Membrane associated matrix metalloproteinases in metastasis

Ellerbroek, Shawn M.; Stack, M. Sharon

doi:10.1002/(sici)1521-1878(199911)21:11<940::aid-bies6>3.0.co;2-j

Cited by 137 publications

(52 citation statements)

References 69 publications

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“…MMPs are secreted by stromal or tumor cells as inactive pro-enzymes and must bind to the cell surface, where they are processed and activated (34). For MMP-2, this is mediated by an MT1-MMP͞TIMP-2͞MMP-2 ternary complex or an alternative protein C-dependent pathway (34,35). It may involve integrin ␣v␤3 on sprouting endothelial cells, where ␣v␤3 recognizes the C-terminal hemopexin homology domain of MMP-2 (36) and colocalizes with MMP-2 at the invasive cell front (34).…”

Section: Discussionmentioning

confidence: 99%

Activated integrin αvβ3 cooperates with metalloproteinase MMP-9 in regulating migration of metastatic breast cancer cells

Rolli

Fransvea

Pilch

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

287

250

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Expression of adhesion receptor integrin ␣v␤3 in an activated functional form strongly promotes metastasis in human breast cancer cells. Here, we report that ␣v␤3 cooperates with matrix metalloproteinase type 9 (MMP-9) in breast cancer cell migration. This cooperation is regulated by the activation state of the integrin. Expression of activated ␣v␤3 in metastatic variants of MDA-MB 435 human breast cancer cells and primary metastatic cells from breast cancer patients strongly enhanced migration toward vitronectin and fibrinogen. This enhancement was mediated by a soluble factor produced by breast cancer cells expressing activated ␣v␤3. When transferred, this factor also up-regulated ␣v␤3-dependent migration of breast cancer cells that express the nonactivated integrin. The factor was identified as metalloproteinase MMP-9. Whereas all tested breast cancer cell variants produced latent MMP-9, only those with activated ␣v␤3 produced the mature form of this metalloproteinase. Recombinant mature MMP-9, but not latent MMP-9 or either form of MMP-2, enhanced ␣v␤3-dependent breast cancer cell migration. The migratory response was inhibited by tissue inhibitors of metalloproteinase or when MMP-9 was depleted from the inducing supernatants. The results indicate a causal relationship between the expression of activated integrin ␣v␤3 and production of enzymatically active MMP-9 in metastatic breast cancer cells. These molecules cooperate to enhance breast cancer cell migration toward specific matrix proteins, and this may contribute to the strongly enhanced metastatic capacity of breast cancer cells that express activated ␣v␤3.M etastasis is the primary cause of death in breast cancer patients. Metastatic dissemination depends on tumor cell adhesion, migration, and invasion. These steps involve integrins, a family of transmembrane adhesion receptors, composed of noncovalently linked ␣ and ␤ subunits (1). Integrins are known to exist in distinct states of activation, and these determine integrin functionality and affinity for ligands (2). For example, integrin activation controls which ligands are recognized, whether an integrin can support cell arrest under dynamic flow conditions or only stationary adhesion, and whether cells can migrate on or toward specific substrates (3). The importance of integrin activation has long been appreciated in leukocytes and platelets, where it controls inflammatory responses and thrombus formation (4, 5). Recent findings indicate that other cell types, such as endothelial cells and tumor cells, can also regulate their interaction with extracellular matrix proteins by integrin activation (6-9). This regulation may help to control angiogenesis and tumor metastasis.In breast and ovarian cancer, as well as in melanoma and glioma, malignant progression is associated with expression of tumor cell integrin ␣v␤3 (10-14). We recently found that ␣v␤3 can exist in human breast cancer cells in an activated or a nonactivated functional state. Only the activated state supports breast cancer cell arrest du...

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Section: Discussionmentioning

confidence: 99%

Activated integrin αvβ3 cooperates with metalloproteinase MMP-9 in regulating migration of metastatic breast cancer cells

Rolli

Fransvea

Pilch

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

287

250

View full text Add to dashboard Cite

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“…7 -9 The MT-MMPs contain a transmembrane domain anchoring the enzyme to the cell surface. 10 Of five MT-MMPs (MT1 -MT5-MMP) identified so far, 11 -15 MT1-MMP is the most characterized and, in association with TIMP-2, is involved in the activation of pro-MMP-2 16,17 and pro-MMP-13. 18 MT2-and MT3-MMP can also activate pro-MMP-2 but with lower efficiency.…”

Section: Introductionmentioning

confidence: 99%

Characterization of expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases in prostate cancer cell lines

Daja

Niu

Zhao

et al. 2003

Prostate Cancer Prostatic Dis

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Stromal expression of some matrix metalloproteinases (MMPs) has been associated with increasing tumour burden in prostate cancer. We investigated the expression of mRNA (by RT-PCR) and protein (by zymography and western blotting) of MMPs and endogenous inhibitors (tissue inhibitors of metalloproteinases, TIMPs) in two parent epithelial prostate cancer cell lines and sublines of increasing invasive/metastatic potential. Expression of membrane type MMPs, MT1-MMP and MT3-MMP mRNA was higher in PC3-derived than in LNCaPderived lines, whereas MT2-MMP mRNA expression was higher in the LNCaPderived than in PC3-derived cell lines. Active MT1, MT2 and MT3-MMP protein levels were similar in all lines, but processed MT-MMPs, indicative of latent MMP activation, were increased in more aggressive sublines. Expression of MMP-1, MMP-13 and TIMP-1 was higher in the more aggressive sublines and may be implicated in invasive/metastatic ability. Regulation of MMP-1 and MMP-13 expression may offer important therapeutic options for treating patients with prostate cancer.

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“…The capacity of tumor cells to form metastatic foci correlates with the ability to proteolytically degrade basement membrane barriers and to adhere to and migrate through extracellular matrix layers. 1,2 Two classes of molecules are mainly involved in these processes: the matrix metalloproteinases (MMPs) 3 and integrins. 4,5 Integrins are a large family of adhesion receptors involved in cell-cell and cellextracellular matrix interactions.…”

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confidence: 99%

Phosphorylation of ectopically expressed L‐plastin enhances invasiveness of human melanoma cells

Klemke

Rafael

Wabnitz

et al. 2007

Intl Journal of Cancer

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The leukocyte specific actin-binding protein L-plastin is aberrantly expressed in several nonhematopoetic malignant tumors. However, little is known about the functional consequences of Lplastin expression. Here, we investigated the function of L-plastin in human malignant melanoma cells. Knock-down of endogenous L-plastin by siRNA treatment reduced migration of the melanoma cell line IF6. However, in melanoma patients, no correlation existed between L-plastin expression and tumor stages. This implied that additional factors such as phosphorylation of L-plastin may influence its function in tumor cells. To investigate this further, EGFP-tagged wild-type L-plastin (wt-LPL-EGFP) and a mutated, nonphosphorylatable L-plastin protein (5A7A-LPL-EGFP), were expressed in the L-plastin negative melanoma cell line MV3. Biochemical analysis revealed that wt-LPL-EGFP is phosphorylated in MV3 cells while 5A7A-LPL-EGFP is not. Although both wt-LPL-EGFP and 5A7A-LPL-EGFP were targeted to, and promote the formation of, vinculin-containing adhesion sites, static adhesion to either Matrigel or isolated extracellular matrix molecules was neither influenced by expression of wt-LPL-EGFP nor by expression of 5A7A-LPL-EGFP when compared with EGFP expressing control cells. In contrast, haptotactic, but not chemotactic, migration of melanoma cells towards either Matrigel or isolated extracellular matrix molecules was similarly enhanced, if either 5A7A-LPL-EGFP or wt-LPL-EGFP were expressed in MV3 cells. Interestingly, only cells expressing the phosphorylatable wt-LPL-EGFP protein showed enhanced invasion into Matrigel. In line with these findings the in vivo metastatic capacity of mouse B16 melanoma cells correlates with expression and phosphorylation of L-plastin. These data show that an increase in melanoma cell invasiveness requires not only expression but also phosphorylation of L-plastin. ' 2007 Wiley-Liss, Inc.Key words: migration; invasion; adhesion; L-plastin; melanoma Malignant melanoma is a very aggressive type of cancer that frequently metastasizes to distant organs. The capacity of tumor cells to form metastatic foci correlates with the ability to proteolytically degrade basement membrane barriers and to adhere to and migrate through extracellular matrix layers. 1,2 Two classes of molecules are mainly involved in these processes: the matrix metalloproteinases (MMPs) 3 and integrins. 4,5 Integrins are a large family of adhesion receptors involved in cell-cell and cellextracellular matrix interactions. They consist of heterodimers of 2 noncovalently associated a-and b-subunits. 6 The role of integrins in tumor cell metastasis has been intensively studied. 4,5,7 In human melanoma, especially b1-and b3-subunit containing integrins play important roles in metastasis, through an enhancement of adhesion, migration and invasion. 8,9 Moreover, the cell surface expression levels of many integrins can be directly correlated with the metastatic potential of melanoma cells. [10][11][12] Modulation of the actin cytoskeleton is critical f...

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Membrane associated matrix metalloproteinases in metastasis

Cited by 137 publications

References 69 publications

Activated integrin αvβ3 cooperates with metalloproteinase MMP-9 in regulating migration of metastatic breast cancer cells

Activated integrin αvβ3 cooperates with metalloproteinase MMP-9 in regulating migration of metastatic breast cancer cells

Characterization of expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases in prostate cancer cell lines

Phosphorylation of ectopically expressed L‐plastin enhances invasiveness of human melanoma cells

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