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

We have previously reported the identification of the endogenous angiogenesis inhibitor angiostatin, a specific inhibitor of endothelial cell proliferation in vitro and angiogenesis in vivo. In our original studies, we demonstrated that a Lewis lung carcinoma (LLC-LM) primary tumor could suppress the growth of its metastases by generating angiostatin. Angiostatin, a 38-kDa internal fragment of plasminogen, was purified from the serum and urine of mice bearing LLC-LM, and its discovery provides the first proven mechanism for concomitant resistance (O'Reilly, M. S., Holmgren, L., Shing, Y., Chen, C., Rosenthal, R. A., Moses, M. A., Lane, W. S., Cao, Y., Sage, E. H., and Folkman, J. (1994) Cell 79, 315-328). Subsequently, we have shown that systemic administration of angiostatin can regress a wide variety of malignant tumors in vivo. However, at the time of our initial discovery of angiostatin, the source of the protein was unclear. We hypothesized that the tumor or stromal cells might produce an enzyme that could cleave plasminogen sequestered by the primary tumor into angiostatin. Alternatively, we speculated that the tumor cells might express angiostatin. By Northern analysis, however, we have found no evidence that the tumor cells express angiostatin or other fragments of plasminogen (data not shown). We now report that gelatinase A (matrix metalloproteinase-2), produced directly by the LLC-LM cells, is responsible for the production of angiostatin, which suppresses the growth of metastases in our original model.
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PMID:Regulation of angiostatin production by matrix metalloproteinase-2 in a model of concomitant resistance. 1050 24

The plasmin activation system plays a key role in extracellular matrix degradation in many malignant tumors. Because no data are available on the involvement of the plasmin activation system in matrix degradation by thyroid carcinoma, the present study was performed using follicular thyroid carcinoma cell lines obtained from a primary tumor (FTC-133) and metastases (FTC-236 and FTC-238) of one patient. Matrix degradation by these cell lines was studied assessing the release of radioactivity from S35-methionine labeled extracellular matrix coated onto plastic. The involvement of constituents of the plasmin activation system as well as matrix metalloproteinases (MMPs), another class of proteolytic enzymes, which can be activated by plasmin, were assessed by semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR) and zymography. In the matrix degradation experiment, S35 release by FTC-133 was significantly higher than FTC-236 and FTC-238. S35 degradation could be inhibited by the plasmin inhibitor aprotinin and by anti-human urokinase-type plasminogen activator (uPA) antibody, indicating the involvement of the plasmin activation system. Matrix degradation could also be inhibited by the MMP inhibitor marimastat, thus demonstrating the involvement of MMPs in matrix degradation by these cell lines. Zymographic assays revealed activity of uPA in all cell lines. However, in contrast with FTC-236 and FTC-238, no plasminogen activator inhibitor (PAI) or PAI1 mRNA were found in FTC-133. Therefore, the differences in PAI activity as observed between the cell lines may originate from differences in PAI1 gene transcription. Differences in PAI1 expression did not affect the attachment of these cell lines to vitronectin. We conclude that the plasmin activation system is involved in extracellular matrix degradation by these metastatic follicular thyroid carcinoma cell lines. Differences in extracellular matrix degradation between the cell lines correspond with differences in PAI1 gene expression, indicating the significance of PAI1 in extracellular matrix degradation by metastatic follicular thyroid carcinoma.
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PMID:Degradation of extracellular matrix by metastatic follicular thyroid carcinoma cell lines: role of the plasmin activation system. 1052 70

We examined the antiangiogenic and antitumor efficacy of a newly-developed matrix metalloproteinase (MMP) inhibitor, BPHA (N-biphenyl sulfonyl-phenylalanine hydroxiamic acid). BPHA potently inhibits MMP-2, 9 and 14 but not MMP-1, 3 or 7. In contrast, (-)BPHA, an enantiomer of BPHA, was inactive against all MMP tested. Daily oral administration of BPHA in mice resulted in potent inhibition of tumor-induced angiogenesis, primary tumor growth and liver metastasis, whereas (-)BPHA did not. These results demonstrate that selective MMP inhibition is correlated with antiangiogenic and antitumor efficacy and that the selective MMP inhibitor BPHA has therapeutic potential without hematotoxic effect or loss of body weight.
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PMID:[Antiangiogenic and antitumor effect of BPHA, an orally-active matrix metalloproteinase inhibitor, in in vivo murine and human tumor model]. 1055 17

Node-positive breast carcinoma is associated with a poor prognosis. Some patients benefit from adjuvant chemotherapy but new treatment modalities should still be developed in order to further increase the cure rate in this patient group. Prognostic factors are needed to define patients for such studies. Here, the prognostic value of matrix metalloproteinase-2 (MMP-2) and age was evaluated in 108 premenopausal, node-positive breast carcinoma patients treated with an adjuvant chemotherapy. Expression of MMP-2 protein was studied in paraffin-embedded tissue sections from primary tumors by using specific MMP-2 monoclonal antibody in an immunohistochemical staining. Age less than 40 years predicted 5-year recurrence free survival (RFS) as unfavorable, being 74% in patients 41-49 years of age and 54% in those under age 40 (p = 0.02). The 5-year RFS rate was 85% in patients with an MMP-2 negative primary tumor while it was 65% in the MMP-2 positive patient group. This difference was not, however, statistically significant (p = 0.07). Correlation between hematogenous metastasis and MMP-2 positivity in breast carcinoma was demonstrated for the first time (p = 0.03). A risk group for a relapse was identified using MMP-2 immunohistochemistry and age. The RFS rate in patients less than 40 years with an MMP-2 positive primary tumor was only 50% while it was 74% in other premenopausal patients (p = 0.007). Young age and MMP-2 positivity may, thus, associate with early relapse in node-positive breast carcinoma.
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PMID:MMP-2 positivity and age less than 40 years increases the risk for recurrence in premenopausal patients with node-positive breast carcinoma. 1071 90

There are fundamental issues regarding the role of integrins in human disease which remain to be elucidated. Human cutaneous melanoma is an attractive model for studying integrin involvement in tumor progression because it generally follows a sequential series of definable stages. Furthermore, the most specific marker for the transition of cells from the more benign, non-metastatic radial growth phase stage to the more malignant, metastatically competent vertical growth phase stage is associated with the onset of alpha v beta 3 integrin expression and function. This same pattern, however, does not hold true for human ocular/uveal melanomas which do not progress through these stages, but preferentially metastasize to the liver by dissemination of the cells via a direct hematogenous pathway. It is also unclear whether the alpha v beta 3 integrin is functionally involved in uveal melanoma metastasis or not. Our results show that perturbation of the alpha v beta 3 integrin on moderately invasive A375M human cutaneous melanoma cells with either specific antibodies or ligands results in an increase in the cells' ability to invade in vitro coincident with an increase in the cells' expression and extracellular levels of matrix metalloproteinase-2 (MMP-2, gelatinase A). The highly invasive C8161 human cutaneous melanoma cells express little-to-no alpha v beta 3 integrin, but are more invasive and express higher levels of MMPs after perturbation of their alpha 5 beta 1 integrin. This augmented invasiveness could subsequently be abrogated with a function-blocking anti-MMP-2 antibody. Primary uveal melanoma cells and cells derived from uveal metastases appear to grow in either a spindle or epithelioid morphology. The less invasive uveal melanoma cells are spindle shaped and express higher levels of the alpha v beta 3 integrin, while the more invasive cell lines are epithelioid shaped and express reduced levels of the alpha v beta 3 integrin. The apparent conflict between these results and the current model for cutaneous melanoma progression may be addressed as follows: The expression and function of the alpha v beta 3 integrin plays an important role(s) during the transition of cells from the radial growth phase stage to the vertical growth phase stage. However, further progression leading to metastases may require changes in the cells' integrins that would facilitate their ability to leave the primary tumor, and aid in their ability to invade and ultimately form metastases. It is also conceivable that the alpha v beta 3 integrin is reexpressed during various stages of metastatic dissemination, and, in particular, during tumor reestablishment.
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PMID:Molecular role(s) for integrins in human melanoma invasion. 1072 90

The alteration in sinusoidal collagen type IV occurrence, and myofibroblastic (alpha-SMA-positive) Ito cellular transformation are described in the liver of patients with malignant gastric and colorectal tumors, using electron microscopy as well as light microscopical and ultrastructural immunohistochemistry. The ultrastructural finding revealed transformation of Ito cells mostly into transitional cells in highly differentiated primary tumors and into transitional and myofibroblast-like cells with expressed changes in the other sinusoidal cells in poorly differentiated tumors. Ito cell numbers increased significantly in the livers of cancer patients. A highly significant statistical association was obtained between Ito cell numbers on the one hand and collagen type IV and alpha-SMA immunoreactivity on the other hand in the pericentral zone of the liver lobule. Ultrastructural immunohistochemistry showed increased collagen IV immune deposits in the space of Disse, assembled for the most part around and inside transitional cells. Alpha-SMA immunoreactivity was detected in activated Ito cells diffuse in the lobule, with stronger expression in the intermediate and pericentral zones. It is suggested that stimuli which can influence Ito cell transformation are produced by tumor cells from the primary tumor (TGF-beta1, TNF-alpha, PDGF-beta etc.) and from the metastasizing gastric or colorectal tumor cells--matrix metalloproteinase-2 (MMP-2). It is suggested that sinusoidal extracellular matrix deterioration creates a barrier for cancer invasion on the one hand, or possibly facilitates metastasizing by ensurance of matrix for adhesion on the other hand.
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PMID:Ito cell morphology, alpha-smooth muscle actin and collagen type IV expression in the liver of patients with gastric and colorectal tumors. 1084 10

Previously we reported that when cells from the human transitional cell carcinoma cell line 253J B-V growing orthotopically within the bladder of athymic nude mice were treated with the anti-epidermal growth factor receptor monoclonal antibody C225, angiogenesis was inhibited, resulting in regression of the primary tumor and inhibition of metastasis. In this study, we evaluated whether paclitaxel enhanced this therapeutic effect of C225. In vitro, the proliferation of 253J B-V cells was inhibited more by the combination of C225 and paclitaxel than with either agent alone. In vivo therapy with C225 and paclitaxel resulted in significantly greater regression of tumors compared with either agent alone. Median bladder tumor weight was 85 mg (range, 69-133 mg) compared with 168 mg (range, 72-288 mg) after C225 alone (P < 0.05), and 273 mg (range, 83-563 mg) after paclitaxel alone (P < 0.005). The incidence of spontaneous lymph node metastasis was also reduced by the combination of C225 with paclitaxel, although this result did not significantly differ from results after the use of C225 alone. Treatment with paclitaxel and C225 down-regulated the expression of basic fibroblast growth factor, vascular endothelial cell growth factor, interleukin-8, and matrix metalloproteinase type 9 and inhibited tumor-induced neovascularity compared with untreated controls (P < 0.005). Moreover, the combination of C225 and paclitaxel enhanced apoptosis in tumor and endothelial cells compared with either agent alone (P < 0.005). These studies indicate that therapy with paclitaxel increases the ability of C225 to inhibit tumorigenicity and metastasis. This effect is mediated by inhibition of angiogenesis and induction of apoptosis.
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PMID:Paclitaxel enhances the effects of the anti-epidermal growth factor receptor monoclonal antibody ImClone C225 in mice with metastatic human bladder transitional cell carcinoma. 1115 47

The present study was aimed at evaluating the effect of the matrix metalloproteinase (MMP) inhibitor prinomastat (AG3340) on tumor progression using an orthotopic pancreatic carcinoma model in severe combined immunodeficient mice. In controls, receiving vehicle only, the poorly differentiated ductal adenocarcinoma invaded into adjacent organs and metastasized to different sites in the abdomen and to the lungs. Treatment with prinomastat, intraperitoneally twice daily for 21 days, reduced primary tumor volume significantly to 19.0 (+/-7.7)% of control, with induction of necrosis, differentiation, and fibrotic tissue in the pancreatic tumors. Invasion was not observed in 63% of prinomastat-treated mice, and metastases were reduced markedly. Surprisingly, prinomastat-treated tumors had on average higher microvessel densities as a consequence of an increased angiogenesis in perinecrotic tumor areas. We conclude that prinomastat is highly effective in inhibiting pancreatic carcinoma growth and progression in an orthotopic cancer model. This model appears to be a valuable tool to investigate the potency of novel antimetastatic strategies in pancreatic ductal adenocarcinoma by specifically targeting certain MMPs.
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PMID:Inhibitory effect of a matrix metalloproteinase inhibitor on growth and spread of human pancreatic ductal adenocarcinoma evaluated in an orthotopic severe combined immunodeficient (SCID) mouse model. 1127 65

Cell migration and proteolysis are two essential processes during tumor invasion and metastasis. Matrix metalloproteinase (MMP)-2 (type IV collagenase; gelatinase A), is implicated in tumor metastasis as well as in primary tumor growth. The Rho family of small GTPases regulates the dynamics of actin cytoskeleton associated with cell motility. In this report, we provide evidence that Rac1, one member of Rho-related small GTPases, is a mediator of MMP-2 activation in HT1080 fibrosarcoma cells cultured in three-dimensional collagen gel (3D-col) and that MMP-2 activation is required for Rac1-promoted cell invasion through collagen barrier. Stable expression of dominant negative (Rac1V12N17) and constitutively active Rac1 (Rac1V12), respectively, in HT1080 cells demonstrates that Rac1 promoted cell invasiveness across type I collagen and collagen-dependent MMP-2 activation. Active Rac1 is sufficient to induce MMP-2 activation in cells cultured in fibrin gel, an extracellular matrix component that does not support MMP-2 activation. The Rac1-dependent MMP-2 activation occurred in a cell-associated fashion and required MMP activities. Because the cell membrane-mediated MMP-2 activation requires MT1-MMP and low amount of issue inhibitor of matrix metalloproteinase-2 (TIMP-2), their expression was examined. Rac1 modulated MT1-MMP mRNA level and the accumulation of a 43-kDa form of MT1-MMP protein, in correlation with MMP-2 activation profile. However, TIMP-2 expression was independent of Rac1 activity. The coordinate modulation of MMP-2 activity and MT1-MMP expression/processing by Rac1 is consistent with cell collagenolytic activity. The C-terminal hemopexin-like domain of MMP-2, which interferes with the cell membrane activation of MMP-2, reduced Rac1-promoted cell invasiveness as monitored by collagen invasion assay. These results suggest that collagen-dependent MMP-2 activation and MT1-MMP expression/processing contribute to Rac-promoted tumor cell invasion through interstitial collagen barrier.
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PMID:Rac1 mediates type I collagen-dependent MMP-2 activation. role in cell invasion across collagen barrier. 1134 84

(-)-Epigallocatechin-3-gallate (EGCG), a major polyphenol in green tea, was shown to have cancer chemopreventive activity. In this study, we examined the antimetastatic effects of EGCG or the combination of EGCG and dacarbazine on B16-F3m melanoma cells in vitro and in vivo. First, the antimetastatic potentials of five green tea catechins were examined by soft agar colony formation assay, and the results show that EGCG was more effective than the other catechins in inhibiting soft agar colony formation. Second, EGCG dose-dependently inhibited B16-F3m cell migration and invasion by in vitro Transwell assay. Third, EGCG significantly inhibited the spread of B16-F3m cells on fibronectin, laminin, collagen, and Matrigel in a dose-dependent manner. In addition, EGCG significantly inhibited the tyrosine phosphorylation of focal adhesion kinase (FAK) and the activity of matrix metalloproteinase-9 (MMP-9). In animal experiments, EGCG alone reduced lung metastases in mice bearing B16-F3m melanomas. However, a combination of EGCG and dacarbazine was more effective than EGCG alone in reducing the number of pulmonary metastases and primary tumor growths, and increased the survival rate of melanoma-bearing mice. These results demonstrate that combination treatment with EGCG and dacarbazine strongly inhibits melanoma growth and metastasis, and the action mechanisms of EGCG are associated with the inhibition of cell spreading, cell-extracellular matrix and cell-cell interactions, MMP-9 and FAK activities.
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PMID:Inhibition of melanoma growth and metastasis by combination with (-)-epigallocatechin-3-gallate and dacarbazine in mice. 1174 6


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