Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

From breast cancer cDNA libraries, we have cloned cDNAs that proved to correspond to the membrane-type matrix metalloproteinase (MT-MMP) recently identified in human placenta and proposed to be an activator of progelatinase A [Sato, H., Takino, T., Okada, Y., Cao, J., Shinagawa, A., Yamamoto, E. & Seiki, M. (1994) Nature (London) 370, 61-65]. Using one of these cDNAs as a probe, we have detected MT-MMP gene expression in all 83 human carcinoma specimens examined by RNA in situ hybridization and have found MT-MMP transcripts in fibroblastic cells of tumor stroma but not in cancer cells. Comparison with other MMP genes expressed in fibroblastic cells of human carcinomas indicated that the expression pattern of the MT-MMP gene was more closely related to that of the gelatinase A gene than to those of the stromelysin 3 or interstitial collagenase genes. These observations are consistent with the hypothesis that MT-MMP and gelatinase A are cooperating during tumor progression and strengthen the concept that proteolytic activities originating from the stromal component of human carcinomas have a critical role in tumor progression.
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PMID:Membrane-type matrix metalloproteinase (MT-MMP) gene is expressed in stromal cells of human colon, breast, and head and neck carcinomas. 770 15

Analysis of bovine interphotoreceptor matrix and conditioned medium from human Y-79 retinoblastoma cells by gelatin SDS-PAGE zymography reveals abundant activity of a 72-kDa M(r) gelatinase. The 72-kDa gelatinase from either source is inhibited by EDTA but not aprotinin or NEM, indicating that it is a metalloproteinase (MMP). The 72-kDa MMP is converted to a 62-kDa species with APMA treatment after gelatin sepharose affinity purification, typical of previously described gelatinase MMP-2. The latent 72-kDa gelatinase from either bovine IPM or Y-79 media autoactivates without APMA in the presence of calcium and zinc after 72 hr at 37 degrees C, producing a fully active mixture of proteinase species, 50 (48 in Y-79 medium), 38 and 35 kDa in size. The presence of inhibitory activity was examined in both whole bovine IPM and IPM fractions separated by SDS-PAGE. Whole IPM inhibited gelatinolytic activity of autoactivated Y-79-derived MMP in a dose-dependent manner. Inhibitory activities are observed in two protein fractions of 27-42 and 20-25 kDa. Western blots using antibodies to human tissue inhibitor of metalloproteinase 1 and 2 (TIMP-1 and -2) reveal the presence of two TIMP-1-like proteins at 21 and 29 kDa in inhibitory fractions of the bovine IPM. TIMP-2 was not detected in the inhibitory IPM fractions, consistent with the observed autoactivation of bovine IPM 72-kDa gelatinase. Potential roles for this IPM MMP-TIMP system include physiologic remodelling of the neural retina-RPE cell interface and digestion of shed rod outer segment as well as pathological processes such as retinal detachment, PE cell migration, neovascularization and tumor progression. Cultured Y-79 cells appear to be a good model for studying the production and regulation of this proteinase system.
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PMID:Characterization and novel activation of 72-kDa metalloproteinase in retinal interphotoreceptor matrix and Y-79 cell culture medium. 782 70

The expression of the stromelysin 3 (ST3) gene, which encodes a putative matrix metalloproteinase, was studied during breast cancer progression. The ST3 gene is expressed in all invasive breast carcinomas, in a number of their metastases, and in some in situ carcinomas where the probability of detecting ST3 transcripts correlates with the known risk of these carcinomas to become invasive. ST3 RNA and protein were specifically detected in fibroblastic cells immediately surrounding the neoplastic cells in both primary and metastatic tumors. This expression pattern distinguishes the ST3 gene from other matrix metalloproteinase genes, most notably from the 72-kDa type IV collagenase gene, which can be expressed in fibroblastic cells distributed throughout the stroma of primary breast carcinomas. Furthermore, high levels of 72-kDa type IV collagenase, but not of ST3 transcripts, are detected in benign breast fibroadenomas. Interestingly, the urokinase and ST3 genes exhibit very similar patterns of expression in breast carcinomas, which suggests that their products may cooperate during cancer progression.
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PMID:Stromelysin 3 belongs to a subgroup of proteinases expressed in breast carcinoma fibroblastic cells and possibly implicated in tumor progression. 844 98

Hepatocyte growth factor (HGF) is known to have a number of biological properties including promoting tumor progression of human carcinomas. Metastasis involves a number of events that are attributed to induction by paracrine factors such as HGF. Identification of natural inhibitors of these events would allow better control of tumor progression. Recently we demonstrated that interleukin 4 (IL-4) can regulate proliferation of various human carcinoma cell lines. In the present study, we used established human colon carcinoma cell lines and primary colon carcinoma cell cultures to determine if IL-4 could regulate HGF-induced cell proliferation and other events of tumor progression such as MMP (matrix metalloproteinases)-1, -2, and -9 production, cell migration and cell-matrix invasive activity. All colon carcinoma cell lines expressed HGF and IL-4 receptors. IL-4 significantly inhibited HGF-induced proliferation of one cell line. Cell-matrix invasion was significantly enhanced by HGF (0.1-10 ng/ml); IL-4 (1-10 U/ml) significantly inhibited HGF-induced invasion in a dose-dependent manner. IL-4 also inhibited HGF-induced cell-matrix invasion of metastatic colon carcinoma cells and HGF-induced cell migration. HGF enhanced MMP-1, -2, and -9 production by cell lines. This effect could be inhibited by IL-4. These findings indicate that IL-4 is a potent inhibitor of HGF-induced invasion and metastasis-related functions of human colon carcinoma cells.
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PMID:Interleukin 4 inhibits hepatocyte growth factor-induced invasion and migration of colon carcinomas. 889 90

Correlative and functional evidence support a crucial role for metalloproteinase (MMP) activity in tumor progression. Dysregulation of MMP production at local tumor sites is thought to participate in the remodeling of the local stromal tissue necessary for tumor growth. The extent of damages in local tissues is often reflected by the high concentration of MMP released in the bloodstream of cancer patients. The integrity of the thymic architecture plays a crucial role in the development of mature T cells, but it is compromised by extensive remodeling occurring during the development of thymic lymphomas. In the present work, we have used an experimental thymic lymphoma model to investigate the regulation of MMP-9 (gelatinase B) production in animals bearing large thymic lymphomas. We show a 3-fold increase in serum gelatinase B (Gel B) levels in animals bearing thymic lymphoma compared with those found in normal animals and a correlation between these levels and the size of the tumor. Although Gel B was found within the thymic tumor, lymphoma cells did not express it in vivo, indicating that Gel B expression was associated with thymic stromal cells rather than lymphoma cells. This was corroborated by evidence that lymphoma cells have the capacity to stimulate Gel B gene expression in stromal cells. Our results suggest that lymphoma cells can exert a significant control over Gel B expression by local stromal cells, thereby inducing the extensive remodeling necessary for tumor growth.
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PMID:Gelatinase B (MMP-9) production and expression by stromal cells in the normal and adult thymus and experimental thymic lymphoma. 909 68

Tumor cells at the stage of tumor progression build up a high tolerance to intrinsic and extrinsic defence systems and/or therapeutic procedures, and the cells deeply infiltrate the adjacent tissue, which is followed by tumor metastasis to remote organs and tissues. This study was designed to investigate the relationship between expression of matrix metalloproteinase-2 (MMP-2) and invasiveness of human bladder cancer cells, using cell lines derived from a parental human urinary bladder tumor cell line, T24. Two subpopulations of the human bladder cancer cell line T24, Hi-T24 and Lo-T24, were selected using an invasion assay and then expression of MMP-2 mRNA and protein was analyzed by reverse-transcription polymerase chain reaction (RT-PCR) and enzyme immunoassay (EIA). The gross morphology, cell growth rate, and adhesion activity to a basement membrane extract (matrigel) of the high-invasive Hi-T24 cells were similar to those of the low-invasive Lo-T24 cells, but the Hi-T24 cells were 3.8-fold more haptotactic through matrigel than the Lo-T24 cells. The haptotactic activity of the Hi-T24 cells was suppressed by the addition of an anti-MMP-2 antibody, and the amounts of MMP-2 protein secreted into the spent medium by the Hi-T24 and Lo-T24 cells were 7.8+/-0.2 and 3.8+/-0.3 ng/ml (P<0.05), respectively. The quantities of tissue inhibitor of metalloproteinase-2 (TIMP-2) protein secreted by Hi-T24 and Lo-T24 cells were 133.2+/-4.3 and 168.7+/-5.6 ng/ml, respectively (P<0.05). The levels of transcription of the genes encoding MMP-2 and the transmembrane MMP, MT-MMP, evaluated by RT-PCR, were higher in the Hi-T24 cells than in the Lo-T24 cells. Expression of the TIMP-2 gene was slightly lower in the Hi-T24 cells than in the Lo-T24 cells. These results indicate that expression of the metalloproteinases are imbalanced at the gene level in human urinary bladder cancer cells at the stage of tumor progression.
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PMID:Tumor progression and expression of matrix metalloproteinase-2 (MMP-2) mRNA by human urinary bladder cancer cells. 987 15

The demonstration that matrix metalloproteinases [MMPs] play an active role in the invasion and metastasis stages of tumor progression has led to the development of a new class of anti-metastatic chemotherapeutic agent, the matrix metalloproteinase inhibitors [MMPIs]. We present evidence to suggest that the MMP matrilysin, in particular, plays an essential role in much earlier stages of intestinal tumorigenesis. Matrilysin is detected in a high percentage of pre-invasive lesions, in contrast to its absence in most normal tissues, and is expressed by the epithelial-derived tumor cells. Manipulating levels of this enzyme in vitro results in cell lines with enhanced tumorigenic potential, while ablating the gene in vivo leads to a significant reduction in tumor number in two different animal models of intestinal tumorigenesis. Additionally, regulation of matrilysin gene expression appears to be under the control of genetic pathways which are activated very early in the tumor development sequence. Although the precise mechanism by which matrilysin activity contributes to tumor formation is not yet clear, we propose that MMPIs may be of benefit as chemopreventative agents in addition to their therapeutic potential for metastatic disease.
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PMID:Matrilysin in early stage intestinal tumorigenesis. 1019 Feb 86

Activation of matrix metalloproteinase-2 (MMP-2) by the membrane-type matrix metalloproteinases (MT-MMPs) has been associated with tumor progression. In the present study, we examined the role of MMP-2 and its activators MT1-MMP, MT2-MMP and MT3-MMP in pancreatic tumor cell invasion and the development of the desmoplastic reaction characteristic of pancreatic cancer tissues. Northern blot analyses revealed that transcript levels of MT1-MMP and MT2-MMP, but not MT3-MMP, were enhanced in pancreatic cancer tissues (n = 18) compared with both chronic pancreatitis (n = 9) and healthy pancreas (n = 9). A good correlation was found between MT1-MMP and both MMP-2 expression (p < 0.01) and activity in pancreatic cancer tissues. In addition, expression and activation of MMP-2 were strongly associated with the extent of the desmoplastic reaction in pancreatic cancer tissues. Invasion assays showed a good correlation between MMP-2 expression and activity and the invasive potential of pancreatic cancer cell lines. In cell lines with high levels of MMP-2 expression and activity, the MMP inhibitor Batimastat led to significant reduction of the number of invading cells. Our results suggest that MT1-MMP is involved in the progression of pancreatic cancer via activation of MMP-2. MMP-2 itself plays an important role in tumor cell invasion and appears to be associated with the development of the characteristic desmoplastic reaction in pancreatic cancer.
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PMID:Role of MT-MMPs and MMP-2 in pancreatic cancer progression. 1058 76

Invasive breast cancer varies widely in biologic aggressiveness, from fairly indolent tumors to rapidly disseminating carcinomas. Matrix metalloproteinases have enzymatic activity and assist in tumor invasion by degrading basement membranes and extracellular matrix. The extracellular matrix metalloproteinase inducer EMMPRIN is thought to stimulate fibroblasts to produce the zymogen pro-gelatinase A. The membrane type 1-matrix metalloproteinase (MT1-MMP) is thought to assist in tumor invasion and metastasis by activating pro-gelatinase A, which shows enhanced expression in various tumors. Overexpression of gelatinase A has shown to correlate with a malignant phenotype in many tumor forms. The aim of the study was to investigate the mRNA expression pattern of MT1-MMP, gelatinase A, and EMMPRIN in breast tumors. Formalin-fixed paraffin-embedded breast tissue samples from 18 patients operated on with breast-conserving surgery for invasive breast carcinoma <20 mm between 1977 and 1985 were analyzed using the mRNA in situ hybridization technique. Most of the patients were node-negative (15/18) and underwent postoperative irradiation to the breast (16/18). The median age at diagnosis was 52 years (21-83 years). At the time of the study 11 patients were alive, 4 without recurrence; 7 patients had been operated for ipsilateral breast tumor recurrences, and 2 had distant metastases. The median follow-up was 112 months (102-193 months). Seven patients died of disseminated breast cancer; their median follow-up was 43 months (22-116 months). (35)S-labeled antisense and sense mRNA probes transcribed from linearized plasmids containing cDNA for the matrix metalloproteinases gelatinase A and MT1-MMP and the glycoprotein EMMPRIN were hybridized to 5 microm paraffin-embedded tissue sections. Several invasive carcinomas were surrounded by normal tissue and carcinoma in situ lesions. Gelatinase A, MT1-MMP, and EMMPRIN mRNA expression were detected in all of the carcinomas. The gelatinase A mRNA expression was mainly localized to stromal cells at moderate to high levels surrounding the invading carcinoma cells but was also seen in single cells at low levels in in situ lesions and in some normal glandular cells. MT1-MMP and EMMPRIN were expressed in all of the carcinomas and were mainly localized to tumor cells; but they were also seen to some extent in single cells at low levels in in situ lesions and in normal glandular cells. No differences in levels of expression for gelatinase A, MT1-MMP, or EMMPRIN were seen in patients who survived compared to patients who died from metastatic disease. The co-expression of gelatinase A, MT1-MMP, and EMMPRIN mRNA in invasive breast carcinoma supports the theory that these proteins interact and are important for the invasive phenotype in breast carcinoma. Hence EMMPRIN may be a central factor for stimulation of gelatinase A activation. Specific inhibition for individual MMP members could in the future be target-specific events in breast tumor progression. Inhibition of EMMPRIN could be such a target.
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PMID:Gelatinase A, membrane type 1 matrix metalloproteinase, and extracellular matrix metalloproteinase inducer mRNA expression: correlation with invasive growth of breast cancer. 1065 69

After major developments in the diagnosis and therapy of the primary cancer, at the turn of the century clinical oncology is still facing the major challenge: management of the disseminated disease. Cancer biology provided basic information on the genetic and biochemical background of the process, however, it turned out that the individual tumor types use a wide range of mechanisms for invasion and metastasis. Recent major discoveries concerning invasion are identification of the invasion organelle (invadopodia) and identification of certain molecular mechanisms leading to organ-selective metastatization. Prognostic pathology emerged as a new diagnostic field, specialized in predicting the metastatic behavior of the tumor based on the geno- and phenotype of the primary tumor. Ultimately, the first drugs which were designed on the principles of tumor progression entered clinical trials (angiogenesis- and MMP-inhibitors) indicating a slow but steady transfer of cancer biology knowledge to clinical oncology predicting a significant development in the management of disseminated cancer patients.
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PMID:[Problems of tumor progression: doubts or hopes at the turn of the Millennium?]. 1082 69


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