Trends in Cell Biology
Volume 11, Issue 11, 1 November 2001, Pages S37-S43
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Review
The many faces of metalloproteases: cell growth, invasion, angiogenesis and metastasis

https://doi.org/10.1016/S0962-8924(01)02122-5Get rights and content

Abstract

Metalloproteases are important in many aspects of biology, ranging from cell proliferation, differentiation and remodeling of the extracellular matrix (ECM) to vascularization and cell migration. These events occur several times during organogenesis in both normal development and during tumor progression. Mechanisms of metalloprotease action underlying these events include the proteolytic cleavage of growth factors so that they can become available to cells not in direct physical contact, degradation of the ECM so that founder cells can move across tissues into nearby stroma, and regulated receptor cleavage to terminate migratory signaling. Most of these processes require a delicate balance between the functions of matrix metalloproteases (MMPs) or metalloprotease-disintegrins (ADAMs) and natural tissue inhibitors of metalloproteases (TIMPs). In this review, we discuss recent progress in identifying an essential role for metalloproteases in axon outgrowth, as an example of a focal invasive event. We also discuss the evolving concept of how MMPs might regulate stem cell fate during tumor development.

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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