Proteolytic exposure of a cryptic site within collagen type IV is required for angiogenesis and tumor growth in vivo

Evidence is provided that proteolytic cleavage of collagen type IV results in the exposure of a functionally important cryptic site hidden within its triple helical structure. Exposure of this cryptic site was associated with angiogenic, but not quiescent, blood vessels and was required for angiogenesis in vivo. Exposure of the HUIV26 epitope was associated with a loss of α1β1 integrin binding and the gain of αvβ3 binding. A monoclonal antibody (HUIV26) directed to this site disrupts integrin-dependent endothelial cell interactions and potently inhibits angiogenesis and tumor growth. Together, these studies suggest a novel mechanism by which proteolysis contributes to angiogenesis by exposing hidden regulatory elements within matrix-immobilized collagen type IV.

[1]  Chandra L. Theesfeld,et al.  Involvement of integrins alpha v beta 3 and alpha v beta 5 in ocular neovascular diseases. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[2]  M. Burdick,et al.  MIP-1alpha as a critical macrophage chemoattractant in murine wound repair. , 1998, The Journal of clinical investigation.

[3]  F Pozza,et al.  Tumor angiogenesis: a new significant and independent prognostic indicator in early-stage breast carcinoma. , 1992, Journal of the National Cancer Institute.

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

[5]  W. Stetler-Stevenson,et al.  Localization of matrix metalloproteinase MMP-2 to the surface of invasive cells by interaction with integrin alpha v beta 3. , 1996, Cell.

[6]  Pamela F. Jones,et al.  Requisite Role of Angiopoietin-1, a Ligand for the TIE2 Receptor, during Embryonic Angiogenesis , 1996, Cell.

[7]  Thiennu H. Vu,et al.  Matrix‐degrading proteases and angiogenesis during development and tumor formation , 1999, APMIS : acta pathologica, microbiologica, et immunologica Scandinavica.

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

[9]  W. Stetler-Stevenson,et al.  Matrix metalloproteinases in angiogenesis: a moving target for therapeutic intervention. , 1999, The Journal of clinical investigation.

[10]  L. Liotta,et al.  Cancer metastasis and angiogenesis: An imbalance of positive and negative regulation , 1991, Cell.

[11]  R. Timpl,et al.  Supramolecular assembly of basement membranes , 1996, BioEssays : news and reviews in molecular, cellular and developmental biology.

[12]  A. Koch,et al.  Angiogenesis mediated by soluble forms of E-selectin and vascular cell adhesion molecule-1 , 1995, Nature.

[13]  J. Risteli,et al.  Aggressive breast cancer leads to discrepant serum levels of the type I procollagen propeptides PINP and PICP. , 1997, Cancer research.

[14]  George E. Davis,et al.  Affinity of integrins for damaged extracellular matrix: αvβ3 binds to denatured collagen type I through RGD sites , 1992 .

[15]  R. Timpl.  Macromolecular organization of basement membranes. , 1996, Current opinion in cell biology.

[16]  G. G. Stokes.  "J." , 1890, The New Yale Book of Quotations.

[17]  H. Schnaper,et al.  Type IV collagenase(s) and TIMPs modulate endothelial cell morphogenesis in vitro , 1993, Journal of cellular physiology.

[18]  J. Xu,et al.  Generation of monoclonal antibodies to cryptic collagen sites by using subtractive immunization. , 2000, Hybridoma.

[19]  Lars Holmgren,et al.  Angiostatin: A novel angiogenesis inhibitor that mediates the suppression of metastases by a lewis lung carcinoma , 1994, Cell.

[20]  J W Smith,et al.  The Arg-Gly-Asp binding domain of the vitronectin receptor. Photoaffinity cross-linking implicates amino acid residues 61-203 of the beta subunit. , 1988, The Journal of biological chemistry.

[21]  K. Tryggvason,et al.  Type IV collagen: structure, gene organization, and role in human diseases. Molecular basis of Goodpasture and Alport syndromes and diffuse leiomyomatosis. , 1993, The Journal of biological chemistry.

[22]  D. Cheresh,et al.  Integrin α v β 3 antagonists promote tumor regression by inducing apoptosis of angiogenic blood vessels , 1994, Cell.

[23]  J. Bowersox,et al.  Chemotaxis of aortic endothelial cells in response to fibronectin. , 1982, Cancer research.

[24]  M. Humphries,et al.  Effects of collagenase-cleavage of type I collagen on alpha2beta1 integrin-mediated cell adhesion. , 1998, Journal of cell science.

[25]  G. Giannelli,et al.  Induction of cell migration by matrix metalloprotease-2 cleavage of laminin-5. , 1997, Science.

[26]  M. Humphries,et al.  Effects of collagenase-cleavage of type I collagen on α 2 β 1 integrin-mediated cell adhesion , 1998 .

[27]  W. Risau,et al.  Changes in the vascular extracellular matrix during embryonic vasculogenesis and angiogenesis. , 1988, Developmental biology.

[28]  B. Zetter,et al.  Tumor interactions with the vasculature: angiogenesis and tumor metastasis. , 1990, Biochimica et biophysica acta.

[29]  F. Mitjans,et al.  Integrin αVβ3 Promotes M21 Melanoma Growth in Human Skin by Regulating Tumor Cell Survival , 1999 .

[30]  D. Cheresh,et al.  Integrin alpha v beta 3 rescues melanoma cells from apoptosis in three-dimensional dermal collagen. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[31]  C. Perruzzi,et al.  Cell migration promoted by a potent GRGDS-containing thrombin-cleavage fragment of osteopontin. , 1996, Biochimica et biophysica acta.

[32]  Richard W. Farndale,et al.  Structural Basis of Collagen Recognition by Integrin α2β1 , 2000, Cell.

[33]  M. Aumailley,et al.  Extracellular matrix, integrins and focal adhesions. , 1999, Current topics in pathology. Ergebnisse der Pathologie.

[34]  L. Tsai.  Stuck on the ECM. , 1998, Trends in cell biology.

[35]  E. Tsilibary,et al.  Differential effects of laminin, intact type IV collagen, and specific domains of type IV collagen on endothelial cell adhesion and migration , 1988, The Journal of cell biology.

[36]  S. Weiss,et al.  Matrix Metalloproteinases Regulate Neovascularization by Acting as Pericellular Fibrinolysins , 1998, Cell.

[37]  D. Cheresh,et al.  Use of the 10-day-old chick embryo model for studying angiogenesis. , 1999, Methods in molecular biology.

[38]  J. Folkman,et al.  Tumor angiogenesis and metastasis--correlation in invasive breast carcinoma. , 1991, The New England journal of medicine.

[39]  W. Stetler-Stevenson,et al.  Localization of Matrix Metalloproteinase MMP-2 to the Surface of Invasive Cells by Interaction with Integrin αvβ3 , 1996, Cell.

[40]  G. Davis,et al.  Regulation of tissue injury responses by the exposure of matricryptic sites within extracellular matrix molecules. , 2000, The American journal of pathology.

[41]  Gabriele Bergers,et al.  MMP-9/Gelatinase B Is a Key Regulator of Growth Plate Angiogenesis and Apoptosis of Hypertrophic Chondrocytes , 1998, Cell.