Quantification of matrix metalloproteinases and tissue inhibitors of metalloproteinase in prostatic tissue: Analytical aspects

Jung, Klaus; Lein, Michael; Ulbrich, Norbert; Rudolph, Birgit; Henke, Wolfgang; Schnorr, Dietmar; Loening, Stefan A.

doi:10.1002/(sici)1097-0045(19980201)34:2<130::aid-pros8>3.0.co;2-o

Cited by 32 publications

(16 citation statements)

References 24 publications

(32 reference statements)

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“…Consistent with these results, studies in PC tissues revealed an inverse correlation between tumor invasion and levels of TIMP-1 and TIMP-2. 9,10,16,17 Despite the reduced levels of TIMPs in the co-cultures, only the zymogen form of MMP-9 (pro-MMP-9) was consistently detected in the media. Activation of pro-MMP-9 depends not only on the balance of enzyme and inhibitor but also on the presence of specific activators.…”

Section: Discussionmentioning

confidence: 98%

“…8 -14 Concomitant with the increased expression of MMPs, other studies have demonstrated a reduction in the levels of TIMP-1 and TIMP-2 in PC, suggesting that a MMP/ TIMP imbalance may contribute to PC progression. 9,10,[15][16][17] Interestingly, both the tumor and stroma were shown to express MMPs while the TIMPs were expressed in the stroma, 8,9,16 suggesting a role for tumor-stromal interactions in the regulation of MMP and TIMP levels. Indeed, previous studies have shown that the interaction of PC cells with stromal cells can influence tumor progression.…”

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confidence: 99%

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Differential regulation of matrix metalloproteinase-9, tissue inhibitor of metalloproteinase-1 (TIMP-1) and TIMP-2 expression in co-cultures of prostate cancer and stromal cells

et al. 2001

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Tumor-stromal interactions have been suggested to be a critical factor in both tumor invasion and tumor metastasis. Here, we examined the role of tumor-stromal interactions using co-cultures of prostate cancer (PC) cells derived from primary and metastatic tumors with primary or immortalized stromal (fibroblast and smooth muscle) cells and their effect on matrix metalloproteinase (MMP) and tissue inhibitor of metalloproteinase (TIMP) expression. Co-cultures of PC and stromal cells showed enhanced levels of pro-MMP-9 and reduced levels of TIMP-1 and TIMP-2. Whereas enhanced expression of pro-MMP-9 occurred in PC cells, the TIMPs were down-regulated in stromal cells. Induction of pro-MMP-9 and reduction of TIMP expression did not require cell-cell contact and were mediated by a soluble factor(s) present in the conditioned medium of the effector cell. Collagen I is a potent inducer of pro-MMP-9 in PC cells. Consistently, preliminary characterization of the soluble factor in the fibroblast conditioned medium revealed m.w. of approximately 100 to 250 kDa, and its effect on pro-MMP-9 expression was partly inhibited by an anti-␣2 integrin antibody, a major collagen I receptor. Expression of pro-MMP-9 protein and mRNA was also induced in metastatic PC-3 cells grown in human fetal bone implants in SCID mice. Metastasis formation is the hallmark of cancer and the major cause of mortality. Tumor metastasis involves extensive interactions of the invasive cancer cells with host stromal components, and such interactions promote degradation of the extracellular matrix (ECM) by specialized proteolytic enzymes produced by both the cancer and the stromal cells. These interactions are likely to occur in both primary and metastatic sites. Among the proteases involve in ECM degradation during tumor invasion, the family of matrix metalloproteinases (MMPs) has been shown to play a key role due to their ability to degrade a variety of ECM and basement membrane components. 1-3 All MMPs are specifically inhibited by the tissue inhibitors of matrix metalloproteinases (TIMPs), a family of proteins that presently includes TIMP-1, TIMP-2, TIMP-3 and TIMP-4. 4 The TIMPs inhibit all active MMPs, albeit with different affinities, by binding to the active site of the enzyme. Consequently, the balance between MMP and TIMP levels has been considered to be a critical determinant of the net proteolytic activity at any given time. 5 In tumor tissues, differential expression of MMPs and TIMPs in the tumor and stromal cells may tilt the balance and thus influence MMP activity and eventually tumor cell invasion. However, little is known about the regulation of MMP and TIMP levels in tumor and stromal tissues.Prostate cancer (PC) is the most common cancer and the second leading cause of cancer death in American men. 6 Metastatic PC cells invade initially into the prostate stroma, where they intimately interact with stromal cells and ECM components. Eventually, PC cells metastasize preferentially to bone tissues, where they interact with bone stromal cell...

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Section: Discussionmentioning

confidence: 98%

mentioning

confidence: 99%

Differential regulation of matrix metalloproteinase-9, tissue inhibitor of metalloproteinase-1 (TIMP-1) and TIMP-2 expression in co-cultures of prostate cancer and stromal cells

et al. 2001

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“…The increased proteolytic activity seen in tumor tissues is a reflection of an imbalance between the proteases (MMPs) and their inhibitors (tissue inhibitor of metalloproteases, TIMP). In prostate tumors, of low-grade Gleason scores, expression of TIMPs is elevated in comparison to MMPs' expression, whereas in higher Gleason tumors, the reverse correlation is observed (53).…”

Section: Tumor Microenvironmentmentioning

confidence: 90%

Anoikis and Survival Connections in the Tumor Microenvironment: Is There a Role in Prostate Cancer Metastasis?

2005

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Overcoming the androgen independence of prostate tumors is considered the most critical therapeutic end point for improving survival in patients with metastatic prostate cancer. Normal epithelial and endothelial cells can undergo apoptosis when detached from the extracellular matrix (ECM), via the anoikis phenomenon. In contrast, tumor cells upon detachment from the ECM are capable of evading anoikis and metastasizing to different distant organs. Is the biological repertoire of the epithelial and endothelial cells sufficient to account for the events associated with the process of anoikis during prostate cancer metastasis? Although there is no clear answer to this question, what has become increasingly evident from the existing evidence is that molecules that induce anoikis in tumor epithelial and endothelial cells provide exciting new leads into effective therapeutic targeting as well as markers of prostate cancer progression and prediction of therapeutic resistance. This review analyzes recent findings on anoikis regulators and discusses the relevance of this unique apoptosis mode in the development of metastatic prostate cancer and identification of molecular signatures for treatment of advanced disease. (Cancer Res 2005; 65(24): 11230-5)

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“…Mast cells express ␣-chymase at levels of ϳ5 pg/cell (48), yielding a cellular concentration of ϳ300 M (which underestimates the concentration in secretory granules due to differences in granule and cytosolic volumes) that predicts even higher local tissue concentrations upon degranulation. In human tissues, ␣-chymase is found at a concentration of as much as ϳ45 g/g of tissue (48,49), compared with a TIMP-1 concentration of ϳ12.4 g/g (50). Immunolocalization studies in a murine model of squamous epithelial carcinogenesis demonstrate limited diffusability of chymase; thus, it remains in the vicinity of degranulating mast cells situated near basement membranes, which are sites of extracellular matrix remodeling (11).…”

Section: Discussionmentioning

confidence: 99%

Mast Cell Tissue Inhibitor of Metalloproteinase-1 Is Cleaved and Inactivated Extracellularly by α-Chymase

Frank

Rossall

Caughey

et al. 2001

The Journal of Immunology

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We previously reported that mast cell α-chymase cleaves and activates progelatinase B (progel B). Outside of cells, progel B is complexed with tissue inhibitor of metalloproteinase (TIMP)-1, which hinders zymogen activation and inhibits activity of mature forms. The current work demonstrates that dog BR mastocytoma cells, HMC-1 cells, and murine bone marrow-derived mast cells secrete TIMP-1 whose electrophoretic profile in supernatants suggests degranulation-dependent proteolysis. α-Chymase cleaves uncomplexed TIMP-1, reducing its ability to inhibit gel B, whereas tryptase has no effect. Sequencing of TIMP-1’s α-chymase-mediated cleavage products reveals hydrolysis at Phe12-Cys13 and Phe23-Val24 in loop 1 and Phe101-Val102 and Trp105-Asn106 in loop 3 of the NH2-terminal domain. TIMP-1 in a ternary complex with progel B and neutrophil gelatinase-associated lipocalin is also susceptible to α-chymase cleavage, yielding products like those resulting from processing of free TIMP-1. Thus, α-chymase cleaves free and gel B-bound TIMP-1. Incubation of the progel B-TIMP-1-neutrophil gelatinase-associated lipocalin complex with α-chymase increases gel B activity 2- to 5-fold, suggesting that α-chymase activates progel B whether it exists as free monomer or as a complex with TIMP-1. Furthermore, inhibition of α-chymase blocks degranulation-induced TIMP-1 processing (absent in α-chymase-deficient HMC-1 cells). Purified α-chymase processes TIMP-1 in BR supernatants, generating products like those induced by degranulation. In summary, these results suggest that controlled exocytosis of mast cell α-chymase activates progel B even in the presence of TIMP-1. This is the first identification of a protease that overcomes inhibition by bound TIMP-1 to activate progel B without involvement of other proteases.

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Quantification of matrix metalloproteinases and tissue inhibitors of metalloproteinase in prostatic tissue: Analytical aspects

Cited by 32 publications

References 24 publications

Differential regulation of matrix metalloproteinase-9, tissue inhibitor of metalloproteinase-1 (TIMP-1) and TIMP-2 expression in co-cultures of prostate cancer and stromal cells

Differential regulation of matrix metalloproteinase-9, tissue inhibitor of metalloproteinase-1 (TIMP-1) and TIMP-2 expression in co-cultures of prostate cancer and stromal cells

Anoikis and Survival Connections in the Tumor Microenvironment: Is There a Role in Prostate Cancer Metastasis?

Mast Cell Tissue Inhibitor of Metalloproteinase-1 Is Cleaved and Inactivated Extracellularly by α-Chymase

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