Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0677930 (primary tumor)
 20,210 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Numerous studies have reported a correlation between production of 72-kDa (MMP-2) and 92-kDa (MMP-9) type-IV collagenases/gelatinases and the metastatic potential of cancer cells. An abrogating effect of tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2) on metastases has also been noted. In this report we have used sensitive enzyme-linked immunoassays to measure MMP-2, MMP-9, TIMP-1 and TIMP-2 levels in eight human lung-cancer cell lines which were characterized for biological behavior in nude mice. We demonstrated that the Calu-6 and A549 cell lines with the highest metastatic, invasive and tumorigenic potential secreted the highest levels of MMP-2. MMP-9 and TIMP-1 secretions were comparatively low in all cell lines. TIMP-2 secretion, which exceeded MMP-2 secretion for all cell lines, did not correlate with metastatic potential. To further explore these correlations, the metastatic Calu-6 cell line was transfected with a K-rev-1 cDNA expression construct. The K-rev revertant cell lines demonstrated a more differentiated phenotype and were less tumorigenic, invasive and metastatic in nude mice. Nonetheless, the Calu-6 revertant cell lines secreted higher levels of MMP-2 than the parent cell line. In conclusion, invasion and metastasis by lung-cancer cells requires not only enhanced MMP production, but also other less well-understood tumorigenic characteristics. The multiplicity of factors required by cancer cells for dissemination helps to explain the minute fraction of cancer cells from a primary tumor that ever develop into a metastasis.
 ...
PMID:Secretion of gelatinases and tissue inhibitors of metalloproteinases by human lung cancer cell lines and revertant cell lines: not an invariant correlation with metastasis. 139 11

Over-production of gelatinase A (MMP-2) or under-production of its inhibitor (TIMP-2) may result in the matrix degradation crucial for metastasis, and early evaluation of their expression in primary tumor would offer important prognostic informations. RT-PCR amplicons of MMP-2 and TIMP-2 mRNA from tissue biopsies of 13 breast carcinomas and one fibrocystic mastopathy were quantitated. In comparison with their normal-tissue counterparts, their expression trends were not uniform: in some cases MMP-2 increased in the tumor without changes in TIMP-2, in others TIMP-2 expression also increased, although to a lesser extent than MMP-2; only in 2 cases was it slightly lower in the tumor tissue. Nevertheless, clearer insights were gained from the comparison of the ratio (R) between MMP-2tumor/normal and TIMP-2tumor/normal: as in the fibrocystic mastopathy, the R in carcinomas without lymph-node involvement (LN-) was usually lower than I in most cases. In contrast, in 5 out of 6 patients with lymph-node metastasis (LN+), the ratio ranged between 2 and 4. While the R magnitude was not related to the frequency of positive lymph nodes out of the total analyzed, nor to relapse status at follow-up (all relapse-free), the clear-cut difference between the LN- and LN+ groups was statistically significant. Results suggest that evaluation of MMP-2/TIMP-2 mRNA balance may constitute an early prognostic approach, which may also be more reliable concerning cancer aggressiveness as compared with the MMP-2 alone, and that boosting TIMP-2 expression may be a therapeutic strategy to prevent metastasis.
 ...
PMID:Gelatinase A/TIMP-2 imbalance in lymph-node-positive breast carcinomas, as measured by RT-PCR. 759 Dec 76

The extra-cellular matrix (ECM) related antigens, type IV collagen, laminin, M(r) 68,000 laminin receptor (LR), M(r) 72,000 type IV collagenase (MMP-2), its inhibitor TIMP-2, and alpha 2-macroglobulin expression have been immunohistochemically investigated in 100 cases of human gastric carcinoma with a 5-yr follow up. Basement membranes were inversely related to tumoral differentiation. At the early intramucosal stage of both intestinal and diffuse histological types, TIMP-2 was expressed by the majority of tumor cells (60/63%), whereas MMP-2+ and LR+ cells were in the minority (24/19%, 23/0%, respectively). At the early submucosal stage, TIMP-2+ cells moderately decreased in both histological types (49/49%), whereas a consistently higher number of both MMP-2+ and LR+ cells were detected only in the diffuse carcinomas (72%). In the advanced stage, the expression of TIMP-2 further declined (22/24%), although the other two antigens increased or maintained high levels of expression. AMG+ cells never exceeded 10% in either histological type at any stage. In the liver metastases, both MMP-2+ and LR+ cells were more numerous than in the primary tumor (P < 0.002 and P < 0.01). Patients who died from their primary tumor had higher percentages of LR+, MMP-2+, and AMG+ cells and lower percentages of TIMP-2+ cells with respect to survivors. We believe evaluation of ECM-related antigens, and especially TIMP-2, may help determine a confident prognosis for gastric cancer.
 ...
PMID:Prognosis of gastric carcinoma revealed by interactions between tumor cells and basement membrane. 800 47

In this study, we describe the activity of CT1746, an orally-active synthetic MMP inhibitor that has a greater specificity for gelatinase A, gelatinase B and stromelysin than for interstitial collagenase and matrilysin, in a nude mouse model that better mimics the clinical development of human colon cancer. The model is constructed by surgical orthotopic implantation (SOI) of histologically-intact tissue of the metastatic human colon tumor cell line Co-3. Animals were gavaged with CT1746 twice a day at 100 mg/kg for 5 days after the SOI of Co-3 for 43 days. In this model CT1746 significantly prolonged the median survival time of the tumor-bearing animals from 51 to 78 days. Significant efficacy of CT1746 was observed on primary tumor growth (32% reduction in mean tumor area at day 36), total spread and metastasis (6/20 treated animals had no detectable spread and metastasis at autopsy compared to 100% incidence of secondaries in control groups). Efficacy of CT1746 could also be seen on reducing tumor spread and metastasis to individual organ sites such as the abdominal wall, cecum and lymph nodes compared to vehicle and untreated controls. We conclude that chronic administration of a peptidomimetic MMP inhibitor via the oral route is feasible and results in inhibition of solid tumor growth, spread and metastasis with increase in survival in this model of human cancer, thus converting aggressive cancer to a more controlled indolent disease.
 ...
PMID:Conversion of highly malignant colon cancer from an aggressive to a controlled disease by oral administration of a metalloproteinase inhibitor. 906 95

Degradation of the extracellular matrix is necessary for invasion and metastasis by cancer cells. Two gelatinolytic matrix metalloproteinase enzymes, MMP-2 and MMP-9, are supposed to be key enzymes in this process. The purpose of this study was to correlate the presence of MMP-2, MMP-9 and their inhibitors with the tissue inhibitors of metalloproteinases TIMP-1 and TIMP-2 RNA using reverse transcriptase PCR technique with tumor stage in 17 samples of renal cell carcinoma. The ratio of tissues expressing MMP-2 and MMP-9 to those expressing TIMP-1 and TIMP-2 was defined to be 1 in normal kidney tissue. This MMP:TIMP ratio was significantly increased to 2.43 (standard deviation, SD = 0.8) in locally confined renal cell carcinoma and to 4.86 (SD = 1.1) in advanced carcinoma (p <0.01). In primary tumor cell lines the ratio of MMP:TIMP expression was 3.44 (SD = 0.6). These data suggest that the balance of MMP-2 and MMP-9 to TIMP-1 and TIMP-2 expression is an essential factor in the aggressiveness of renal cell carcinoma.
 ...
PMID:Expression of metalloproteinase 2 and 9 and their inhibitors in renal cell carcinoma. 978 85

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.
 ...
PMID:[Problems of tumor progression: doubts or hopes at the turn of the Millennium?]. 1082 69

Gelatinase A (MMP-2) and gelatinase B (MMP-9) play a key role in the proteolytic cascade leading to ECM degradation during invasion and metastasis. The enzyme activity is regulated both at the intra- and extra-cellular level. Extracellular regulation is achieved mainly through the balance between proenzyme activation and inhibition, which appears to be altered in cancer patients. One of the mechanisms of MMP inhibition is the binding of the enzymes to appropriate tissue inhibitors (TIMP). In the recent literature, it has been suggested that MMP-2 and/or MMP-9 are indeed over-produced in many carcinomas, while the identity of the various enzymatic forms (latent, activated and enzyme/inhibitor complexes) remains to be elucidated. In this study we have analyzed the circulating forms of MMP-9 and MMP-2 in serum samples of patients with colon carcinoma, as well as the enzymatic activities present in tissue extracts from surgical fragments (primary tumor and its paired healthy tissue). Proteins were separated by means of mono-dimensional or bidimensional electrophoresis, and the enzymes detected by gelatin zymography and immunological assays. The results of densitometric analyses demonstrate that proMMP-9, but not proMMP-2, is significantly higher in the oncologic sera vs. the normal sera. In addition, several oligomeric circulating and tissue forms of MMP-9 are preferentially found in the oncologic samples, both in mono- and second-dimension zymograms. The activated forms of MMP-2 and MMP-9 are uniquely present in the primary tumor extracts, thus confirming the involvement of the tissue microenvironment in gelatinase activation and function.
 ...
PMID:Zymographic analysis of circulating and tissue forms of colon carcinoma gelatinase A (MMP-2) and B (MMP-9) separated by mono- and two-dimensional electrophoresis. 1222 1

Urokinase plasminogen activator (uPA) and metalloproteinases (MMP) play key roles in invasion and metastasis, degrading extracellular matrix compounds and modulating tumor cell motility. Their regulation is an attractive therapeutic target for controlling tumor metastasis. Previously we have demonstrated that urokinase overexpression in murine mammary tumor cells is regulated by a Ca2+-dependent pathway and that blockage of Ca2+ channels by verapamil partially inhibited their invasive and metastatic ability. Moreover, the catalytic inhibition of uPA by a synthetic uPA inhibitor B428 reduced local tumor invasiveness but not tumor cell dissemination. We evaluated the effect of a combined treatment with verapamil and B428 on the murine mammary carcinoma F3II behavior in vivo and in vitro. In vivo administration of the combined treatment was not associated to an overt toxicity. Only the daily combined treatment, beginning after tumor take, reduced the incidence and the number of spontaneous lung metastasis, while no differences were found in the subcutaneous growth of the primary tumor. Interestingly, a remarkable reduction in plasma MMP-9 activity was found associated to metastasis impairment. In addition, the number of experimental lung metastases was also significantly diminished, with respect to the control group, only when both compounds were co-administered daily, beginning three days after i.v. tumor cell injection. In vitro, both compounds, either separately or combined, could inhibit secreted uPA activity. F3II cell migration was significantly inhibited by incubation with 50 microM verapamil, 15 microM B428 or the co-treatment with 7.5 microM B428 + 25 microM verapamil. The cell spread was also significantly reduced when F3II cells were exposed to the compounds, with an additive effect when B428 + verapamil combination was used. The combination of two compounds acting through different molecular targets may be useful to improve the control of metastatic dissemination.
 ...
PMID:Combined treatment with verapamil, a calcium channel blocker, and B428, a synthetic uPA inhibitor, impairs the metastatic ability of a murine mammary carcinoma. 1268 50

In human carcinomas, stromelysin-3/matrix metalloproteinase 11 (ST3, MMP11) expression by nonmalignant fibroblastic cells located in the immediate vicinity of cancer cells is a bad prognostic factor. Using mouse models of primary tumors, it has been demonstrated that ST3 is a key player during local invasion, favoring cancer cell survival in connective tissue through an antiapoptotic function. To investigate the ST3 impact on additional phases of cancer cell invasion, we developed mammary gland cancer prone MMTV-ras transgenic mice in wild-type (ras+/+;ST3+/+) or ST3-deficient (ras+/+;ST3-/-) genotype and studied their whole natural cancer history. The tumor-free survival and delay between the first ras oncogenic hit and primary tumor appearance increased in ras+/+;ST3-/- mice (P < 0.000001 and <0.0000007, respectively). A systematic search for occult primary tumors and metastases revealed, in addition to a lower total number and size of primary tumors (P < 0.02), an unexpected higher number of metastases (P < 0.01) in ras+/+;ST3-/- mice. Moreover, for a similar number and size of primary invasive tumors, ras+/+;ST3-/- mice developed more metastases, indicating that the cancer cells evolving in ST3-deficient stroma have an increased potential to hematogenous dissemination. We conclude that the ST3 microenvironment is a consistently active partner of invading cancer cells but that its function differs throughout cancer progression, being tumor enhancer or repressor in processes leading to local or distal invasion. Such a dual effect for an MMP might shed light, at least partially, for the absence of survival benefit for patients included in anti-MMP clinical trials.
 ...
PMID:Dual stromelysin-3 function during natural mouse mammary tumor virus-ras tumor progression. 1452 8

The purpose of these studies was to explore the genes associated with invasion and metastasis of human prostatic carcinoma line PC-3M in nude mice. After PC-3M cells were inoculated in orthotopic site (prostate) in male nude mice for two months, tumor cells were isolated from primary tumor and lymph node metastasis in the same mouse, respectively. Cell invasion and adhesion ability in vitro were first compared between two cell lines. Then human metastasis-related genes differentially expressed between them were analyzed by utilizing cDNA microarray technique. The in vitro cell invasion and adhesion potential of tumor cells from lymph node metastasis was significantly higher than those from primary tumor, Metastasis-related genes differentially expressed between those two cell lines were identified, all of them were up-regulated in the tumor cells from lymph node metastasis and could be categorized as: (1) genes encoding cellular matrix-degrading proteolytic enzyme including cathepsin and MMP; (2) genes encoding transcription factors; (3) genes related to heterotypic adhesion of tumor cells; (4) genes encoding cell surface receptors. Moreover, Four genes were chosen for semi-quantitative RT-PCR analysis, they showed a consistent expression pattern with that of cDNA microarray analysis. We concluded that the lymph node metastasis in nude mice given an injection of PC-3M cells in the prostate is a selective process favoring the survival and growth of a special subpopulation derived from primary tumor with specific genetic alterations, which may play a pivotal role in the metastasis of prostate cancer. Identification and further characterization of these genes may allow a better understanding of lymphatic metastasis in prostate carcinoma.
 ...
PMID:Differential metastasis-associated gene analysis of prostate carcinoma cells derived from primary tumor and spontaneous lymphatic metastasis in nude mice with orthotopic implantation of PC-3M cells. 1588 94


1 2 3 Next >>