Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

During melanoma progression, migrating cells must cross human dermis, a type I collagen-rich tissue. We have show that MMP-1 and MMP-2 act in a cumulative manner in the in vitro invasion of a three-dimensional type I collagen matrix by melanoma cells. Two melanoma cell lines (M1Dor and M3Da) previously reported to secrete proMMP-2 in a direct relationship with their tumorigenic potential into nude mice were used (F. Capon et al., 1999, Clin. Exp. Metastasis 17, 463-469). The highly tumorigenic cell line (M3Da) displayed a five-fold faster migration rate in type I collagen matrix, compared to its lower tumorigenic counterpart (M1Dor). In parallel, activation of proMMP-2 was evidenced in M3Da- but not M1Dor-populated collagen lattices. Such enzyme activation was associated with a significant decrease in TIMP-2 and TIMP-1 production. Agents known to interfere with proMMP-2 activation, i.e., excess TIMP-2, furin convertase inhibitor, and alphavbeta3 blocking antibody, reduced by 30-40% the type I collagen invasive capacity of M3Da cells. By comparison, batimastat, a wide-spectrum MMP inhibitor, exhibited a more pronounced inhibitory effect (>70%). It suggested that other collagenases than MMP-2 could participate in type I collagen invasion. Collagenase-3 (MMP-13) was produced at low levels by melanoma cells whatever the cell culture conditions. In contrast, M3Da and M1Dor cells secreted collagenase-1 (MMP-1) following 48 h of culture on plastic dishes. Growing melanoma cells in type I collagen gel did not modify enzyme production, but induced proMMP-1 activation in M3Da but not M1Dor cell-populated lattices. Blocking the plasmin-mediated proMMP-1 activation by aprotinin inhibited type I collagen gel invasion by 30%. Since the combination of aprotinin and furin convertase inhibitor reduced collagen invasiveness by melanoma cells to a level comparable to that attained with batimastat, we conclude that both MMP-2 and MMP-1 are involved in such tissue invasion.
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PMID:Cumulative influence of matrix metalloproteinase-1 and -2 in the migration of melanoma cells within three-dimensional type I collagen lattices. 1159 33

The mammalian subtilisin/kexin-like proprotein convertase (PC) family has been implicated in the activation of a wide spectrum of proteins. These proteins are usually synthesized as inactive precursors before their conversion to fully mature bioactive forms. A large majority of these active proteins such as matrix metalloproteases, growth factors, and adhesion molecules are crucial in the processes of cellular transformation, acquisition of the tumorigenic phenotype, and metastases formation. Inhibition of PCs significantly affects the malignant phenotype of various tumor cells. In addition to direct tumor cell proliferation and migration blockade, PC inhibitors can also be used to target tumor angiogenesis. In this Review article we discuss a number of recent findings on the clinical relevance of PCs in cancer patients, their implication in the regulation of multiple cellular functions that impact on the invasive/metastatic potential of cancer cells. Thus, PC inhibitors may constitute new promising agents for the treatment of multiple tumors and/or in adjuvant therapy to prevent recurrence.
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PMID:Proprotein convertases in tumor progression and malignancy: novel targets in cancer therapy. 1205 95

Although proprotein convertases are involved in tumor development, nothing is known about their role in metastatic dissemination. To investigate the involvement of convertase inhibition, we used human colon carcinoma cells overexpressing alpha1-antitrypsin Portland (alpha1-PDX, PDX39P cells), a potent convertase inhibitor. We previously reported that these cells bear uncleaved integrin alpha subunits and display an altered attachment to vitronectin that is correlated with defects in the intracellular signaling pathways activated by alphavbeta5 integrin ligation. In this study, we demonstrate that the inhibition of proprotein convertase activity either by overexpression of alpha1-PDX or with the synthetic inhibitor decanoyl-Arg-Val-Lys-Arg-chloromethylketone (dec-RVKR-cmk) led to a significant increase in cell migration supported by the alphavbeta5 integrin. A collagen gel invasion assay showed that PDX39P cells also displayed an invasive ability, contrary to control cells. Moreover, when injected to immunosuppressed newborn rats, PDX39P cells were highly invasive, as they induce 10 times more metastases than mock-transfected cells. In addition, the aggressiveness of PDX39P cells can be greatly reduced by a function-blocking monoclonal antibody (mAb) against the alphav subunit. It thus seems that inhibition of proprotein convertases enhances the in vivo invasiveness of colon tumor cells likely due to an increase in cell migration mediated by alphav integrins.
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PMID:Inhibition of proprotein convertases enhances cell migration and metastases development of human colon carcinoma cells in a rat model. 1516 29

Emerging evidence indicates a link between inflammation and cancer metastasis, but the molecular mechanism(s) remains unclear. Uteroglobin (UG), a potent anti-inflammatory protein, is constitutively expressed in the lungs of virtually all mammals. UG-knock-out (UG-KO) mice, which are susceptible to pulmonary inflammation, and B16F10 melanoma cells, which preferentially metastasize to the lungs, provide the components of a model system to determine how inflammation and metastasis are linked. We report here that B16F10 cells, injected into the tail vein of UG-KO mice, form markedly elevated numbers of tumor colonies in the lungs compared with their wild type littermates. Remarkably, UG-KO mouse lungs overexpress two calcium-binding proteins, S100A8 and S100A9, whereas B16F10 cells express the receptor for advanced glycation end products (RAGE), which is a known receptor for these proteins. Moreover, S100A8 and S100A9 are potent chemoattractants for RAGE-expressing B16F10 cells, and pretreatment of these cells with a blocking antibody to RAGE suppressed migration and invasion. Interestingly, in UG-KO mice S100A8/S100A9 concentrations in blood are lowest in tail vein and highest in the lungs, which most likely guide B16F10 cells to migrate to the lungs. Further, B16F10 cells treated with S100A8 or S100A9 overexpress matrix metalloproteinases, which are known to promote tumor invasion. Most notably, the metastasized B16F10 cells in UG-KO mouse lungs express MMP-2, MMP-9, and MMP-14 as well as furin, a pro-protein convertase that activates MMPs. Taken together, our results suggest that a lack of an anti-inflammatory protein leads to increased pulmonary colonization of melanoma cells and identify RAGE as a potential anti-metastatic drug target.
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PMID:Lack of an endogenous anti-inflammatory protein in mice enhances colonization of B16F10 melanoma cells in the lungs. 2011 37

Proprotein convertases are a family of kexin-like serine proteases that process proteins at single and multiple basic residues. Among the predicted and identified PC substrates, an increasing number of proteins having functions in cancer progression indicate that PCs may be potential targets for antineoplastic drugs. In support of this notion, we identified PACE4 as a vital PC involved in prostate cancer proliferation and progression, contrasting with the other co-expressed PCs. The aim of the present study was to test the importance of PCs in ovarian cancer cell proliferation and tumor progression. Based on tissue-expression profiles, furin, PACE4, PC5/6 and PC7 all displayed increased expression in primary tumor, ascites cells and metastases. These PCs were also expressed in variable levels in three model ovarian cell lines tested, namely SKOV3, CAOV3 and OVCAR3 cells. Since SKOV3 cells closely represented the PC expression profile of ovarian cancer cells, we chose them to test the effects of PC silencing using stable gene-silencing shRNA strategy to generate knockdown SKOV3 cells for each expressed PC. In vitro and in vivo assays confirmed the role of PACE4 in the sustainment of SKOV3 cell proliferation, which was not observed with the other three PCs. We also tested PACE4 peptide inhibitors on all three cell lines and observed consequent reduced cell proliferation which was correlated with PACE4 expression. Overall, these data support a role of PACE4 in promoting cell proliferation in ovarian cancer and provides further evidence for PACE4 as a potential therapeutic target.
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PMID:Implications of Proprotein Convertases in Ovarian Cancer Cell Proliferation and Tumor Progression: Insights for PACE4 as a Therapeutic Target. 2481 56

Ewing sarcoma is a highly resistant disease with a <10% chance of survival at 5 years after failure of frontline chemotherapy. This is a case report of an Ewing sarcoma patient with metastatic disease recurrence <2 years after standard chemotherapy/radiation who achieved a durable and sustained complete response after 2 series of treatments with Vigil (GMCSF/bi-shRNA furin DNA autologous tumor immunotherapy) serially manufactured from first and second recurrences with ELISPOT assay correlation. Results support justification of further testing of Vigil with ELISPOT assay as a biomarker to assess level of immune response and correlation with disease control.
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PMID:Case Report: Immune-mediated Complete Response in a Patient With Recurrent Advanced Ewing Sarcoma (EWS) After Vigil Immunotherapy. 2833 69

Although recent therapeutic developments raise hope, melanoma remains a devastating disease with a need for new treatment targets. In other tumours prohormone convertases have been shown to be pro-tumourigenic as they are involved in processing preforms of matrix-metalloproteinases, growth factors and adhesion molecules. The aim of this study was to look for new treatment options for melanoma, by investigating the role of the prohormone convertase Paired basic Amino acid-Cleaving Enzyme 4 (PACE4/PCSK6) in melanoma cell lines and human melanoma tissue. PACE4-transfected A375 melanoma cells displayed significantly increased proliferation, MMP-2 production, gelatinase activity and migratory capacity in vitro compared with sham-transfected cells. In vivo, elevated PACE4 expression resulted in significantly increased tumour growth on immunodeficient mice. In the majority of 45 human primary melanomas and melanoma metastases ex vivo PACE4 immunoreactivity was detectable, while it was absent in in situ melanomas. These results indicate PACE4 as a regulator of melanoma cell aggressiveness.
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PMID:Paired Basic Amino Acid-cleaving Enzyme 4 (PCSK6): An Emerging New Target Molecule in Human Melanoma. 3244 80