R. Albrechtsen ADAM12 Is a Four-leafed Clover: THE EXCISED PRODOMAIN REMAINS BOUND TO THE MATURE ENZYME J. Biol. Chem., April 7, 2006; 281(14): 9418 - 9422. [Abstract] [Full Text] [PDF]
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M. D. Vos, A. Dallol, K. Eckfeld, N. P. C. Allen, H. Donninger, L. B. Hesson, D. Calvisi, F. Latif, and G. J. Clark The RASSF1A Tumor Suppressor Activates Bax via MOAP-1 J. Biol. Chem., February 24, 2006; 281(8): 4557 - 4563. [Abstract] [Full Text] [PDF]
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