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)

The mts1 (S100A4) gene, encoding a Ca(2+)-binding protein of the S-100 subfamily, is involved in the control of tumor metastasis in some murine tumor cell lines. To further analyze its role, we transfected hormone-responsive human breast cancer MCF-7 cells with the mts1 gene under the control of a strong constitutive promoter. All of the 3 tested clones (MCF-7/mts1) producing Mts1 protein acquired an ability for hormone-independent growth in nude mice. Tumors derived from mts1 transfectants revealed local invasiveness into surrounding muscle and adipose tissues and metastasized to regional lymph nodes and lungs, characteristics which are rarely observed with parental MCF-7 cells. Electron-microscopic analysis of MCF-7/mts1 cells demonstrated structural changes in anchoring junctions, particularly in intermediate filament attachment site (desmosomes). The mts1-transfected clones expressed estrogen receptor, and their growth in tissue culture was both estrogen- and anti-estrogen responsive. Changes in regulation of the estrogen-dependent proteins progesterone receptor and cathepsin D were observed in some of the transfected clones. Our results indicate that mts1 expression in human breast cancer cells induces several changes characteristic of malignant phenotype and tumor progression.
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PMID:Effect of mts1 (S100A4) expression on the progression of human breast cancer cells. 882 56

The murine 18A2/mts1 and its human homolog h-mts1 (S100A4), encoding a Ca2+-binding protein belonging to the S-100 family, are associated with high invasive and metastatic potentials of murine tumors, human tumor cell lines in vitro, and human tumors growing as xenografts. The nm23 is a putative metastasis-suppressor gene whose expression has been found to correlate inversely with the metastatic potential of some forms of human cancer. The products of both human genes alter cytoskeletal dynamics, with antagonistic effects. In view of the equivocal association of nm23 with the metastatic potential of human cancer, we suspected that the relative expression of h-mts1 and nm23 might reflect tumor progression more accurately than either of them alone. We describe here the expression of these genes in infiltrating ductal carcinomas of the breast and show that high h-mts1 expression is associated with metastatic spread to the regional lymph nodes. The expression of nm23 on its own did not show a statistically significant inverse correlation with nodal spread. However, the expression status of the two genes, taken together, correlated strongly with the occurrence of nodal metastases. Breast cancers with no detectable expression of h-mts1 were found to be estrogen and progesterone receptor positive. Expression of h-mts1 was not related to tumor differentiation. The clinical data, together with the state of expression of steroid receptors and the expression levels of h-mts1 and nm23 genes, were analyzed using artificial neural networks for accuracy in predicting nodal spread of the carcinomas. These analyses support the conclusion that, overall, h-mts1 expression appears to be associated with and indicative of more aggressive disease. Complemented with nm23, h-mts1 could provide a powerful marker of breast cancer prognosis.
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PMID:Expression of metastasis-associated genes h-mts1 (S100A4) and nm23 in carcinoma of breast is related to disease progression. 957 Jan 50

The S100 family of calcium binding proteins has been shown to be involved in a variety of physiological function, such as cell proliferation, extracellular signal transduction, intercellular adhesion, motility as well as cancer metastasis. The role played by a member of the S100 gene family, viz. S100A4 (also referred to as mtsl, 18A2/mtsl, pEL-98, p9Ka, metastasin) in the control of cell proliferation as well as in cancer invasion and metastasis has now been extensively studied in a number of laboratories. The protein encoded by S100A4 gene is now known to be capable of regulating cell cycle progression, modulating intercellular adhesion and invasive and metastatic properties of cancer cells. The S100A4 protein appears to be able to sequester and disable the p53 suppressor protein which controls G1-S transition of cells as well as the exit of cells from the S phase into mitosis G2-M transition is believed to involve the induction of stathmin (Op18) gene expression. The expression of this gene has been found to parallel that of S100A4, S100A4 also appears to take part in the homeostasis of growth, with apparent involvement also in growth factor signal transduction and apoptotic cell death. There is considerable evidence that S100A4 expression alters the adhesive properties of cells, possibly by remodelling the extracellular matrix and promoting a redeployment of adhesion-mediating macromolecules occurring in the extracellular matrix. Using transfection technology, it has been shown that over-expression of S100A4 enhances lung colonisation by cancer cells. The transfection and expression of antisense constructs, in contrast, inhibit metastatic localisation in the lung. S100 proteins levels in serum and in tumour tissue are increasingly being monitored and have been regarded as good indicators of the state of cancer progression. Valuable evidence has accumulated regarding the expression of S100A4 in human melanomas. In carcinoma of the breast, the level of expression of S100A4 has been found to be closely related to metastatic spread of the cancer to regional lymph nodes. The purpose of this review is to emphasise the need to focus sharply upon the mechanisms by which S100 proteins in general and S100A4 in particular subserve the wide variety of functions currently attributable to them.
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PMID:S100A4 (MTS1) calcium binding protein in cancer growth, invasion and metastasis. 970 88

A physical and functional interaction between the Ca(2+)-binding protein Mts1 (S100A4) and the tumor suppressor p53 protein is shown here for the first time. We demonstrate that Mts1 binds to the extreme end of the C-terminal regulatory domain of p53 by several in vitro and in vivo approaches: co-immunoprecipitation, affinity chromatography, and far Western blot analysis. The Mts1 protein in vitro inhibits phosphorylation of the full-length p53 and its C-terminal peptide by protein kinase C but not by casein kinase II. The Mts1 binding to p53 interferes with the DNA binding activity of p53 in vitro and reporter gene transactivation in vivo, and this has a regulatory function. A differential modulation of the p53 target gene (p21/WAF, bax, thrombospondin-1, and mdm-2) transcription was observed upon Mts1 induction in tet-inducible cell lines expressing wild type p53. Mts1 cooperates with wild type p53 in apoptosis induction. Our data imply that the ability of Mts1 to enhance p53-dependent apoptosis might accelerate the loss of wild type p53 function in tumors. In this way, Mts1 can contribute to the development of a more aggressive phenotype during tumor progression.
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PMID:Tumor suppressor p53 protein is a new target for the metastasis-associated Mts1/S100A4 protein: functional consequences of their interaction. 1127 47

The involvement of Mts1(S100A4), a small Ca(2+)-binding protein in tumor progression and metastasis had been demonstrated. However, the mechanism by which mts1(S100A4) promoted metastasis had not been identified. Here we demonstrated that Mts1(S100A4) had significant stimulatory effect on the angiogenesis. We detected high incidence of hemangiomas--benign tumors of vascular origin in aged transgenic mice ubiquitously expressing the mts1(S100A4) gene. Furthermore, the serum level of the Mts1(S100A4) protein increased with ageing. Tumors developed in Mts1-transgenic mice revealed an enhanced vascular density. We showed that an oligomeric, but not a dimeric form of the Mts1(S100A4) protein was capable of enhancing the endothelial cell motility in vitro and stimulate the corneal neovascularization in vivo. An oligomeric fraction of the protein was detected in the conditioned media as well as in human serum. The data obtained allowed us to conclude that mts1(S100A4) might induce tumor progression via stimulation of angiogenesis.
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PMID:The metastasis-associated Mts1(S100A4) protein could act as an angiogenic factor. 1149 91

In previous studies, we have shown that numbers of S100 calcium-binding proteins (including S100A4) are expressed differentially in astrocytic tumors according to their levels of malignancy. S100A4 is involved in tumor progression, cell migration and metastasis. This protein is able to play extracellular roles such as neuritogenic and angiogenic activities. The present study aims to investigate the possible role played by extracellular S100A4 in the in vitro migration of astrocytic tumor cells. The speed and rate of migration of living cells were measured using computer-assisted videomicroscopy. In parallel, we also analyzed the effects of extracellular S100A4 on the organization of the actin cytoskeleton and the expression of a number of its molecular regulators. These included small Rho-GTPases (RhoA, Rac1 and Cdc42) and some of their direct effectors (mDia and N-WASP), and also actin-binding proteins such as profilin and alpha-actinin. Our data demonstrate the influence of S100A4 on astrocytic tumor cells with respect to these different aspects. Indeed, we show that extracellular S100A4 treatments decrease both the amount of polymerized F-actin and the levels of expression of RhoA, mDia and profilin. While a decrease in the Cdc42 and N-WASP expression was also observed, the Rac1 expression remained unchanged. All these activities, which result in the stimulation of cell motility, contribute to the understanding of the extracellular role of S100A4.
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PMID:Extracellular S100A4 stimulates the migration rate of astrocytic tumor cells by modifying the organization of their actin cytoskeleton. 1244 62

Elevated S100A4 protein expression is associated with metastatic tumor progression and appears to be a strong molecular marker for clinical prognosis. S100A4 is a calcium-binding protein that is known to form homodimers and interacts with several proteins in a calcium-dependent manner. Here we show that S100A4 localizes to lamellipodia structures in a migrating breast cancer-derived cell line and colocalizes with a known S100A4-interacting protein, myosin heavy chain IIA, at the leading edge. We demonstrate that S100A4 mutants that are defective in either their ability to dimerize or in calcium binding are unable to interact with myosin heavy chain IIA. An S100A4 mutant that is deficient for calcium binding retains the ability to form homodimers, suggesting that S100A4 can exist as calcium-free or calcium-bound dimers in vivo. However, a calcium-bound S100A4 monomer only interacts with another calcium-bound monomer and not with an S100A4 mutant that does not bind calcium. Interestingly, despite the calcium dependence for interaction with known protein partners, calcium binding is not necessary for localization to lamellipodia. Both wild type and a mutant that is deficient for calcium binding colocalize with known markers of actively forming leading edges of lamellipodia, Arp3 and neuronal Wiskott-Aldrich syndrome protein. These data suggest that S100A4 localizes to the leading edge in a calcium-independent manner, and identification of the proteins that are involved in localizing S100A4 to the lamellipodial structures may provide novel insight into the mechanism by which S100A4 regulates metastasis.
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PMID:Characterization of the metastasis-associated protein, S100A4. Roles of calcium binding and dimerization in cellular localization and interaction with myosin. 1275 52

Microarray technology provides important information for diagnostic, prognostic, and even therapeutic applications. Several S100 proteins have been proposed to play important roles in tumor progression and are recognized as potential tumor markers. To substantiate these limited earlier findings, we screened hundreds of tumor specimens from patients of eight different tumor types using tissue microarrays. The results validated the expression of S100A4, S100A6, and S100B in specific tumor types. A significant S100A2 expression was observed in lymphoma biopsies, which implies a possible link between this S100 protein and lymphoma development. In contrast, S100A5 and S100A12 were not significantly expressed in any of the tumor tissues tested. Interestingly, expression of RAGE (receptor for advanced glycation end products) was found in breast and lung tumor tissues where abundant S100A4 and S100A6 expression was also observed. This suggests a possible role of RAGE-mediated signal transduction in the development of these particular cancers.
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PMID:Expression analysis of S100 proteins and RAGE in human tumors using tissue microarrays. 1285 67

This study for the first time demonstrates a physical and functional interaction between the Ca(2+)-binding protein Mts1/S100A4 and tumor suppressor p53 protein. Using different in vitro and in vivo approaches, we have found that Mts1 can bind to the C-terminal regulatory domain of p53. The Mts1 binding to p53 promotes activation of the reporter gene transcription in vivo. A modulation of the p53 target gene (p21/WAF, bax, mdm-2, and thrombospondin-1) expression was observed upon Mts1 induction in the cells expressing the wild-type p53. These results suggest that the ability of Mts1 to enhance p53-dependent apoptosis of tumor cells leads to the decrease/disappearance of the tumor cells expressing the wild-type p53. Thus, Mts1 promotes selection of more aggressive, metastatic phenotype during tumor progression.
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PMID:[Activator of metastasis in cancer cells, Mst1/S100A4 protein binds to tumor suppressor protein p53]. 1294 74

Causal implication of S100A4 in inducing metastases was convincingly shown previously. However, the mechanisms that associate S100A4 with tumor progression are not well understood. S100A4 protein, as a typical member of the S100 family, exhibits dual, intracellular and extracellular, functions. This work is focused on the extracellular function of S100A4, in particular its involvement in tumor-stroma interplay in VMR (mouse adenocarcinoma cell line) tumor cells, which exhibit stroma-dependent metastatic phenotype. We demonstrated the reciprocal influence of tumor and stroma cells where tumor cells stimulate S100A4 secretion from fibroblasts in culture. In turn, extracellular S100A4 modifies the cytoskeleton and focal adhesions and triggers several other events in tumor cells. We found stabilization of the tumor suppressor protein p53 and modulation of its function. In particular, extracellular S100A4 down-regulates the pro-apoptotic bax and the angiogenesis inhibitor thrombospondin-1 genes. For the first time, we demonstrate here that the S100A4 protein added to the extracellular space strongly stimulates proteolytic activity of VMR cells. This activity most probably is associated with matrix metalloproteinases and, in particular, with matrix metalloproteinase-13. Finally, the application of the recombinant S100A4 protein confers stroma-independent metastatic phenotype on VMR tumor cells. In conclusion, our results indicate that metastasis-inducing S100A4 protein plays a pivotal role in the tumor-stroma environment. S100A4 released either by tumor or stroma cells triggers pro-metastatic cascades in tumor cells.
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PMID:Functional significance of metastasis-inducing S100A4(Mts1) in tumor-stroma interplay. 1504 14


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