Dual stromelysin-3 function during natural mouse mammary tumor virus-ras tumor progression.

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.

[1]  B. Fingleton,et al.  Matrix Metalloproteinase Inhibitors and Cancer—Trials and Tribulations , 2002, Science.

[2]  B. Vogelstein,et al.  Prevalence of ras gene mutations in human colorectal cancers , 1987, Nature.

[3]  R. Kerbel,et al.  A paradigm for therapy-induced microenvironmental changes in solid tumors leading to drug resistance. , 2002, Differentiation; research in biological diversity.

[4]  A. Krüger,et al.  Hydroxamate-type matrix metalloproteinase inhibitor batimastat promotes liver metastasis. , 2001, Cancer research.

[5]  F. Basolo,et al.  Early Pathologic Changes in Experimental and Human Breast Cancer: Facts and Comments a , 1986, Annals of the New York Academy of Sciences.

[6]  H. Lijnen,et al.  Generation of an angiostatin-like fragment from plasminogen by stromelysin-1 (MMP-3). , 1998, Biochemistry.

[7]  M. Raff,et al.  Social controls on cell survival and cell death , 1992, Nature.

[8]  Allan Balmain,et al.  Activation of the mouse cellular Harvey-ras gene in chemically induced benign skin papillomas , 1984, Nature.

[9]  A. Noël,et al.  Stromelysin-3 in the biology of the normal and neoplastic mammary gland , 1996, Journal of Mammary Gland Biology and Neoplasia.

[10]  M. Rio.  STROMELYSIN-3, A PARTICULAR MEMBER OF THE MATRIX METALLOPROTEINASE FAMILY , 2002 .

[11]  L. Trusolino,et al.  Invasive growth: from development to metastasis. , 2002, The Journal of clinical investigation.

[12]  S. Frisch,et al.  Disruption of epithelial cell-matrix interactions induces apoptosis , 1994, The Journal of cell biology.

[13]  P. Basset,et al.  Matrix metalloproteinases as stromal effectors of human carcinoma progression: therapeutic implications. , 1997, Matrix biology : journal of the International Society for Matrix Biology.

[14]  A. McClatchey.  Modeling metastasis in the mouse , 1999, Oncogene.

[15]  I. Fidler,et al.  Macrophage-Derived Metalloelastase Is Responsible for the Generation of Angiostatin in Lewis Lung Carcinoma , 1997, Cell.

[16]  L. Matrisian,et al.  Matrix metalloproteinases: they're not just for matrix anymore! , 2001, Current opinion in cell biology.

[17]  Robert A. Weinberg,et al.  Creation of human tumour cells with defined genetic elements , 1999, Nature.

[18]  René Bernards,et al.  A progression puzzle. , 2002, Nature.

[19]  I. Macdonald,et al.  Cancer spread and micrometastasis development: Quantitative approaches for in vivo models , 2002, BioEssays : news and reviews in molecular, cellular and developmental biology.

[20]  C. Sautès-Fridman,et al.  High cancer cell death in syngeneic tumors developed in host mice deficient for the stromelysin-3 matrix metalloproteinase. , 2001, Cancer research.

[21]  D. Hanahan,et al.  Effects of angiogenesis inhibitors on multistage carcinogenesis in mice. , 1999, Science.

[22]  M J Bissell,et al.  Tumors are unique organs defined by abnormal signaling and context. , 2001, Seminars in cancer biology.

[23]  M. Shipp,et al.  Stromelysin‐3 suppresses tumor cell apoptosis in a murine model * , 2001, Journal of cellular biochemistry.

[24]  William E. Grizzle,et al.  Detection of high incidence of K-ras oncogenes during human colon tumorigenesis , 1987, Nature.

[25]  S. Itohara,et al.  Reduced angiogenesis and tumor progression in gelatinase A-deficient mice. , 1998, Cancer research.

[26]  D. Hanahan,et al.  MMP-9 Supplied by Bone Marrow–Derived Cells Contributes to Skin Carcinogenesis , 2000, Cell.

[27]  A. Noël,et al.  Stromelysin-3: a paradigm for stroma-derived factors implicated in carcinoma progression. , 1997, Critical reviews in oncology/hematology.

[28]  N. Fusenig,et al.  Tumor-stroma interactions directing phenotype and progression of epithelial skin tumor cells. , 2002, Differentiation; research in biological diversity.

[29]  J. Gregg,et al.  Contributions of mouse biology to breast cancer research. , 2002, Comparative medicine.

[30]  A. Pozzi,et al.  Low plasma levels of matrix metalloproteinase 9 permit increased tumor angiogenesis , 2002, Oncogene.

[31]  Carlos López-Otín,et al.  Strategies for MMP inhibition in cancer: innovations for the post-trial era , 2002, Nature Reviews Cancer.

[32]  T. Mcclanahan,et al.  Involvement of chemokine receptors in breast cancer metastasis , 2001, Nature.

[33]  S. Zucker,et al.  Critical appraisal of the use of matrix metalloproteinase inhibitors in cancer treatment , 2000, Oncogene.

[34]  B. Hogan,et al.  Intestinal tumorigenesis is suppressed in mice lacking the metalloproteinase matrilysin. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[35]  S. Hilsenbeck,et al.  Increased tumor proliferation and genomic instability without decreased apoptosis in MMTV-ras mice deficient in p53 , 1997, Molecular and cellular biology.

[36]  J. Foidart,et al.  In Vivo Evidence That the Stromelysin-3 Metalloproteinase Contributes in a Paracrine Manner to Epithelial Cell Malignancy , 1998, The Journal of cell biology.

[37]  B. Têtu,et al.  Stromelysin‐3 expression by mammary tumor‐associated fibroblasts under in vitro breast cancer cell induction , 2002, International journal of cancer.

[38]  A. Pellicer,et al.  Mutational activation of oncogenes in animal model systems of carcinogenesis. , 1987, Mutation research.

[39]  J. Foidart,et al.  Demonstration in vivo that stromelysin-3 functions through its proteolytic activity , 2000, Oncogene.

[40]  P. Leder,et al.  Coexpression of MMTV/v-Ha-ras and MMTV/c-myc genes in transgenic mice: Synergistic action of oncogenes in vivo , 1987, Cell.

[41]  M. Shipp,et al.  Stromelysin-3 Is Induced in Tumor/Stroma Cocultures and Inactivated via a Tumor-specific and Basic Fibroblast Growth Factor-dependent Mechanism* , 1998, The Journal of Biological Chemistry.

[42]  I. Macdonald,et al.  Metastasis: Dissemination and growth of cancer cells in metastatic sites , 2002, Nature Reviews Cancer.

[43]  M. Schwartz,et al.  The extracellular matrix as a cell survival factor. , 1993, Molecular biology of the cell.

[44]  D. Hanahan,et al.  Patterns and Emerging Mechanisms of the Angiogenic Switch during Tumorigenesis , 1996, Cell.