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)

Cell interaction with the extracellular matrix (ECM) has profound influence in cancer progression. The secreted protein, acidic and rich in cysteine (SPARC) a component of the ECM, impairs the proliferation of different cell types and modulates tumor cell aggressive features. This apparent paradox might result either from the biochemical properties of the different SPARC sources or from differential responses of malignant and stromal cells to SPARC. To test these hypotheses, we purified SPARC secreted by melanoma cells (hMel-SPARC) and compared its activity with different recombinant SPARC preparations, including a new one produced in insect cells. All 5 SPARC species were effective in inhibiting bovine aortic endothelial cell proliferation, adhesion and migration. We then used the melanoma-derived protein to assess SPARC effect on additional cell types. hMel-SPARC greatly impaired the proliferation of both normal and transformed human endothelial cells and exerted a moderate biphasic effect on human fetal fibroblasts proliferation, irrespective of their endogenous SPARC levels. However, SPARC had no effect on the proliferation of several human cancer cell lines regardless of their endogenous levels of SPARC expression. Importantly, downregulation of SPARC levels in melanoma cells using either an antisense RNA or a shRNA against SPARC sensitized them to hMel-SPARC addition in proliferation and migration assays, suggesting that malignant cells developed a SPARC-resistance mechanism. This was not a general resistance to growth suppressing agents, as melanoma cells with restricted SPARC expression were more resistant to chemotherapeutic agents. Thus, malignant cells expressing or not expressing SPARC developed alternative mechanisms that, in contrary to stromal cells, rendered them SPARC-insensitive.
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PMID:SPARC modulates the proliferation of stromal but not melanoma cells unless endogenous SPARC expression is downregulated. 1805 24

The apoptotic mode of cell death is a major regulatory process in all complex organisms. The low proliferative index and slow accumulation of malignant cells in chronic lymphocytic leukemia (CLL), the most frequent type of leukemia in Europe and North America, suggests that the disease is caused by a defect in apoptosis regulation. Classical apoptosis is executed through the activation of caspases, cysteine proteases which are regulated by a number of pro- and anti-apoptotic proteins. One such checkpoint is the control of caspase activation by a relatively new family of inhibitor of apoptosis proteins (IAPs). They block both the mitochondrial-dependent and -independent apoptotic pathways. The IAP family inhibits apoptosis by binding to specific caspases and possibly by other mechanisms. They also participate in the regulation of cellular and intracellular signal transduction. Six human IAPs have been identified: XIAP, cIAP1, cIAP2, NAIP, livin, and survivin. Because of their important role in regulating apoptosis, IAPs are being investigated as a potential prognostic factor as well as a treatment target in cancer patients. Overexpression of several IAPs has been detected in various hematological malignancies, including acute leukemias, myelodysplastic syndrome (MDS), chronic myeloid leukemia (CML), and many types of lymphoid malignancies, such as chronic lymphocytic leukemia (CLL) and diffuse large B-cell lymphoma (DLBCL). Many publications revealed significant correlation between a high level of IAPs, especially of XIAP and survivin, and tumor progression. It seems that overexpression of XIAP in acute myeloid leukemia (AML) and survivin in acute lymphoblastic leukemia (ALL) and DLBCL could become a new unfavorable prognostic factor. Many studies are now concentrating on evaluating the expression and significance of the other proteins of the IAP family. In this paper the current knowledge of the importance of IAPs in hematological malignancies is presented.
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PMID:[The role of the inhibitor of apoptosis protein (IAP) family in hematological malignancies]. 1828 36

Src-family kinases are critically involved in the control of cytoskeleton organization and in the generation of integrin-dependent signaling responses, inducing tyrosine phosphorylation of many signaling and cytoskeletal proteins. Activity of the Src family of tyrosine kinases is tightly controlled by inhibitory phosphorylation of a carboxy-terminal tyrosine residue, inducing an inactive conformation through binding with its SH2 domain. Dephosphorylation of C-ter tyrosine, as well as its deletion of substitution with phenylalanine in oncogenic Src kinases, leads to autophosphorylation at a tyrosine in the activation loop, thereby leading to enhanced Src activity. Beside this phophorylation/dephosphorylation circuitry, cysteine oxidation has been recently reported as a further mechanism of enzyme activation. Mounting evidence describes Src activation via its redox regulation as a key outcome in several circumstances, including growth factor and cytokines signaling, integrin-mediated cell adhesion and motility, membrane receptor cross-talk as well in cell transformation and tumor progression. Among the plethora of data involving Src kinase in physiological and pathophysiological processes, this review will give emphasis to the redox component of the regulation of this master kinase.
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PMID:Src redox regulation: there is more than meets the eye. 1877 19

Imaging of targeted fluorescent probes offers significant advantages for investigating disease and tissue function in animal models in vivo. Conversely, macroscopic tomographic imaging is challenging because of the high scatter of light in biological tissue and the ill-posed nature of the reconstruction mathematics. In this work, we use the earliest-transmitted photons through Lewis Lung Carcinoma bearing mice, thereby dramatically reducing the effect of tissue scattering. By using a fluorescent probe sensitive to cysteine proteases, the method yielded outstanding imaging performance compared with conventional approaches. Accurate visualization of biochemical abnormalities was achieved, not only in the primary tumor, but also in the surrounding tissue related to cancer progression and inflammatory response at the organ level. These findings were confirmed histologically and with ex vivo fluorescence microscopy. The imaging fidelity demonstrated underscores a method that can use a wide range of fluorescent probes to accurately visualize cellular- and molecular-level events in whole animals in vivo.
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PMID:Early photon tomography allows fluorescence detection of lung carcinomas and disease progression in mice in vivo. 1901 34

The methionine cycle and its metabolites homocysteine and cysteine serve several important functions in cellular metabolism. Abnormalities in metabolism of the methionine cycle have been associated with cancer. We determined plasma levels of methionine, homocysteine and cysteine in nude mice implanted with human cancer cell lines (MDA-MB-435 breast, PC-3 prostate, HT29 colon, BX-PC3 pancreas) over a prolonged period of tumor growth. The data were compared with correspondins values in nontumor-bearing controls. Nude mice were injected s.c. in the right flank with 10(6) cancer cells. Tumor growth was measured over time. Methionine was measured in plasma by HPLC. Cysteine and homocysteine were measured in plasma by recombinant enzyme assays and spectrophotometry to measure products. The concentrations of cysteine and homocysteine in plasma decreased significantly as a result of progression of breast, prostate and the pancreas tumor types implanted in the nude mice at least over a two-month period. Data for the colon tumors were nonsignificant for both cysteine and homocysteine. In the case of methionine, the decrease was significant only due to progression of the breast tumors, grown over a long time period, as compared to the mice without tumors control. The results suggest that sulphur amino acids may be plasma or serum biomarkers for cancer progression.
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PMID:Human tumor growth in nude mice is associated with decreased plasma cysteine and homocysteine. 1903 76

Chemokines (chemotactic cytokines) are a family of proteins associated with the trafficking and activation of leukocytes and other cell types in immune surveillance and inflammatory response. Besides their roles in the immune system, they play pleiotropic roles in tumor initiation, promotion, and progression. Chemokines can be classified into four subfamilies of chemokines, CXC, CC, C, or CX3C, based on their number and spacing of conserved cysteine residues near the N-terminus. This CXC subfamily can be further subclassified into two groups, depending on the presence or absence of a tripeptide motif glutamic acid-leucine-arginine (ELR) in the N-terminal domain. ELR(-)CXCL12, which binds to CXCR4 has been frequently implicated in various cancers. Over the past several years, studies have increasingly shown that the CXCR4/CXCL12 axis plays critical roles in tumor progression, such as invasion, angiogenesis, survival, homing to metastatic sites. This review focuses on involvement of CXCR4/CXCL12 interaction in neuroectodermal cancers and their therapeutic potentials. As an attractive therapeutic target of CXCR4/CXCL12 axis for cancer chemotherapy, development history and application of CXCR4 antagonists are described.
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PMID:Chemokine receptor CXCR4 as a therapeutic target for neuroectodermal tumors. 1908 67

Hypoxia is known to induce the transcriptional activation of pathways involved in angiogenesis, growth factor signaling, and tissue invasion and is therefore a potential key regulator of tumor growth. Cyr61 (cysteine rich 61) is a secreted, matricellular protein with proangiogenic capabilities and is transcriptionally induced under hypoxic conditions. High expression levels of Cyr61 were already detected in various cancer types and linked to tumor progression and advanced stages in breast cancer. Besides hypoxia, there is some evidence that posttranscriptional pre-mRNA processing could be involved in the regulation of Cyr61 expression, but was thus far not investigated. We studied the expression pattern of Cyr61 mRNA and protein in breast cancer cell lines as well as in matched pairs of noncancerous breast tissue, preinvasive lesions, and invasive breast cancers, respectively. In addition, we analyzed the potential regulatory capability of hypoxia on Cyr61 expression by functional tissue culture experiments. Our study revealed a stage-dependent induction of Cyr61 mRNA and protein in breast cancer tumorigenesis and for the first time alternative splicing of the Cyr61 gene due to intron retention. Breast carcinogenesis was accompanied by a shift from an intron 3 retaining toward an intron 3 skipping mRNA phenotype consecutively leading to processing of the biological active Cyr61 protein. The functional analyses strongly emphasize that hypoxia serves as a specific inducer of alternative Cyr61 splicing toward the intron skipping mRNA isoform with potential biological consequences in tumor cells.
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PMID:Alternative splicing of Cyr61 is regulated by hypoxia and significantly changed in breast cancer. 1924 29

Overexpression of FGF receptor 3 (FGFR3) is implicated in the development of t(4;14)-positive multiple myeloma. While FGFR3 is frequently overexpressed and/or activated through mutations in bladder cancer, the functional importance of FGFR3 and its potential as a specific therapeutic target in this disease have not been elucidated in vivo. Here we report that inducible knockdown of FGFR3 in human bladder carcinoma cells arrested cell-cycle progression in culture and markedly attenuated tumor progression in xenografted mice. Further, we developed a unique antibody (R3Mab) that inhibited not only WT FGFR3, but also various mutants of the receptor, including disulfide-linked cysteine mutants. Biochemical analysis and 2.1-A resolution crystallography revealed that R3Mab bound to a specific FGFR3 epitope that simultaneously blocked ligand binding, prevented receptor dimerization, and induced substantial conformational changes in the receptor. R3Mab exerted potent antitumor activity against bladder carcinoma and t(4;14)-positive multiple myeloma xenografts in mice by antagonizing FGFR3 signaling and eliciting antibody-dependent cell-mediated cytotoxicity (ADCC). These studies provide in vivo evidence demonstrating an oncogenic role of FGFR3 in bladder cancer and support antibody-based targeting of FGFR3 in hematologic and epithelial cancers driven by WT or mutant FGFR3.
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PMID:Antibody-based targeting of FGFR3 in bladder carcinoma and t(4;14)-positive multiple myeloma in mice. 1942 94

Human serine proteinase inhibitor Kazal-type 2 (SPINK2) functions as a trypsin/acrosin inhibitor and is synthesized mainly in the testis and seminal vesicle where its activity is engaged in fertility. The SPINK2 protein contains a typical Kazal domain composed by six cysteine residues forming three disulfide bridges. The expression of SPINK2 is closely related to cancer such as lymphomas, in that a high transcript level of SPINK2 in patients with primary cutaneous follicle center cell lymphomas have better prognosis with lower mortality. To clarify the role of SPINK2 in cancer, we performed quantitative real-time PCR and showed that the expression level of SPINK2 is significantly elevated in most leukemia cell lines except B-lymphoblast TK-6 cells. The molecular function and structural features of SPINK2 were also investigated by employing the recombinant active and mutant inactive SPINK2 proteins to determine its key P2-P2' (Pro(23)-Arg(24)-His(25)-Phe(26)) active site. The inhibition assay results demonstrated that Arg(24) at the P1 site is crucial for the specificity of SPINK2 on target enzyme. Although His(25) at the P1' and Phe(26) at the P2' residues are also involved in trypsin-SPINK2 interaction, Pro(23) at the P2 site may not be directly participated in interacting with trypsin. In addition, we determined the 3D solution structure of SPINK2 and used this structure to predict the SPINK2-proteinase complex structure and binding properties. These studies not only provide critical information about the structural properties and biophysical features of the SPINK2 proteinase inhibitor, but also suggest its important role in tumor progression and response to treatment.
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PMID:Identification of trypsin-inhibitory site and structure determination of human SPINK2 serine proteinase inhibitor. 1942 58

Cells that migrate away from a central tumour into brain tissue are responsible for inefficient glioblastoma treatment. This migratory behaviour depends partially on lysosomal cysteine cathepsins. Reportedly, the expression of cathepsins B, L and S gradually increases in the progression from benign astrocytoma to the malignant glioblastoma, although their specific roles in glioma progression have not been revealed. The aim of this study was to clarify their specific contribution to glioblastoma cell invasion. The differences between the matrix invading cells and non-invading core cells from spheroids derived from glioblastoma cell culture and from glioblastoma patients' biopsies, and embedded in type I collagen, have been studied at the mRNA, protein and cathepsin activity levels. Analyses of the two types of cells showed that the three cathepsins were up-regulated post-translationally, their specific activities increasing in the invading cells. The cystatin levels were also differentially altered, resulting in higher ratio of cathepsins B and L to stefin B in the invading cells. However, using specific synthetic inhibitors and silencing strategies revealed that only cathepsin B activity was involved in the invasion of glioblastoma cells, confirming previous notion of cathepsin B as tumour invasiveness biomarker. Our data support the concept of specific roles of cysteine cathepsins in cancer progression. Finally the study points out on the complexity of protease regulation and the need to include functional proteomics in the systems biology approaches to understand the processes associated with glioma invasion and progression.
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PMID:Post-translational regulation of cathepsin B, but not of other cysteine cathepsins, contributes to increased glioblastoma cell invasiveness in vitro. 1943 18


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