ReviewExtrinsic regulators of epithelial tumor progression: metalloproteinases
Introduction
The conversion of normal cells into invasive cancers with metastatic potential is a process that involves several steps. These steps are manifested in distinguishable histological and temporal stages — for instance, normal tissue, hyperplasia with a high incidence of proliferating cells, dysplasia with the induction of angiogenesis before the emergence of frank tumors with metastatic potential. Analysis of the later stages of tumor progression has resulted in a multi-step theory of tumorigenesis on the basis of genetic changes involving activation of oncogenes, inactivation of tumor suppressor genes, and altered expression of tumor-associated molecules. Whereas cancer research has historically focussed on such intrinsic events, it has become evident that extrinsic factors (e.g. the local stromal microenvironment) also regulate critical parameters of tumorigenesis and evolve and undergo multi-step reconstruction paralleling neoplastic progression. Thus, the stroma, and its resident reactive host cells, constitutes a second important component of solid tumors.
Requisite for neoplastic cell and capillary or inflammatory cell invasion during tumorigenic processes are the remodeling events that occur within the stroma or extracellular matrix (ECM). ECM-degrading proteinases are universally expressed during tumor progression and metastasis [1]. In epithelial tumors, the majority of proteinases are synthesized by the responding host stromal cells. The enzymes, if not membrane-spanning proteins, can then bind to the surface of tumor cells, to exert their biological activities. Extracellular proteinases are well known to degrade and/or remodel many substances in the ECM — such as cartilage, tendons, fibrin clots, basement membrane components — that allows for cell migration, deposition of new ECM, and the development of new tissue. Thus, extracellular proteinases are involved in essentially all developmental and pathological situations requiring tissue reorganization and remodeling. Although several types of extracellular proteinases are implicated in these events (metallo-, serine, and cysteine), members of the metzincin family (e.g. matrix metalloproteinases [MMPs]) and adamalysin-related proteinases, have emerged as important extrinsic regulators of tissue remodeling associated with neoplastic progression. Interestingly, new insights into in vivo proteinase substrates extend the role of metzincin proteinases beyond that of mere ECM dissolution 2, 3•. In this review we discuss recent insights into the regulatory functions of adamalysin-related and matrix metalloproteinases and their role in neoplasia, focussing on recently identified substrates as mediators of pericellular proteinase action. We first introduce the structural relationship between metzincin family members, then we highlight salient in vivo studies implicating certain metzincins as important extrinsic regulators of tumor growth.
Section snippets
The metzincin family
The metalloendopeptidases can be divided into several superfamilies and ∼30 sub-families [4]. One superfamily, ‘the metzincins’ (Figure 1), are distinguished by a conserved structural topology, a consensus motif containing three histidines that bind zinc at the catalytic site, and a conserved ‘Met-turn’ motif that sits below the proteinase active site zinc ion (Figure 2) [5]. Thus, the metzincins can be further subdivided into four distinct families on the basis of structural similarity (Figure
Modulation of tumor growth and expansion by metzincins
Proteolysis of ECM components serves several distinct functions — component assembly, editing of excess components and remodeling of ECM structure. These three processes are key to ECM synthesis and assembly, to physiological remodeling during growth, differentiation, morphogenesis and wound healing, and in pathological situations such as arthritis and tumor development. Several new, important insights into the mechanisms underlying these proteolytic processes as well as identification of new
MMPs as negative regulators of neoplastic growth: release of bioactive ECM fragments
Historically, MMPs were thought to facilitate neoplastic progression by merely degrading ECM structural components, thereby allowing a cleared path for migrating tumor cells. It is now clear, however, that cryptic protein fragments exist within some ECM proteins that are released by proteolytic cleavage and which affect critical parameters of tumor evolution (e.g. angiogenesis and metastasis [17]). The first example for the release of a bioactive ECM fragment was the isolation of angiostatin
Conclusions
Collectively, the body of data at present indicates that proteinases may benefit either the host or the tumor depending upon tumor stage, spatial expression, proteolytic capacity and binding affinity for matrix versus neoplastic cells. Nevertheless, variably specific MMP inhibitors are effective in inhibiting growth of various primary tumors and metastases in animal models 41••, 46. The ability of these compounds to inhibit tumor growth suggests that metalloproteinases are more important for
Acknowledgements
We acknowledge all the scientists who made contributions to the areas of research reviewed here that we could not cite due to space constraints. We also thank Douglas Hanahan and Zena Werb for critical comments. This work was supported in part by funds from the National Institutes of Health and the American Cancer Society.
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
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