Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0598934 (tumor growth)
 58,965 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Copper-64 (T(1/2) = 12.7 h; beta(+): 17.8%, beta(-): 41%) has applications in both positron emission tomography (PET) imaging and targeted radiotherapy of cancer. Copper-64 radiopharmaceuticals have shown tumor growth inhibition with a relatively low radiation dose in animal models; however, the mechanism of cytotoxicity has not been fully elucidated. Here, we report an investigation on the potential role of the tumor suppressor protein p53 in trafficking (64)Cu to tumor cell nuclei. Two EGFR expressing human colorectal cell lines (HCT 116 +/+ and HCT 116 -/-) that are positive or negative for p53 expression respectively, were used to compare internalization and nuclear localization of [(64)Cu]copper acetate and of (64)Cu-DOTA-cetuximab, a monoclonal anti-EGFR antibody. [(64)Cu]copper acetate uptake into cells was similar between the two cell lines during a 24 h time course. In contrast, the uptake of [(64)Cu]copper acetate in the nuclei of HCT 116 +/+ cells was significantly higher than in HCT 116 -/- cells (p < 0.0001) at 24 h. There was no difference in receptor binding, receptor-mediated internalization, and efflux of (64)Cu-DOTA-cetuximab between the two HCT 116 cells lines. However, nuclear localization of (64)Cu-DOTA-cetuximab showed increased uptake in the nuclei of HCT 116 +/+ cells as early as 4 h. These data demonstrate that (64)Cu is delivered to tumor cell nuclei in a p53 positive cell line in significantly greater amounts than in p53 negative cells by both non-specific and receptor-mediated uptake mechanisms.
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PMID:The role of p53 in the trafficking of copper-64 to tumor cell nuclei. 1793 76

JNJ-28871063 is a potent and highly selective pan-ErbB kinase inhibitor from a novel aminopyrimidine oxime structural class that blocks the proliferation of epidermal growth factor receptor (EGFR; ErbB1)- and ErbB2-overexpressing cells but does not affect the growth of non-ErbB-overexpressing cells. Treatment of human cancer cells with JNJ-28871063 inhibited phosphorylation of functionally important tyrosine residues in both EGFR and ErbB2 and blocked downstream signal transduction pathways responsible for proliferation and survival. A single dose of compound reduced phosphorylation of ErbB2 receptors in tumor-bearing mice, demonstrating target suppression in vivo. Tissue distribution studies show that JNJ-28871063 crosses the blood-brain barrier and penetrates into tumors, where it is able to accumulate to higher levels than those found in the plasma. JNJ-28871063 showed oral antitumor activity in human tumor xenograft models that overexpress EGFR and ErbB2. In an intracranial ErbB2-overexpressing tumor model, JNJ-28871063 extended survival relative to untreated animals. The brain is a primary site of metastasis for EGFR-overexpressing lung cancers and ErbB2-overexpressing breast cancers. Therefore, the ability to penetrate into the brain could be an advantage over existing therapies such as trastuzumab (Herceptin) and cetuximab (Erbitux), which are antibodies and do not cross the blood-brain barrier. These results show that JNJ-28871063 is orally bioavailable, has activity against EGFR and ErbB2-dependent tumor xenografts, and can penetrate into the brain and inhibit ErbB2-overexpressing tumor growth.
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PMID:Cellular and in vivo activity of JNJ-28871063, a nonquinazoline pan-ErbB kinase inhibitor that crosses the blood-brain barrier and displays efficacy against intracranial tumors. 1798 94

Oncogenic events play an important role in cancer-related coagulopathy (Trousseau syndrome), angiogenesis and disease progression. This can, in part, be attributed to the up-regulation of tissue factor (TF) and release of TF-containing microvesicles into the pericellular milieu and the circulation. In addition, certain types of host cells (stromal cells, inflammatory cells, activated endothelium) may also express TF. At present, the relative contribution of host- vs tumor-related TF to tumor progression is not known. Our recent studies have indicated that the role of TF in tumor formation is complex and context-dependent. Genetic or pharmacological disruption of TF expression/activity in cancer cells leads to tumor growth inhibition in immunodeficient mice. This occurred even in the case of xenotransplants of human cancer cells, in which TF overexpression is driven by potent oncogenes (K-ras or EGFR). Interestingly, the expression of TF in vivo is not uniform and appears to be influenced by many factors, including the level of oncogenic transformation, tumor microenvironment, adhesion and the coexpression of markers of cancer stem cells (CSCs). Thus, minimally transformed, but tumorigenic embryonic stem (ES) cells were able to form malignant and angiogenic outgrowths in the absence of TF. However, these tumors were growth inhibited in hosts (mice) with dramatically reduced TF expression (low-TF mice). Depletion of host TF also resulted in changes affecting vascular patterning of some, but not all types of tumors. These observations suggest that TF may play different roles growth and angiogenesis of different tumors. Moreover, both tumor cell and host cell compartments may, in some circumstances, contribute to the functional TF pool. We postulate that activation of the coagulation system and TF signaling, may deliver growth-promoting stimuli (e.g. fibrin, thrombin, platelets) to dormant cancer stem cells (CSCs). Functionally, these influences may be tantamount to formation of a provisional (TF-dependent) cancer stem cell niche. As such these changes may contribute to the involvement of CSCs in tumor growth, angiogenesis and metastasis.
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PMID:The role of tumor-and host-related tissue factor pools in oncogene-driven tumor progression. 1802 19

More and more evidence indicates that N-glycan regulates signal transduction by modulating receptor functions. Previous studies suggested that glycosylation of EGFR is involved in dimerization and endocytosis. We further determined the role of N-glycosylation of ErbB family. A series of human ErbB3 mutants that lack each of the 10 N-glycosylation sites were prepared and transfected to Flp-In-CHO cells for stable expression. A crosslinking study showed that Asn 418 to Gln mutant (N418Q) of ErbB3 underwent autodimerization without its ligand, heregulin, and the heterodimer formation with ErbB2 was also increased. The N418Q mutant of ErbB3 co-expressed with ErbB2 promoted downstream signaling, anchorage-independent cell growth and the tumor growth in athymic mice. These findings suggest that the specific N-glycan in domain III of ErbB family plays an essential role in regulating receptor dimerization and transforming activity. We assume that the N-glycans affect the conformation of ErbB family, which is crucial for their activity. Together with findings from other laboratories, it is suggested that N-glycosylation controls ErbB signaling by various mechanisms.
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PMID:N-glycan of ErbB family plays a crucial role in dimer formation and tumor promotion. 1803 67

Carcinoids of the intestine are the most common gastrointestinal carcinoid tumors. Therapeutic options to treat patients with these tumors are limited. There are very few ileal carcinoid cell lines available for in vitro studies to analyze new drugs that could be effective in treating patients with metastatic tumors. A replication defective recombinant adenovirus with an SV40 early T-antigen insert was used to infect two intestinal carcinoid tumors to create carcinoid cell lines. The cell lines were studied by cell culture, reverse transcription polymerase chain reaction, Western blotting, and immunohistochemistry. Both cell lines expressed SV40 large T antigen and receptors for TGFbeta1, TGFbeta2, EGFR, and somatostatin receptors. Treatment with TGFbeta1 led to growth inhibition and increased apoptosis in the cultured cells. Octreotide inhibited cell growth of both cell lines while stimulating apoptosis. Treatment of the HC45 cells with gefitinib also inhibited cell growth in a concentration-dependent manner. TGFbeta treatment stimulated chromogranin A expression while expression of two other granins, chromogranin B and 7B2, did not change significantly. RNA profiling of cells treated with TGFbeta1 showed increased expression of vitamin D3 receptor. This finding was validated by real-time quantitative polymerase chain reaction, Western blotting, and immunohistochemistry. These results indicate that these carcinoid cell lines can be used to study the proliferative and apoptotic mechanisms involved in intestinal carcinoid tumor growth regulation.
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PMID:Characterization of the functional and growth properties of cell lines established from ileal and rectal carcinoid tumors. 1824 65

Ultrasonically induced effects of hematoporphyrin (HPD) on cell damage and membrane protein alteration of S180 isolated tumor cells in vitro were investigated, and the potential mechanisms of sonodynamic therapy (SDT) inhibiting tumor growth were discussed. Tumor cells suspended in air-saturated PBS (pH 7.2) were exposed to ultrasound at 1.8 MHz for up to 180s in the presence and absence of HPD. The viability of cells was determined by a trypan blue exclusion test. To estimate the damage effects of SDT on plasma membrane of tumor cells primarily, membrane integral proteins (EGFR, Ras, Fas, FasL) and cell proliferation associated enzymes (adenylate cyclase and guanylate cyclase) were checked with immunochemical methods. The results indicated that the intensity threshold for ultrasonically induced cell damage at 1.8 MHz was 3 W/cm2. At this condition, the expression of the integral proteins was obviously inhibited and the activity of the enzymes was decreased post ultrasound treatment in the presence of 20 microg/ml HPD. Loss of the membrane proteins and inactivity of AC and GC post SDT was time-dependent. This paper reveals SDT can cause the loss of tumor cell membrane integral proteins and inactivity of the enzymes associated with cell proliferation which might be attributed to a sonochemical activation mechanism. The mechanisms by that tumor growth is inhibited by SDT can be understood as that the growth signaling pathway is partially interdicted and the resistance of tumor cells to the specifically activated immune cells is weakened.
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PMID:Ultrasound exposure in the presence of hematoporphyrin induced loss of membrane integral proteins and inactivity of cell proliferation associated enzymes in sarcoma 180 cells in vitro. 1827 19

In this study, we report a plasma proteomic analysis of a mouse MCF7 xenograft, using a novel platform named M-LAC (multilectin affinity chromatography), in an attempt to identify putative serum biomarkers of tumor presence and response to therapy. The use of the M-LAC platform enabled us to focus on secreted proteins as well as remove interference from serum albumin and other nonglycosylated proteins. The study focused on the MCF7 human xenograft tumor model which enabled us to distinguish tumor proteins (human peptide sequences) from host-derived murine proteins, potentially discriminating tumor- versus supporting tissue-derived markers. A large set of murine proteins was identified in this study, including several signaling molecules such as EGFR, interleukin-6 receptor, protein-kinase C, and phosphatidylinositol kinase which changed in plasma levels relative to tumor-free animals. We also detected in the samples with maximal tumor growth a number of human tumor-derived proteins linked to cell signaling, immune response, and transcriptional regulation. This is the first report where tumor-derived peptides could be detected in the serum of a xenograft model. We conclude that the M-LAC approach may be used to detect plasma proteins of potential biological significance in tumor-bearing animals and warrants further study in terms of increasing the sensitivity of the method for the characterization of low level tumor markers and to explore the applicability of these markers for human studies.
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PMID:A proteomic analysis of the plasma glycoproteins of a MCF-7 mouse xenograft: a model system for the detection of tumor markers. 1833 3

Basic knowledge in oncogenesis has dramatically improved in the last decade providing more recently new drugs for cancer treatment. These new targeted compounds usually act by inhibiting tyrosine kinase activity of one or more than one proteins involved in tumor growth and cancer progression. This pharmacological effect is the result of monoclonal or small molecule action. Many of these new compounds have cutaneus secondary effects. Cancer patients are now facing new toxicity, essentially skin toxicity. The cutaneous side effects observed in the patients depend on the drug. For example, EGFR inhibitors induce acneiform rash whereas multitarget tyrosine kinase inhibitors induce different more complex effects which physiopatholgy is not yet completely understood. The secondary effects that are frequently observed are described is this article. A better clinical long term management of these effects is a clear medical need as of these effects could be surrogate markers of drug efficacy.
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PMID:[Cutaneous side effects associated with epidermal growth factor receptor and tyrosine kinase inhibitors]. 1834 13

Hyperactivation of ErbB signaling is implicated in metastatic breast cancer. However, the mechanisms that cause dysregulated ErbB signaling and promote breast carcinoma cell invasion remain poorly understood. One pathway leading to ErbB activation that remains unexplored in breast carcinoma cell invasion involves transactivation by G-protein-coupled receptors (GPCRs). Protease-activated receptor-1 (PAR1), a GPCR activated by extracellular proteases, is overexpressed in invasive breast cancer. PAR1 is also proposed to function in breast cancer invasion and metastasis, but how PAR1 contributes to these processes is not known. In this study, we report that proteolytic activation of PAR1 by thrombin induces persistent transactivation of EGFR and ErbB2/HER2 in invasive breast carcinoma, but not in normal mammary epithelial cells. PAR1-stimulated EGFR and ErbB2 transactivation leads to prolonged extracellular signal-regulated kinase-1 and -2 signaling and promotes breast carcinoma cell invasion. We also show that PAR1 signaling through Galpha(i/o) and metalloprotease activity is critical for ErbB transactivation and cellular invasion. Finally, we demonstrate that PAR1 expression in invasive breast carcinoma is essential for tumor growth in vivo assessed by mammary fat pad xenografts. These studies reveal a critical role for PAR1, a receptor activated by tumor-generated proteases, in hyperactivation of ErbB signaling that promotes breast carcinoma cell invasion.
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PMID:Persistent transactivation of EGFR and ErbB2/HER2 by protease-activated receptor-1 promotes breast carcinoma cell invasion. 1837 13

Chromosomal translocation is the best-characterized genetic mechanism for oncogene activation. However, there are documented examples of activation by alternate mechanisms, for example gene dosage increase, though its prevalence is unclear. Here, we answered the fundamental question of the contribution of DNA amplification as a molecular mechanism driving oncogenesis. Comparing 104 cancer lines representing diverse tissue origins identified genes residing in amplification 'hotspots' and discovered an unexpected frequency of genes activated by this mechanism. The 3431 amplicons identified represent approximately 10 per hematological and approximately 36 per epithelial cancer genome. Many recurrently amplified oncogenes were previously known to be activated only by disease-specific translocations. The 135 hotspots identified contain 538 unique genes and are enriched for proliferation, apoptosis and linage-dependency genes, reflecting functions advantageous to tumor growth. Integrating gene dosage with expression data validated the downstream impact of the novel amplification events in both cell lines and clinical samples. For example, multiple downstream components of the EGFR-family-signaling pathway, including CDK5, AKT1 and SHC1, are overexpressed as a direct result of gene amplification in lung cancer. Our findings suggest that amplification is far more common a mechanism of oncogene activation than previously believed and that specific regions of the genome are hotspots of amplification.
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PMID:DNA amplification is a ubiquitous mechanism of oncogene activation in lung and other cancers. 1839 78


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