The paradoxical role of matrix metalloproteinase-11 in cancer.

The microenvironment surrounding the tumor affects biological processes, such as cell proliferation, angiogenesis, apoptosis, and invasion. Therefore, the ability to change these environments is an important attribute for tumor cells to obtain specific functions necessary for growth and metastasis. Matrix metalloproteinases (MMPs) are zinc-dependent proteolytic metalloenzymes that facilitate protease-dependent tumor progression by degrading extracellular matrix (ECM) proteins, releasing cytokines, growth factors, and other cell surface molecules. As one of the most widely studied MMPs, MMP-11 is an important protease that is expressed in cancer cells, stromal cells, and the adjacent microenvironment. MMP-11 has a dual effect on tumors. On one hand, MMP-11 promotes tumor development by inhibiting apoptosis and promoting the migration and invasion of cancer cells in the early stage. On the other hand, in animal models, MMP-11 has a protective effect on tumor growth and metastasis at an advanced stage. Based on current findings regarding the importance of MMP-11 in altering the tumor microenvironment, there is a need to further understand how stromal cells and the ECM regulate tumor progression, which may result in the re-examination of MMPs as drug targets for cancer and other diseases. In this review, we summarize the dual role of MMP-11 in cancer and its potential clinical significance.

Transdifferentiation of tadpole pancreatic acinar cells to duct cells mediated by Notch and stromelysin-3.

The tadpole pancreas has differentiated acinar cells but an underdeveloped ductal system. At the climax of metamorphosis thyroid hormone (TH) induces the tadpole acinar cells to dedifferentiate to a progenitor state. After metamorphosis is complete the exocrine pancreas redifferentiates in the growing frog forming a typical vertebrate pancreas including a complex ductal system. A micro array analysis found that TH up regulates stromelysin 3 (ST3, matrix metalloproteinase 11) in the exocrine pancreas at metamorphic climax. Transgenic tadpoles were prepared with an elastase promoter driving either the ST3 gene or the constitutively active form of Notch (IC). Expression of the transgenes was controlled by the tetracycline system. A few days after either of these transgenes is activated by doxycycline the pancreatic acinar cells turn into duct-like cells. This transdetermination occurs without cell division since both acinar and ductal markers can be visualized transiently in the same cell. We propose that remodeling of the tadpole acinar cells is initiated when ST3 is up regulated by TH. Stromelysin-3 then cleaves and activates Notch.

Tissue-dependent induction of apoptosis by matrix metalloproteinase stromelysin-3 during amphibian metamorphosis.

Matrix metalloproteinases (MMPs) are a superfamily of Zn(2+)-dependent proteases that are capable of cleaving the proteinaceous component of the extracellular matrix (ECM). The ECM is a critical medium for cell-cell interactions and can also directly signal cells through cell surface ECM receptors, such as integrins. In addition, many growth factors and signaling molecules are stored in the ECM. Thus, ECM remodeling and/or degradation by MMPs are expected to affect cell fate and behavior during many developmental and pathological processes. Numerous studies have shown that the expression of MMP mRNAs and proteins associates tightly with diverse developmental and pathological processes, such as tumor metastasis and mammary gland involution. In vivo evidence to support the roles of MMPs in these processes has been much harder to get. Here, we will review some of our studies on MMP11, or stromelysin-3, during the thyroid hormone-dependent amphibian metamorphosis, a process that resembles the so-called postembryonic development in mammals (from a few months before to several months after birth in humans when organ growth and maturation take place). Our investigations demonstrate that stromelysin-3 controls apoptosis in different tissues via at least two distinct mechanisms.

Matrix metalloproteinase-11/stromelysin-3 exhibits collagenolytic function against collagen VI under normal and malignant conditions.

The substrate of matrix metalloproteinase 11 (MMP11) remains unknown. We have recently shown that MMP11 is a negative regulator of adipogenesis, able to reduce and even to revert mature adipocyte differentiation. Here, we have used mouse 3T3L1 cells and human U87MG and SaOS cells to show that MMP11 cleaves the native alpha3 chain of collagen VI, which is an adipocyte-related extracellular matrix component. It is known that extracellular proteolytic processing of this chain is required for correct collagen VI folding. Interestingly, MMP11-deficient fat tissue is less cohesive and exhibits collagen VI alteration, dramatic adipocyte plasma and basement membrane abnormalities and lipid leakage. MMP11 is thus required for correct collagen VI folding and therefore for fat tissue cohesion and adipocyte function. Both MMP11 and collagen VI favor tumor progression. Similar spatio-temporal overexpression at the adipocyte-cancer cell interface has been reported for the two proteins. MMP11-dependent collagen VI processing might therefore be expected to occur during malignancy. Accordingly, collagen VI no longer delineates adipocytes located at the invasive front of breast carcinomas. In conclusion, the native alpha3 chain of collagen VI constitutes a specific MMP11 substrate. This MMP11 collagenolytic activity is functional in fat tissue ontogenesis as well as during cancer invasive steps.

Regulation of extracellular matrix remodeling and cell fate determination by matrix metalloproteinase stromelysin-3 during thyroid hormone-dependent post-embryonic development.

Interactions between cells and extracellular matrix (ECM), in particular the basement membrane (BM), are fundamentally important for the regulation of a wide variety of physiological and pathological processes. Matrix metalloproteinases (MMP) play critical roles in ECM remodeling and/or regulation of cell-ECM interactions because of their ability to cleave protein components of the ECM. Of particular interest among MMP is stromelysin-3 (ST3), which was first isolated from a human breast cancer and also shown to be correlated with apoptosis during development and invasion of tumor cells in mammals. We have been using intestinal remodeling during thyroid hormone (TH)-dependent amphibian metamorphosis as a model to study the role of ST3 during post-embryonic tissue remodeling and organ development in vertebrates. This process involves complete degeneration of the tadpole or larval epithelium through apoptosis and de novo development of the adult epithelium. Here, we will first summarize expression studies by us and others showing a tight spatial and temporal correlation of the expression of ST3 mRNA and protein with larval cell death and adult tissue development. We will then review in vitro and in vivo data supporting a critical role of ST3 in TH-induced larval epithelial cell death and ECM remodeling. We will further discuss the potential mechanisms of ST3 function during metamorphosis and its broader implications.

Spatio-temporal regulation and cleavage by matrix metalloproteinase stromelysin-3 implicate a role for laminin receptor in intestinal remodeling during Xenopus laevis metamorphosis.

The 37-kd laminin receptor precursor (LR) was first identified as a 67-kd protein that binds laminin with high affinity. We have recently isolated the Xenopus laevis LR as an in vitro substrate of matrix metalloproteinase stromelysin-3 (ST3), which is highly upregulated during intestinal metamorphosis in Xenopus laevis. Here, we show that LR is expressed in the intestinal epithelium of premetamorphic tadpoles. During intestinal metamorphosis, LR is downregulated in the apoptotic epithelium and concurrently upregulated in the connective tissue but with little expression in the developing adult epithelium. Toward the end of metamorphosis, as adult epithelial cells differentiate, they begin to express LR. Furthermore, LR is cleaved during intestinal remodeling when ST3 is highly expressed or in premetamorphic intestine of transgenic tadpoles overexpressing ST3. These results suggest that LR plays a role in cell fate determination and tissue morphogenesis, in part through its cleavage by ST3. Interestingly, high levels of LR are known to be expressed in tumor cells, which are often surrounded by fibroblasts expressing ST3, suggesting that LR cleavage by ST3 plays a role in both physiological and pathological processes.