Trends in Cell Biology
Volume 21, Issue 4, April 2011, Pages 228-237
Journal home page for Trends in Cell Biology

Review
Proteolytic networks in cancer

https://doi.org/10.1016/j.tcb.2010.12.002Get rights and content

Proteases are important for multiple processes during malignant progression, including tumor angiogenesis, invasion and metastasis. Recent evidence reveals that tumor-promoting proteases function as part of an extensive multidirectional network of proteolytic interactions, in contrast to the unidirectional caspase cascade. These networks involve different constituents of the tumor microenvironment and key proteases, such as cathepsin B, urokinase-type plasminogen activator and several matrix metalloproteinases, occupy central nodes for amplifying proteolytic signals passing through the network. The proteolytic network interacts with other important signaling pathways in tumor biology, involving chemokines, cytokines, and kinases. Viewing these proteolytic interactions as a system of activating and inhibiting reactions provides insight into tumor biology and reveals relevant pharmaceutical targets. This review examines recent advances in understanding proteases in cancer and summarizes how the network of activity is co-opted to promote tumor progression.

Section snippets

Proteolytic networks in cancer

Proteases, once thought of as little more than cellular garbage disposals or extracellular matrix (ECM) degraders, are one of the largest groups of enzymes in the human genome. There are 570 known human proteases [1], coupled with a smaller group of endogenous protease inhibitors that tightly regulate their activity. While proteases mediate both terminal protein degradation and ECM remodeling, recent findings have revealed their functions in tumors to be significantly more complex and varied.

Interactions of proteases within smaller, interconnected cascades

Individual proteases, with their broad range of targets, multitude of activation mechanisms and proposed impact on tumor progression and metastasis, cannot be fully understood without placing them in the proper context of upstream and downstream proteases serving as activators or substrates. Proteases are synthesized as inactive (or marginally active) zymogens and require cleavage, usually by other proteases, for activation. Much like the well-studied kinase cascades that control cellular

Fitting nodes into cascades: who's on top?

The interaction of caspases in a cascade leading to cell death has been established for some time and is not discussed further here (for a more extensive review of caspases, see [3]). Even though some proteases with pro-tumor functions can enhance the caspase cascade, the overall cascade is independent of the tumor-promoting interactions described above.

The major tumor-promoting roles ascribed to proteases in the tumor microenvironment usually include migration, invasion, angiogenesis,

Viewing proteolytic interactions in networks provides insight into in vivo results

Given the difficulty in finding a consistent entry point into a unified cascade, an alternative is to unite the smaller cascades discussed earlier. This provides a more accurate view of proteolytic interactions in the form of a network of small, interconnected proteolytic cascades (Figure 1). This perspective allows for constant modulation of proteolytic activity by any number of proteases, with up- or downregulation of the activity of one protease potentially affecting the overall activity of

Conclusions

Our understanding of the proteolytic network in the tumor microenvironment is expanding rapidly as the result of an increased interest in protease biology and new techniques that allow for comprehensive analysis of protease activity in physiologically relevant conditions. Much like the well established kinase signaling networks, proteolytic networks consist of multiple points of entry/activation, several key nodes through which a majority of signals pass, and inhibitors/deactivators that can

Acknowledgments

We thank members of the Joyce laboratory for discussion on this topic, and Dr Lisa Sevenich for critical review of the manuscript. Research in the Joyce laboratory is supported by the National Cancer Institute, the Breast Cancer Research Foundation and the Geoffrey Beene Foundation. S.M. was supported by a Ruth Kirschstein National Research Service Award from the NIH.

References (99)

  • K. Kessenbrock

    Matrix metalloproteinases: regulators of the tumor microenvironment

    Cell

    (2010)
  • H.J. Ra et al.

    Control of matrix metalloproteinase catalytic activity

    Matrix Biol.

    (2007)
  • N. Ramos-DeSimone

    Activation of matrix metalloproteinase-9 (MMP-9) via a converging plasmin/stromelysin-1 cascade enhances tumor cell invasion

    J. Biol. Chem.

    (1999)
  • Y.P. Han

    Proteolytic activation of matrix metalloproteinase-9 in skin wound healing is inhibited by alpha-1-antichymotrypsin

    J. Invest. Dermatol.

    (2008)
  • G.S. Makowski et al.

    Autoactivation profiles of calcium-dependent matrix metalloproteinase-2 and -9 in inflammatory synovial fluid: effect of pyrophosphate and bisphosphonates

    Clin. Chim. Acta

    (2005)
  • E. Tchougounova

    A key role for mast cell chymase in the activation of pro-matrix metalloprotease-9 and pro-matrix metalloprotease-2

    J. Biol. Chem.

    (2005)
  • R.G. Rowe et al.

    Breaching the basement membrane: who, when and how?

    Trends Cell Biol.

    (2008)
  • U. Auf dem Keller

    A statistics-based platform for quantitative N-terminome analysis and identification of protease cleavage products

    Mol. Cell Proteomics

    (2010)
  • A. Doucet et al.

    Protease proteomics: revealing protease in vivo functions using systems biology approaches

    Mol. Aspects Med.

    (2008)
  • P. Ovaere

    The emerging roles of serine protease cascades in the epidermis

    Trends Biochem. Sci.

    (2009)
  • C.J. Morrison

    Matrix metalloproteinase proteomics: substrates, targets, and therapy

    Curr. Opin. Cell Biol.

    (2009)
  • L.R. Dick et al.

    Building on bortezomib: second-generation proteasome inhibitors as anti-cancer therapy

    Drug Discov. Today

    (2010)
  • C. Palermo et al.

    Cysteine cathepsin proteases as pharmacological targets in cancer

    Trends Pharmacol. Sci.

    (2008)
  • J.A. Joyce

    Cathepsin cysteine proteases are effectors of invasive growth and angiogenesis during multistage tumorigenesis

    Can. Cell

    (2004)
  • L.M. Coussens

    MMP-9 supplied by bone marrow-derived cells contributes to skin carcinogenesis

    Cell

    (2000)
  • P.A. O’Connell

    S100A10 regulates plasminogen-dependent macrophage invasion

    Blood

    (2010)
  • K.M. Heutinck

    Serine proteases of the human immune system in health and disease

    Mol. Immunol.

    (2010)
  • N. Bidere

    Cathepsin D triggers Bax activation, resulting in selective apoptosis-inducing factor (AIF) relocation in T lymphocytes entering the early commitment phase to apoptosis

    J. Biol. Chem.

    (2003)
  • E. Liaudet-Coopman

    Cathepsin D: newly discovered functions of a long-standing aspartic protease in cancer and apoptosis

    Can. Lett.

    (2006)
  • J. Haendeler

    Cathepsin D and H2O2 stimulate degradation of thioredoxin-1: implication for endothelial cell apoptosis

    J. Biol. Chem.

    (2005)
  • J.N. Lilla et al.

    Mast cells contribute to the stromal microenvironment in mammary gland branching morphogenesis

    Dev. Biol.

    (2010)
  • K. Mendelson

    Stimulation of platelet-derived growth factor receptor beta (PDGFRbeta) activates ADAM17 and promotes metalloproteinase-dependent cross-talk between the PDGFRbeta and epidermal growth factor receptor (EGFR) signaling pathways

    J. Biol. Chem.

    (2010)
  • J. Van Damme

    Chemokine-protease interactions in cancer

    Semin. Can. Biol.

    (2004)
  • A. Mortier

    Regulation of chemokine activity by posttranslational modification

    Pharmacol. Ther.

    (2008)
  • J. Sivaraman

    Crystal structure of human procathepsin X: a cysteine protease with the proregion covalently linked to the active site cysteine

    J. Mol. Biol.

    (2000)
  • V. Dalet-Fumeron

    Competition between plasminogen and procathepsin B as a probe to demonstrate the in vitro activation of procathepsin B by the tissue plasminogen activator

    Arch. Biochem. Biophys.

    (1996)
  • Z. Wang

    TIMP-2 is required for efficient activation of proMMP-2 in vivo

    J. Biol. Chem.

    (2000)
  • V. Knauper

    Cellular mechanisms for human procollagenase-3 (MMP-13) activation. Evidence that MT1-MMP (MMP-14) and gelatinase a (MMP-2) are able to generate active enzyme

    J. Biol. Chem.

    (1996)
  • G. Kostoulas

    Stimulation of angiogenesis through cathepsin B inactivation of the tissue inhibitors of matrix metalloproteinases

    FEBS Lett.

    (1999)
  • C.C. Taggart

    Cathepsin B, L, and S cleave and inactivate secretory leucoprotease inhibitor

    J. Biol. Chem.

    (2001)
  • W.J. Higgins

    Heparin enhances serpin inhibition of the cysteine protease cathepsin L

    J. Biol. Chem.

    (2010)
  • D.A. Johnson

    Cathepsin L inactivates alpha 1-proteinase inhibitor by cleavage in the reactive site region

    J. Biol. Chem.

    (1986)
  • V. Quesada

    The Degradome database: mammalian proteases and diseases of proteolysis

    Nucleic Acids Res.

    (2009)
  • J.A. Joyce et al.

    Microenvironmental regulation of metastasis

    Nat. Rev. Can.

    (2009)
  • J. Li et al.

    Caspases in apoptosis and beyond

    Oncogene

    (2008)
  • B. Turk

    Regulating cysteine protease activity: essential role of protease inhibitors as guardians and regulators

    Curr. Pharm. Des.

    (2002)
  • J. Hedrich

    Fetuin-A and cystatin C are endogenous inhibitors of human meprin metalloproteases

    Biochemistry

    (2010)
  • C. Lopez-Otin et al.

    Protease degradomics: a new challenge for proteomics

    Nat. Rev. Mol. Cell Biol.

    (2002)
  • C.M. Overall et al.

    Degradomics: systems biology of the protease web. Pleiotropic roles of MMPs in cancer

    Can. Metast. Rev.

    (2006)
  • Cited by (432)

    • The roles of collagens and fibroblasts in cancer

      2023, Biochemistry of Collagens, Laminins and Elastin: Structure, Function and Biomarkers, Third Edition
    View all citing articles on Scopus
    View full text