Metalloproteinase Family

MMPs can degrade all components of the basement membrane and ECM and play important physiological roles in tissue repair, morphogenesis, and angiogenesis. Currently, over 24 MMPs have been identified and classified according to their domain structures: archetypal MMPs, matrilysins, gelatinases, and convertase-activatable MMPs.181 Although

MMPs occur predominantly as secreted proteins, a subgroup is found on the cell surface, attached via a transmembrane domain or a glycosylphosphatidylinositol anchor. MMP activity is regulated at multiple levels although transcriptional control and posttranslational activation/inhibition appear to be the most important. Several growth factors and cytokines have been demonstrated to upregulate levels and activity of MMPs. Most MMPs are secreted as inactive zymogens, remaining latent until cleaved by another MMP or other protease. Refolding follows and typically a second cleavage, occuring either autocatalytically or via another MMP, is required for full activity.182 Endogenous MMP

inhibitors, tissue inhibitors of metalloproteinases (TIMPs), provide a further level of regulation of protease activity.

TIMPs are expressed within the extracellular space, either as soluble or membrane-anchored proteins, that directly bind MMPs with high affinity but little specificity within different MMP subclasses.183

Cleavage of MMPs at the tumor cell-matrix interface is highly regulated by cell surface MT-MMP, as well as by adhesion molecules that have been implicated in proangiogenic and proinvasive activities (see above). Malignant cells within primary tumors have been reported to express MMPs; MMP-7 is commonly expressed by epithelial tumors, but it is apparent that stromal cells within the vicinity of tumors a represent a major, if not the principal, source of MMP

activity.184 Stromal myofibroblasts and inflammatory cells, such as mast cells, appear to be responsible for the production of MMPs at the tumor-matrix interface. In agreement with this, mice deficient in particular MMPs (MMP-

2 and MMP-9) display resistance to tumor development in response to carcinogenic insult and delayed growth of experimentally implanted tumors.184,185

A number of MMP targets relevant for cancer invasion have been identified (see 7.09 Recent Development in Novel

Anticancer Therapies). Cleavage products of laminin-5 and elastin, frequently observed at the invasive front of tumors, possess chemotactic properties. MMPs can also target the extracellular domains of adhesion molecules; MMP3 has been proposed to shed the ectodomain of E-cadherin, thereby disrupting cell-cell attachment. Administration of

TIMP1, or pharmacological inhibitors, blocked this process, restoring cell membrane localization of E-cadherin and beta-catenin. MMPs can additionally increase local growth factor concentrations and bioavailablity by releasing them from the extracellular matrix, e.g., fibroblast growth factor (FGF) and transforming growth factor beta (TGF-b), or inhibitory proteins, e.g., insulin-like growth factor binding proteins 1. Consistently, transgenic mice with reduced MMP

activity, due to high TIMP-1 expression levels, display decreases in IGF1 availability and activation of IGF1R.186,187

Epidemiological studies have clearly demonstrated that cancer progression is associated with the upregulation of multiple MMPs, redundancy rather than specificity being the rule. MMP levels correlate with tumor aggressiveness, and increased expression of MMPs has been linked to poorer prognosis in locally invasive cancers, such as gastric and 188 189

esophageal carcinoma. , MMP activity has been implicated in positive and negative regulation of tumor angiogenesis. MMP-9 is upregulated in highly vascularized tumors, such as lung, colon and renal carcinoma, and was shown experimentally to mediate angiogenesis and intravascular colonization of the lung by implanted tumor cells. In contrast, as described above, the action of MMP on type IV, type XVIII, and type XV collagen releases peptides with potent antiangiogenic activity. Expression of MMP-12 is associated with increased survival in colon carcinoma patients, presumably due to its inhibitory actions on angiogenesis and invasion, mediated by cleaving the urokinase-type plasminogen activator receptor (uPAR).190 Extensive studies, using antisense RNA, small interfering RNA (siRNA), and low-molecular-weight inhibitors, have demonstrated that decreasing MMP activity can reduce tumor growth, invasion, and vascularization. Several MMP inhibitors, with broad specificity, have been tested in clinical trials. However, the observed patient response has not replicated the effectiveness seen in preclinical studies, potentially due to dose-limiting toxicities and to redundancy of action that occurs between MMPs and plasminogen activation (see below).181

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