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

Cell lines with high metastatic capacity to the lung were established by sequential passage of a human pancreatic cancer cell line (SUIT-2) through the lung of a nude mouse, via the lateral tail vein and from a subcutaneous inoculum. Cells of the parental SUIT-2 and sublines S2-VPx (x-cycle selection from SUIT-2 cells, by Vein-Pulmonary metastasis-culture) and S2-CPx (x-cycle selection, by Cutis-Pulmonary metastasis-culture) were injected intravenously or subcutaneously into nude mice to produce experimental or spontaneous lung metastasis. The S2-VP10 cell line produced pulmonary metastases in 100% of the nude mice, when injected intravenously. It failed, however, to produce more lung colonies than its parent cell line, when injected subcutaneously. The S2-CP8 cell line produced extensive pulmonary metastases in 100% of the nude mice, when injected either intravenously or subcutaneously. This study indicates that the nude mouse provided a good model for in vivo selection of metastatic cells from SUIT-2 cells both experimentally and spontaneously, and that the SUIT-2, S2-VPx, and S2-CPx cell lines will be valuable in the study of human cancer metastasis. We previously reported high levels of ezrin expression in the S2-VP10 and S2-CP8 cell lines. Here we show that these cell lines exhibit a greater capacity to invade or attach to various extracellular matrix components than the parent SUIT-2 cells. The S2-CP8 cell lines also exhibit greater level of type-I and type-IV collagen-degrading activity than the parent SUIT-2 cell line and the S2-VP10 cell line, which shows similar collagen-degrading activity to the parent SUIT-2 cells. In RT-PCR studies, SUIT-2, S2-CP8 and S2-VP10 cell lines constitutively expressed many matrix metalloproteinases (MMP-1, MMP-2, MMP-3, MMP7, MMP-9, MMP-10 and MMP-14). These results suggest that some parameters that enhance adhesion and invasion are important to both experimental and spontaneous metastasis and the collagen degrading enzymes are predicted to play a key-role during spontaneous metastasis.
Clin Exp Metastasis 2000
PMID:High collagenolytic activity in spontaneously highly metastatic variants derived from a human pancreatic cancer cell line (SUIT-2) in nude mice. 1168 61

HT-1080 fibrosarcoma cells express at their plasma membrane the elastin-binding protein (EBP). Occupancy of EBP by elastin fragments, tropoelastin or XGVAPG peptides was found to trigger procollagenase-1 (proMMP-1) overproduction by HT-1080 cells at the protein and enzyme levels. RT-PCR analysis indicated that elastin peptides did not modify the MMP-1 mRNA steady state levels, suggesting the involvement of a post-transcriptional mechanism. We previously reported that binding of elastin peptides to EBP induced other matrix metalloproteinases (MMP-2 and MT1-MMP) expression. Since those peptides were here found to also accelerate the secretion of urokinase from HT-1080 cells, culture medium was supplemented with plasminogen together with elastin peptides at aims to induce or potentiate MMPs activation cascades. In such conditions, plasmin activity was generated and exacerbate proMMP-1 and proMMP-2 activation. As a consequence, elastin peptides and plasminogen-treated HT-1080 cells displayed a significant type I collagen matrix invasive capacity.
Clin Exp Metastasis 2002
PMID:Cumulative influence of elastin peptides and plasminogen on matrix metalloproteinase activation and type I collagen invasion by HT-1080 fibrosarcoma cells. 1196 74

The involvement of extracellular matrix-degrading enzymes, such as matrix metalloproteinases and serine proteases, during tumour progression and metastasis is well established. In particular, the activation of pro-matrix metalloproteinase (MMP)-2 on the surface of malignant cells by membrane-bound MT1-MMP has been shown to contribute to the invasive abilities of various tumours. This study presents evidence that in tissue of malignant melanomas, increased effective gelatinolytic activity is mainly located at sites where melanoma cells interact with the surrounding extracellular matrix. Forty-one primary melanomas (30 superficial spreading and 11 nodular type) and six lymph node metastases were investigated by a modified technique of gelatin in situ zymography. This technique localizes areas of effective proteolytic activity within tissue sections. In 28/41 (68%) primary melanomas and in 6/6 (100%) metastases, considerable proteolysis was detected at the invading part of the tumour and especially at sites of tumour-stroma interactions, whereas no or only weak proteolytic activity was localized within the centres of solid nests of tumour cells. Zymographic analysis of extracts obtained from different areas of microdissected melanoma specimens identified activated MMP-2 as the enzyme responsible for this activity. Immunohistochemical analysis detected strong staining for MMP-2 and MT1-MMP, even in areas in which no proteolytic activity was found by in situ zymography, emphasizing the importance of more functional techniques for the investigation of balanced proteolytic systems. This technology makes it possible to draw conclusions regarding the balance between activated proteases and inhibitors, which are frequently found to be present together in close proximity in vivo.
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PMID:Identification of activated matrix metalloproteinase-2 (MMP-2) as the main gelatinolytic enzyme in malignant melanoma by in situ zymography. 1201 41

Early metastasis is the primary cause of death in melanoma patients. The adhesion receptor integrin alpha v beta 3 contributes to tumor cell functions that are potentially involved in melanoma growth and metastasis. We tested whether integrin alpha v beta 3 supports metastasis of human melanoma cells when injected into the bloodstream of immune deficient mice. Comparing variants of the same melanoma cell type that expressed either alpha v beta 3, alpha IIb beta 3 or no beta 3 integrin, we found that only alpha v beta 3 strongly supported metastasis. Inhibition of tumor cell alpha v beta 3 function reduced melanoma metastasis significantly and prolonged animal survival. To understand mechanisms that allow alpha v beta 3, but not alpha IIb beta 3 to support melanoma metastasis, we analyzed proteolytic and migratory activities of the melanoma cell variants. Melanoma cells expressing alpha v beta 3, but not those expressing alpha IIb beta 3 or no beta 3 integrin, produced the active form of metalloproteinase MMP-2 and expressed elevated mRNA levels of MT1-MMP and TIMP-2. This indicates an association between alpha v beta 3 expression and protease processing. Furthermore, alpha v beta 3 expression was required for efficient melanoma cell migration toward the matrix proteins fibronectin and vitronectin. The results suggest that expression of integrin alpha v beta 3 promotes the metastatic phenotype in human melanoma by supporting specific adhesive, invasive and migratory properties of the tumor cells and that the related integrin alpha IIb beta 3 cannot substitute for alpha v beta 3 in this respect.
Clin Exp Metastasis 2002
PMID:Involvement of tumor cell integrin alpha v beta 3 in hematogenous metastasis of human melanoma cells. 1219 71

The events that mediate tumor progression in ovarian carcinoma are poorly understood to date. This review summarizes our results studying metastasis-associated molecules in advanced-stage ovarian carcinomas, details the co-expression of mRNA of these genes, and discusses their prognostic role. Fifty-five primary and metastatic FIGO stage III-IV ovarian carcinomas were analyzed for the expression of alpha v and beta1 integrin subunits, the matrix metalloproteinases MMP-2, MMP-9, and MT1-MMP, the MMP inhibitor TIMP-2, vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), interleukin-8 (IL-8), PEA3 and Ets-1 using mRNA in situ hybridization. Tumor and adjacent stromal cell expression was scored. The association between integrin subunit expression and the expression of MMP, TIMP-2, angiogenic genes, PEA3 and Ets-1 was statistically analyzed. Alpha v integrin subunit mRNA expression in carcinoma cells showed significant association with that of MMP-2 and IL-8 in this cellular compartment, while the presence of beta1 integrin subunit mRNA showed similar association with that of PEA3, Ets-1, IL-8, bFGF and MMP-2. Expression of beta1 integrin subunit mRNA in stromal cells was associated with that of TIMP-2 and Ets-1 in this compartment. In addition, significant intercellular associations were found between alpha v integrin subunit mRNA expression in carcinoma cells and stromal cell expression of Ets-1, as well as between stromal cell expression of alpha v integrin subunit and labeling for IL-8 in carcinoma cells. The presence of beta1 integrin subunit mRNA in carcinoma cells showed a significant association with that of Ets-1, IL-8 and bFGF in stromal cells, while the presence of beta1 integrin subunit mRNA in stromal cells was associated with tumor PEA3 mRNA expression. To the best of our knowledge, this is the first evidence for coordinated autocrine and paracrine expression of members of these four families of metastasis-associated genes in human cancer. The results of this analysis support experimental data regarding cross-talk between carcinoma cells and peritumoral fibroblasts. They also suggest the existence of a putative activation sequence of metastatic genes, involving the beta1 (and possibly alpha v) integrin subunits, IL-8, PEA3, Ets-1 and MMP in ovarian carcinoma.
Cancer Metastasis Rev 2003 Mar
PMID:Coordinated expression of integrin subunits, matrix metalloproteinases (MMP), angiogenic genes and Ets transcription factors in advanced-stage ovarian carcinoma: a possible activation pathway? 1271 42

Previous experimental and biochemical studies on matrix metalloproteinases (MMPs) have indicated that MMPs are implicated in cancer invasion and metastases. Studies on the expression of MMPs and tissue inhibitors of metalloproteinases (TIMPs) in various human cancer tissues have further demonstrated that activation of proMMP-2 mediated by a combination of TIMP-2 and MT1-MMP (the proMMP-2/TIMP-2/MT1-MMP system) correlates well with the progression of most of these cancers such as the breast carcinomas, thyroid papillary carcinomas, gastric adenocarcinomas, oral squamous cell carcinomas and gliomas, whereas MMP-7 plays an important role in the metastases of endometrial and gastrointestinal carcinomas. Although MMP-7 is a typical secreted MMP, a member of transmembrane 4 superfamily (TM4SF) captures proMMP-7 on the carcinoma cell membranes through interaction with its propeptide, leading to its pericellular activation. Thus, these results strongly suggest that proteolysis at the cell-extracellular matrix interfaces of cancer cells by the proMMP-2/TIMP-2/MT1-MMP and proMMP-7/TM4SF systems plays crucial roles in the progression of human cancers. In this article, we address the current views on the roles of these MMPs acting onthe cell membranes in human cancer invasion and metastases.
Cancer Metastasis Rev
PMID:MT1-MMP and MMP-7 in invasion and metastasis of human cancers. 1278 93

RECK was first isolated as a transformation suppressor gene by cDNA expression cloning in a mouse fibroblast cell line transformed by an activated RAS oncogene. Subsequently, reduced expression of RECK in transformed cells and cancer cells were demonstrated. Moreover, in several types of tumors, positive correlation between RECK expression and survival of patients have been noted. RECK encodes a GPI-anchored glycoprotein harboring three protease inhibitor-like domains. The RECK protein regulates at least three members of the matrix metalloproteinase (MMP) family, MMP-2, MMP-9, and MT1-MMP, in vitro or in cultured cells. Restored expression of RECK in cancer cell lines results in strong suppression of invasion, metastasis, and tumor angiogenesis. Mice lacking RECK die in utero with reduced integrity of blood vessels, the neural tube, and mesenchymal tissues. In these mice, MMP activity is elevated, and the amount of collagen type I greatly reduced. The RECK null phenotype is partially rescued (half day delay of death and marked recovery of tissue integrity) by MMP-2 null mutation, demonstrating functional interaction between RECK and MMP-2 in vivo and involvement of other target(s) for RECK in the lethal phenotype. These findings indicate that (i) RECK is an important regulator of extracellular matrix remodeling and that (ii) down-regulation of RECK by oncogenic signaling leads to the excessive activation of MMPs thereby promoting malignant behavior of cancer cells such as invasion, metastasis, and angiogenesis.
Cancer Metastasis Rev
PMID:RECK: a novel suppressor of malignancy linking oncogenic signaling to extracellular matrix remodeling. 1278 95

Tissue inhibitors of metalloproteinases (TIMPs) have been shown to perform several biological functions in tumor promotion, principally by their action of inhibiting matrix metalloproteinases (MMPs) at different steps of the metastatic process. In particular, TIMP-2 is involved in a functional complex with the membrane-type 1 (MT1) MMP to convert the secreted MMP-2 progelatinase into the fully active proteolytic enzyme. We used the human, androgen-sensitive prostate carcinoma cell line LNCaP in coculture with the human osteosarcoma cell line OHS to experimentally address the possibility of androgen-dependent regulatory effects on the functional MT1-MMP/TIMP-2/MMP-2 complex upon interaction between prostate carcinoma and osteoblastic cells in metastasis of prostate cancer to bone. In the LNCaP cells a gradual, time-dependent decline in TIMP-2 mRNA expression was observed in the presence of the synthetic androgen analogue R1881 (100 nM), reaching approximately 25% of the control level after 48 h of incubation. Consistent with this, the accumulation of secreted TIMP-2 in media from R1881-treated cells was significantly inhibited already after 3 h. Neither MMP-2 gelatinolytic activity nor expression of MT1-MMP was detected in LNCaP cells. In contrast, the OHS cells showed membrane-associated MT1-MMP expression as well as MMP-2 secretion. However, R1881 treatment of the LNCaP/OHS coculture model did not seem to change the overall proteolytic activity of the MT1 -MMP/TIMP-2/MMP-2 complex. Hormonal control of TIMP-2 expression in prostate carcinoma cells has not been previously reported, but whether such regulation has any functional role in the development of osteoblastic metastases in prostate cancer is still unclear.
Clin Exp Metastasis 2003
PMID:The metalloproteinase inhibitor TIMP-2 is down-regulated by androgens in LNCaP prostate carcinoma cells. 1459 88

We studied the synthetic matrix metalloproteinase inhibitor (MMPI) prinomastat (AG3340) in a well-established NCI-H460 orthotopic lung cancer model that exhibits highly predictable regional and systemic metastatic patterns. Both primary and metastatic tumors express the matrix metalloproteinases (MMP-2), MT1-MMP (MMP-14) and tissue inhibitor of metalloproteinases (TIMP-2). The anti-tumor activity of prinomastat was investigated both as a single agent and in combination therapy with carboplatin. Treatment with both carboplatin (at two dose levels) and prinomastat commenced when the primary lung cancer was approximately 200-300 mg in size and without gross or microscopic evidence of metastases. As single agents, prinomastat significantly reduced the incidence of kidney metastasis, but had no effect on metastatic frequency to other organs. As single agents neither drug enhanced length of survival over control animals, although microvessel counts in prinomastat-treated tumors were lower than in tumors from control animals (P<0.01). In combination prinomastat and the lower dose of carboplatin significantly enhanced survival over control animals, and over animals treated with carboplatin alone (P<0.05). Tolerance to this combination was assessed with body weight and serum biochemistries. At the higher carboplatin dose, toxicity became evident both as a single agent and in combination with prinomastat. Our results suggest that the administration of prinomastat in combination with standard cytotoxic chemotherapy during early stages of tumor growth and metastasis may prolong survival in non-small cell lung cancer (NSCLC) patients.
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PMID:Early combined treatment with carboplatin and the MMP inhibitor, prinomastat, prolongs survival and reduces systemic metastasis in an aggressive orthotopic lung cancer model. 1464 22

Expression of matrix metalloproteinases (MMPs) and their activation in tumor cells, as well as tumor surrounding stromal cells have been implicated in tumor cell invasion and metastasis. By means of a syngeneic tumor model for either experimental or spontaneous metastases, the differential expression of MMPs and tissue inhibitors of MMPs (TIMPs) in relation to the microenvironment and the way of metastasis induction was characterized. In vitro characterization revealed that increased levels of secreted MMP-2, MMP-9, and TIMP-1 were only detectable in the most aggressive cell line, B16G3.12BM2. Remarkably, active MMP-2 was restricted to this cell line, whereas TIMP-2 and membrane type (MT) 1-MMP expression was comparable in all three of the spontaneously metastasizing melanoma cell lines investigated. In vivo analysis demonstrated that MMP-2, MMP-9, and MT1-MMP were predominantly expressed at the tumor-stroma border of s.c. tumors. Furthermore, functional active MMP-2 was restricted to this invasive front. In spontaneous lymph node or lung metastases, however, MMP-9 was expressed both in the center and the periphery of tumors; these areas were largely negative for MMP-2 and MT1-MMP. Notably, tumor cells of experimental lung metastases did not express MMP-9 at all. These results indicate that expression of MMPs in melanoma metastases is not only influenced by their localization but also the nature of tumor induction, suggesting that individual MMPs serve specific roles during the different stages of metastasis formation.
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PMID:Expression of matrix metalloproteinases in the microenvironment of spontaneous and experimental melanoma metastases reflects the requirements for tumor formation. 1467 78


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