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)

Imaging of enzyme activity is a central goal of molecular imaging. With the introduction of fluorescent smart probes, optical imaging has become the modality of choice for experimental in vivo detection of enzyme activity. Here, we present a novel high-relaxivity nanosensor that is suitable for in vivo imaging of protease activity by magnetic resonance imaging. Upon specific protease cleavage, the nanoparticles rapidly switch from a stable low-relaxivity stealth state to become adhesive, aggregating high-relaxivity particles. To demonstrate the principle, we chose a cleavage motif of matrix metalloproteinase 9 (MMP-9), an enzyme important in inflammation, atherosclerosis, tumor progression, and many other diseases with alterations of the extracellular matrix. On the basis of clinically tested very small iron oxide particles (VSOP), the MMP-9-activatable protease-specific iron oxide particles (PSOP) have a hydrodynamic diameter of only 25 nm. PSOP are rapidly activated, resulting in aggregation and increased T2*-relaxivity.
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PMID:Protease-specific nanosensors for magnetic resonance imaging. 1900 61

Astronauts may be at an increased risk for developing colorectal cancer after a prolonged interplanetary mission given the potential for greater carcinogenic effects of radiation to the colon. In addition, with an increase in age, there is a greater incidence of premalignant colon adenomas with age. In the present study, we have compared the effects of radiation on human colon epithelial cells in two-dimensional (2D) monolayer culture, in three-dimensional (3D) culture, and in intact human colon tissue biopsies. Immortalized colon epithelial cells were irradiated at the NASA Space Radiation Laboratory (NSRL) with either 1 Gy 1 GeV/nucleon (56)Fe particles or 1 Gy 1 GeV/nucleon protons and were stained at various times to assess DNA damage and repair responses. The results show more persisting damage at 24 h with iron-particle radiation compared to protons. Similar results were seen in 3D colon epithelial cell cultures in which (56)Fe-particle-irradiated specimens show more persisting damage at 24 h than those irradiated with low-LET gamma rays. We compared these results to those obtained from human colon tissue biopsies irradiated with 1 Gy gamma rays or 1 Gy 1 GeV (56)Fe particles. Observations of radiation-induced DNA damage and repair in gamma-irradiated specimens revealed more pronounced early DNA damage responses in the epithelial cell compartment compared to the stromal cell compartment. After low-LET irradiation, the damage foci mostly disappeared at 24 h. Antibodies to more than one type of DNA repair factor display this pattern of DNA damage, and staining of nonirradiated cells with nonphosphorylated DNA-PKcs shows a predominance of epithelial staining over stromal cells. Biopsy specimens irradiated with high-LET radiations also show a pattern of predominance of the DNA damage response in the highly proliferative epithelial cell compartment. Persistent unrepaired DNA damage in colon epithelial cells and the differing repair responses between the epithelial and mesenchymal compartments in tissues may enhance tumorigenesis by both stem cell transformation and alterations in the radiation-induced permissive tissue microenvironment that may potentiate cancer progression.
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PMID:Two- and three-dimensional models for risk assessment of radiation-enhanced colorectal tumorigenesis. 1913 51

Pancreatic cancer is a devastating disease with no cure. Therapies that target the tumor vasculature are promising new treatment strategies. Magnetic resonance imaging (MRI) can non-invasively determine a vessel size index and a blood volume fraction to characterize the vascular compartment in a tumor. The changes in the T2 and T2* relaxation rate constants after the administration of superparamagnetic iron oxide (SPIO) particles are dependent on the size and morphology of tissue blood vessels. In this study, MRI was used to investigate changes in the tumor vasculature in an orthotopic primary human pancreatic cancer xenograft model during tumor progression. The SPIO contrast agent Feridex I.V. was first validated as an intravascular contrast agent over the course of the imaging session, and shown to remain in the blood for at least 1.5 h. The average vessel size index was not correlated to the tumor area within an image slice, but the average blood volume fraction was significantly and negatively correlated to the tumor area (p<0.05). Blood volume fraction may serve as a non-invasive biomarker for changes in the tumor vasculature due to tumor growth Further investigation is needed to evaluate this promising technique as a tool to monitor tumor vascular changes in response to antiangiogenic therapies in pancreatic cancer.
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PMID:Assessment of vessel size by MRI in an orthotopic model of human pancreatic cancer. 1916 90

A number of recent observations have suggested a potential role for membrane-bound gamma-glutamyltransferase (GGT) in tumor progression and appearance of more aggressive and resistant phenotypes, through redox interactions leading to production of reactive oxygen species. The present study was aimed to evaluate whether such pro-oxidant activity of GGT can promote oxidative DNA damage, thus contributing to cancer genomic instability. Human GGT-transfected melanoma cells were studied, and DNA damage was measured by using the alkaline comet assay. Our results indicate that higher levels of GGT activity are associated with higher levels of background DNA damage and oxidized bases. This association cannot be explained by differences in cell cycle distribution or apoptotic rates. GGT-over-expressing cells also presented with a markedly higher glucose uptake, a phenomenon potentially leading to higher metabolic rate and oxidative DNA damage. Anyway, when GGT-over-expressing cells were incubated in the presence of GGT substrates and a source of catalytic iron, increased levels of DNA damage and oxidized bases were observed, an effect completely prevented in the presence of GGT inhibitors or various antioxidants.The findings reported indicate that GGT activity is able to promote iron-dependent DNA oxidative damage, thus potentially representing an important mechanism in initiation/progression of neoplastic transformation.
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PMID:Membrane gamma-glutamyl transferase activity promotes iron-dependent oxidative DNA damage in melanoma cells. 1950 83

The epithelial-mesenchymal transition (EMT) plays a critical role in tumor progression. To obtain a broad view of the molecules involved in EMT, we carried out a comparative proteomic analysis of transforming growth factor-beta1 (TGF-beta1)-induced EMT in AML-12 murine hepatocytes. A total of 36 proteins with significant alterations in abundance were identified. Among these proteins, ferritin heavy chain (FHC), a cellular iron storage protein, was characterized as a novel modulator in TGF-beta1-induced EMT. In response to TGF-beta1, there was a dramatic decrease in the FHC levels, which caused iron release from FHC and, therefore, increased the intracellular labile iron pool (LIP). Abolishing the increase in LIP blocked TGF-beta1-induced EMT. In addition, increased LIP levels promoted the production of reactive oxygen species (ROS), which in turn activated p38 mitogen-activated protein kinase. The elimination of ROS inhibited EMT, whereas H2O2 treatment rescued TGF-beta1-induced EMT in cells in which the LIP increase was abrogated. Overexpression of exogenous FHC attenuated the increases in LIP and ROS production, leading to a suppression of EMT. We also showed that TGF-beta1-mediated down-regulation of FHC occurs via 3' untranslated region-dependent repression of the translation of FHC mRNA. Moreover, we found that FHC down-regulation is an event that occurs between the early and highly invasive advanced stages in esophageal adenocarcinoma and that depletion of LIP or ROS suppresses the migration of tumor cells. Our data show that cellular iron homeostasis regulated by FHC plays a critical role in TGF-beta1-induced EMT.
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PMID:Ferritin heavy chain-mediated iron homeostasis and subsequent increased reactive oxygen species production are essential for epithelial-mesenchymal transition. 1953 52

Hypoxia-inducible transcription factor (HIF) is the master regulator of hypoxia-inducible genes involved in the mediation of survival and adaptive responses to insufficient oxygen availability, such as genes involved in hematopoesis, angiogenesis, iron transport, glucose utilization, resistance to oxidative stress, cell proliferation, survival and apoptosis, extracellular matrix homeostasis, and tumor progression. The stability of the HIFalpha subunit is regulated by oxygen-dependent prolyl 4-hydroxylation catalyzed by the HIF prolyl 4-hydroxylases (P4Hs). The 4-hydroxyproline residues generated in normoxic conditions facilitate binding of HIFalpha to the von Hippel-Lindau E3 ubiquitin ligase complex resulting in the attachment of ubiquitin molecules and subsequent rapid proteasomal degradation of HIFalpha. In hypoxia this oxygen-requiring hydroxylation event is inhibited, HIFalpha escapes degradation and can translocate to the nucleus and form a functional dimer with HIFbeta that triggers the hypoxic response. HIF-P4Hs are considered as promising drug development targets in the treatment of diseases such as myocardial infarction, stroke, peripheral vascular disease, inflammation, diabetes and severe anemias. Studies with HIF-P4H inhibitors in various animal models and ongoing clinical trials support this hypothesis by demonstrating efficacy in many applications.
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PMID:HIF prolyl 4-hydroxylases and their potential as drug targets. 1967 Oct 43

Changes in the expression of cell surface glycan are often associated with malignant metastasis. The expression level may be dramatically enhanced during tumor progression. A highly sensitive assay that is capable of detecting low levels of cancer-associated carbohydrate antigens can be a powerful tool for early diagnosis. In this work, an ultrasensitive glycans array using iron oxide/gold core/shell nanoparticles conjugated with antibodies or proteins is developed. A magnetic field is applied to quickly bring nanoparticle labeled proteins or antibodies from a solution to an array of carbohydrates immobilized on glass slides and to help them to encounter the carbohydrates at very low concentration. The gold shell provides a well established platform for conjugation of biomolecules. Well-defined recognition systems, namely, mannose derivatives (Man1, Man4, and Man9) with a mannose binding lectin (Concanavalin A) and a stage-specific embryonic antigens-3 (SSEA-3) with a monoclonal antibody (anti-SSEA-3) were chosen to establish this detection tool. Array systems were conducted to determine their surface dissociation constant (K(D,surface)) and their binding specificity for qualitative and quantitative analysis of carbohydrate-protein and carbohydrate-antibody interactions. When coupled with a signal amplification method based on nanoparticle-promoted reduction of silver, the sensitivity of an iron oxide/gold core/shell nanoparticle-based assay reached to subattomole level in carbohydrate detection.
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PMID:Iron oxide/gold core/shell nanoparticles for ultrasensitive detection of carbohydrate-protein interactions. 1968 35

In 2008, after reports of an association between erythropoietic stimulating agent (ESA) therapy and the potential for either thrombotic cardiovascular events or more rapid tumor progression in some cancers, the Food and Drug Administration changed the product labeling for ESAs, adding a black box warning as well as more restrictive indications, especially in oncology patients. In addition the Centers for Medicare and Medicaid Services has placed significant restrictions on payments for ESA therapy. These new limitations on ESA have led to increased use of transfusions in anemic cancer patients. This increase in allogeneic transfusions potentially will place an additional burden on the US blood supply. Although allogeneic blood transfusion is one answer to ESA restrictions, the use of intravenous iron therapy (IV iron) is another possible alternative. We will discuss the use of IV iron as primary therapy for anemia, the use of combination IV iron and ESA therapy to improve efficiency and decrease costs, and evidence that IV iron with and without ESA therapy can reduce allogeneic blood transfusions in surgical patients. We will also review the available IV iron agents and their comparative safety profiles.
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PMID:Can intravenous iron therapy meet the unmet needs created by the new restrictions on erythropoietic stimulating agents? 1991 55

Matriptase-2 is a newly identified member of the Type II Transmembrane Serine Protease (TTSP) family. The expression profile of many members of this family of proteases is frequently altered in cancerous cells and tissues and a number of TTSPs have been linked to cancer progression and development. Matriptase-2 is structurally similar to matriptase-1, a TTSP which has gained recent interest due to its potential to enhance the aggressive nature of cancer cells and its links with a variety of human cancers. Recently, matriptase-2 has been functionally linked to the regulation of iron metabolism; however, there is also evidence to suggest that, as with other members of the TTSPs, matriptase-2 may have a role in cancer development and progression. This article reviews the current literature on matriptase-2, together with its potential roles in physiological and disease states particularly focusing on cancer.
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PMID:The type II transmembrane serine protease, matriptase-2: Possible links to cancer? 2001 2

Tumour hypoxia is a well-known microenvironmental factor that causes cancer progression and resistance to cancer treatment. This involves multiple mechanisms of which the best-understood ones are mediated through transcriptional gene activation by the hypoxia-inducible factors (HIFs). HIFs in turn are regulated in response to oxygen availability by a family of iron- and 2-oxoglutarate-dependent dioxygenases, the HIF prolyl hydroxylases (PHDs). PHDs inactivate HIFs in normoxia by activating degradation of the HIF-alpha subunit but release HIF activation in poorly oxygenated conditions. The function of HIF in tumours is fairly well characterized but our understanding on the outcome of PHDs in tumours is much more limited. Here we review the function of PHDs on the HIF system, the expression of PHDs in human tumours as well as their putative function in cancer. The PHDs may have either tumour promoting or suppressing activity. Their outcome in cancer depends on the cell and cancer type-specific expression and on the availability of diverse natural PHD inhibitors in tumours. Moreover, besides the action of PHDs on HIF, recent data suggest PHD function in non-HIF signalling. Together the data illustrate a complex operation of the oxygen sensors in cancer.
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PMID:The role of HIF prolyl hydroxylases in tumour growth. 2017 64


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