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)

Carcinoma cell lines are frequently refractory to transforming growth factor-beta (TGF beta)-mediated cell cycle arrest. Whether and how TGF beta signaling is disrupted in the majority of human tumors, however, remains unclear. To investigate whether TGF beta signaling might be disrupted by inactivation of the key signaling molecule, the TGF beta type I (T beta R-I) receptor, and whether or not T beta R-I inactivation is associated with late stage disease, we conducted a comprehensive structural analysis of the T beta R-I gene in fine-needle aspirates of 23 head-&-neck cancer metastases. We encountered 4 different mutations of T beta R-I, 3 of which have not been previously identified. In 1 case, we found a somatic intragenic 4-bp deletion predicting for a truncation of the receptor protein. This is the first example of a true loss-of-function mutation of T beta R-I in a human epithelial neoplasm. In 2 other cases, we identified missense mutations located between the juxtamembrane- and serine-threonine kinase domains. One of these resulted in an alanine-to-threonine substitution (A230T), which disrupts receptor signaling activity by causing rapid protein degradation within the endoplasmatic reticulum. This represents a novel mechanism of inactivation of a TGF beta signaling intermediate. Finally, we identified a serine-to-tyrosine substitution at codon 387 (S387Y) in a metastasis but not in the corresponding primary tumor. We had previously shown this S387Y mutant to be predominantly associated with breast cancer metastases and to have a diminished ability to mediate TGF beta-dependent signaling. In aggregate, these findings provide further support for the hypothesis that inactivation of the TGF beta signaling pathway occurs in a significant subset of human cancers.
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PMID:Novel inactivating mutations of transforming growth factor-beta type I receptor gene in head-and-neck cancer metastases. 1147 74

Maspin is an inhibitor of serine proteinases with tumour suppressor activity. Its expression appears to be reduced in advanced stages of breast cancer. A large series of archival breast tissue specimens has been examined, including normal glands (n=7), fibrocystic change (n=22), ductal carcinoma in situ (DCIS, n=12), infiltrating carcinomas (n=128) and their lymph node metastases (n=65), using a specific monoclonal antibody. Myoepithelium invariably showed strong maspin expression. In epithelial cells, the strongest expression was found in normal breast and fibrocystic change. A significant stepwise decrease in maspin expression (p<0.0001) occurred in the sequence DCIS - invasive cancer - lymph node metastasis. However, a subset of infiltrating carcinomas showed strong maspin expression, significantly associated with a lower rate of lymph node metastasis at the time of diagnosis (p<0.01). This was independent of tumour size and grade. The in vivo observations presented here are in keeping with data obtained in prior in vitro experiments. Maspin emerges as an indicator of tumour progression and metastatic potential, and might be exploited to predict breast cancer prognosis. According to in vitro data, its tumour suppressor activity is likely to involve both the modulation of cell motility/invasiveness and the inhibition of angiogenesis.
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PMID:Decline in the expression of the serine proteinase inhibitor maspin is associated with tumour progression in ductal carcinomas of the breast. 1201 53

Membrane mucins have several functions in epithelial cells including cytoprotection, extravasation during metastases, maintenance of luminal structure, and signal transduction. In this paper we describe a large membrane mucin expressed in the normal intestine. This novel mucin, designated MUC17, contains an extended, repetitive extracellular glycosylation domain and a carboxyl terminus with two EGF-like domains, a SEA module domain, a transmembrane domain, and a cytoplasmic domain with potential serine and tyrosine phosphorylation sites. RNA blot analysis and in situ hybridization indicates that MUC17 is expressed in select pancreatic and colon cancer cell lines and in intestinal absorptive cells. Radiation hybrid mapping localized MUC17 to chromosome 7q22 where it resides in close proximity with three other membrane mucin genes, MUC3A, MUC3B, and MUC12. Thus, these membrane mucins reside together in a gene cluster, but are expressed in different tissues and are likely to have different functions as well.
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PMID:MUC17, a novel membrane-tethered mucin. 1185 12

Bisphosphonates (clodronate, alendronate, pamidronate and zoledronate) at therapeutically attainable non-cytotoxic concentrations inhibited MMP-3, -12, -13 and -20 as well as MMP-1, -2, -8 and -9, but not urokinase-type plasminogen activator (uPA), a serine proteinase and a pro-MMP activator. Dose-dependent inhibition was shown by three independent MMP assays. The inhibition was reduced in the presence of an increased concentration of Ca(2+) when compared to physiologic Ca(2+) concentration. Alendronate inhibited the in vitro invasion (Matrigel) of human HT1080 fibrosarcoma and C8161 melanoma cells, and the random migration of these malignant and endothelial cell lines capable of expressing MMPs and uPA. The concentration of alendronate required to inhibit 50% of the activity (IC(50)=40-70 microM) of MMPs corresponded to the IC(50) of down-regulation of in vitro invasion and migration. The ability of bisphosphonates to down-regulate the in vitro invasion and random migration was comparable or slightly better in relation to the selective gelatinase inhibitor CTTHWGFTLC peptide. Alendronate but not CTTHWGFTLC peptide promoted the adhesion of HT1080 fibrosarcoma and C8161 melanoma cell lines on fibronectin. Bisphosphonates are broad-spectrum MMP inhibitors and this inhibition involves cation chelation. Bisphosphonates further exert antimetastatic, anti-invasive and cell adhesion-promoting properties, which may prevent metastases not only into hard tissues but also to soft tissues.
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PMID:Bisphosphonates inhibit stromelysin-1 (MMP-3), matrix metalloelastase (MMP-12), collagenase-3 (MMP-13) and enamelysin (MMP-20), but not urokinase-type plasminogen activator, and diminish invasion and migration of human malignant and endothelial cell lines. 1198 68

Detailed studies tumor cell-associated procoagulants and fibrinolytic factors have strongly suggested that local thrombin and plasmin generation may be important in tumor progression. Given that one target for both these serine proteases is fibrinogen, a logical extension of this hypothesis is that local fibrin deposition and dissolution may be key determinants of tumor growth and/or dissemination. To directly test this concept, we initiated studies of tumor growth, experimental metastasis, and spontaneous metastasis in C57Bl/6-inbred mice with and without fibrinogen. Using two established C57Bl/6-derived tumor cell lines, Lewis lung carcinoma and B16-BL6 melanoma, fibrinogen deficiency was found to strongly diminish, but not prevent, the development of lung metastases in both experimental and spontaneous metastasis assays. This difference was not a consequence of any obvious difference in tumor stroma formation or the growth of primary or secondary tumors. Rather, tumor cell fate studies argued that there is an important role of fibrin(ogen) in the sustained adhesion and/or survival of tumor cell emboli within the lung. The specific thrombin inhibitor, hirudin, was also shown to strongly diminish metastatic potential, consistent with earlier reports. More importantly, hirudin was found to further diminish the already low metastatic potential of tumor cells in fibrinogen-deficient mice. We conclude that fibrin(ogen) is a critical determinant of metastatic potential, but thrombin appears to contribute to tumor cell dissemination through at least one fibrinogen-independent mechanism. Further, these findings suggest that therapeutic strategies directed at several hemostatic factors might be useful in the suppression of metastatic disease.
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PMID:Fibrinogen and tumor cell metastasis. 1199 Apr 65

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

The complex process of tumor invasion requires the coordinated expression and activity of cell-substratum adhesive interactions and of cell-associated protease systems, which destroy the extracellular matrix (ECM), in order to enable the invading cells to simultaneously grip and destroy the anatomical barriers that control cell spreading. A number of data indicate that such a 'grip and go' process may be performed by an enlarging series of cell membrane-associated serine proteases and serine protease receptors, which provide the invasive cells with a functional unit (the protease and its receptor), able to mediate cell-substratum adhesion through specific receptor domains, to proteolytically degrade ECM and to deliver into the cell signals that up-regulate the expression either of the protease/receptor complex, or of other adhesion molecules, such as integrins. There is evidence that some proteases and protease receptor expression are under the control of tumor hypoxia, which is the result of an imbalance in oxygen supply and demand. The urokinase-type plasminogen activator (u-PA) receptor (u-PAR) is under hypoxic control and cooperates with other serine proteases of the blood coagulation pathways that may extravasate in the tumor milieu as a result of hypoxia-simulated increase of vessel permeability. Other serine proteases and their receptors cooperate with the cell-associated fibrinolytic system to promote cell invasion. Among these, tissue factor and its ligand coagulation factor VII, thrombin and its protease-activated receptors, and type II trans-membrane serine proteases seem to play a crucial role. This Review takes into consideration the complex scenario of the single serine proteases and related receptors that are involved in cell invasion, as well as the protease receptor/adhesion molecule interplay which is necessary to focus the cell surface-driven proteolysis where adhesion provides a grip to the invading cell.
Clin Exp Metastasis 2002
PMID:Multiple pathways of cell invasion are regulated by multiple families of serine proteases. 1206

Hamster tumor cell lines obtained with the Rous sarcoma virus and characterized by a high metastatic activity in vitro were transfected with the gene for C2+/calmodulin-dependent serine-threonine death-associated protein kinase (DAPk). Expression of DAPk in tumor cells dramatically reduced their survival in the blood of syngenic animals and their ability to produce metastases, but did not affect their tumorigenicity or the primary tumor growth. The DAPk-induced change in the metastatic phenotype was not accompanied by substantial changes in production and phosphorylation of v-Src or focal adhesion proteins (focal adhesion kinase and paxilline). The resulting system of transfected cells with a modulated metastatic potential provide a convenient model to study the molecular mechanisms of tumor progression at various steps.
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PMID:[Suppression of the metastatic potential of oncogene v-src-transformed cells as a result of activity of the exogenous DAP kinase]. 1206 33

Associated with the metastatic progression of epithelial tumors is the dynamic regulation of cadherins. Whereas E-cadherin is expressed in most epithelium and carcinomas, recent studies suggest that the up-regulation of other cadherin subtypes in carcinomas, such as N-cadherin, may function in cancer progression. We demonstrate that a signal transduction cascade links the N-cadherin.catenin adhesion complex to up-regulation of the anti-apoptotic protein Bcl-2. In suspension, aggregates of DU-145 cells, an E-cadherin expressing human prostate carcinoma line, survive loss of integrin-dependent adhesion by a different anti-apoptotic signaling pathway than the N-cadherin expressing lines PC3 and PC3N. N-cadherin intercellular adhesion mediates a 3.5-fold increase in Bcl-2 protein expression, whereas the level of the proapoptotic protein Bax remains constant. Only N-cadherin ligation in PC3 cells, which express both N-cadherin and E-cadherin, is sufficient to induce activation of Akt/protein kinase B. N-cadherin homophilic ligation initiates phosphatidylinositol 3-kinase-dependent activation of Akt resulting in Akt phosphorylation of Bad on serine 136. Following N-cadherin homophilic adhesion phosphatidylinositol 3-kinase was identified in immunoprecipitates of the N-cadherin.catenin complex. The recruitment of phosphatidylinositol 3-kinase to the adhesion complex is dependent on ligation of N-cadherin and an organized actin cytoskeleton because cytochalasin D blocks the recruitment. We propose that N-cadherin homophilic adhesion can initiate anti-apoptotic signaling, which enhances the Akt cell survival pathway in metastatic cancer.
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PMID:Signal transduction from N-cadherin increases Bcl-2. Regulation of the phosphatidylinositol 3-kinase/Akt pathway by homophilic adhesion and actin cytoskeletal organization. 1209 80

The prognosis of cancer is primarily dependent on its potential to invade and metastasize. Data from both preclinical and clinical studies strongly suggest that serine proteases, as well as their inhibitors and receptor, play a central role in the processes leading to metastasis. We therefore investigated the prognostic value of plasminogen activator inhibitors type 1 (PAI-1) and type 2 (PAI-2) and the combination of both inhibitors in 332 patients with operable breast cancer. PAI-1 and PAI-2 content was measured in the primary tumor cytosols using an enzyme-linked immunosorbent assay. For PAI-1 the median value (3.9 ng/mg protein) was used as cutoff, while the optimized cutoff for PAI-2 (6.5 ng/mg protein) was obtained using the log-rank statistic. After a median follow-up of 46 months 96 (29%) patients relapsed. In univariate analysis patients with a high PAI-1 or a low PAI-2 content had an increased risk of relapse. The difference was statistically significant for PAI-1 (p<0.0001) and almost statistically significant for PAI-2 (p=0.057). Stage, tumor size, differentiation grade, lymph node status and hormone receptor status also showed significant univariate impact on disease-free survival (DFS). In multivariate analysis (Cox model) PAI-1 (p<0.0001, RR=2.78), PAI-2 (p=0.0075, RR=2.17), UICC stage (p=0.0014, RR=2.2), differentiation grade (p=0.0097, RR=1.91) and nodal status (p<0.0001, RR=2.9) retained their significance. When both inhibitors were combined the worst prognosis was observed in patients with simultaneous high PAI-1 and low PAI-2 levels, whereas low PAI-1 in combination with high PAI-2 values indicated a very favorable prognosis. In conclusion, our study showed that both PAI-1 and PAI-2 had independent prognostic value in breast cancer. Combination of both inhibitors further improved the differentiation of patients with respect to prognosis.
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PMID:Prognostic value of plasminogen activator inhibitors in breast cancer. 1211 88


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