Trends in Cell Biology
ReviewThe many faces of metalloproteases: cell growth, invasion, angiogenesis and metastasis
Section snippets
Role of metalloproteases in cell proliferation and the release of growth regulators
In elucidating the deregulation of tumor cell growth, intercellular signaling between the diverse cell types within a tumor mass is as important as intracellular signaling acquired from growth autonomy. Successful tumor cells are those that induce the release of growth-stimulating signals from neighboring cells. In this review, the release of extracellular domains of proteins from the cell surface by a mechanism involving metalloprotease-directed proteolysis is referred to as ectodomain
Role of metalloproteases in invasion
Throughout cancer progression, the microecology of the local host tissue is a consistently active participant in the evolving tumor (Fig. 2). Invasion occurs at the tumor–host interface, where tumor and stromal cells exchange enzymes and cytokines that modulate the local ECM and stimulate cell migration. Similar mechanisms are shared by physiological and tumorigenic invasion. In either case, the rate-limiting step is the breakdown of connective tissue barriers comprising collagens, laminins,
Role of metalloproteases in angiogenesis
The process of angiogenesis is governed by an integrated signaling circuitry, and its modulation is dependent upon soluble angiogenic factors, cytokines and insoluble ECM components that surround the participating vessels (Fig. 2). Angiogenesis is necessary for persistent tumor growth because the sprouting capillaries are conduits for gas exchange and nutrient supply 15. Without vascular growth, the tumor mass is restricted to within a tissue-diffusion distance of approximately 0.2 mm. Tumor
Role of metalloproteases in metastasis
Because of their ECM-degrading activity, and the correlation between high levels of their activity and increased tumor metastasis, MMPs were initially thought to facilitate tumor cell metastasis by destroying the basement membrane and other components of the ECM. The ECM blocks tumor metastasis not only in the sense of being a physical barrier but also because it forms a self-protective, apoptosis-resistant microenvironment. This model is supported by studies of epithelial cells, under
Insights into cancer from the role of metalloproteases in axon outgrowth
Like epithelial cells, neuronal cells are polarized and must navigate through an ECM-rich environment during development under the influence of attractive and repellent cues. Axon outgrowth can thus act as a paradigm for tissue invasion in tumorigenesis, as described below. It has long been suspected that proteolytic activity on neuronal growth cones controls their migratory activity 30. This possibility is further strengthened by the observation that Drosophila mutants with a mutation in
Concluding remarks
The substantial contribution of the extracellular microenvironment is as important to cell behavior as intracellular events in processes as diverse as neuronal development and neoplastic progression 37. This is demonstrated by the recent discoveries that inflammatory cells stimulate malignant conversion of keratinocytes via paracrine factors and that MMPs play a crucial role 38.
A large body of correlative data suggests that MMPs facilitate neoplastic progression in cancer. Most of these data
Acknowledgements
This work was supported by research grants (R01NS39278, AR46238 and P01CA72006) and an institutional National Research Service Award (T32ES07106) from the NIH.
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