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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mouse lung tumorigenesis is a convenient model for examining all stages of lung adenocarcinoma (AC) progression. Because enhanced cyclooxygenase 2 (COX-2) expression has been observed in advanced human AC, we investigated the intracellular concentrations of the two cyclooxygenases, cyclooxygenase 1 (COX-1) and COX-2, at different times after carcinogen administration to A/J mice. The concentrations of both proteins were much higher in urethane-induced adenomas and carcinomas compared with control A/J mouse lung tissue (P < 0.03 and P < 0.01 in adenomas and AC, respectively, for COX-1; P < 0.003 and P < 0.004 in adenomas and AC, respectively, for COX-2). Small benign tumors that arose spontaneously in 13-month-old mice also stained for COX-1 and COX-2, showing that this elevated enzyme content does not depend on chemical induction. COX-1 and COX-2 immunostaining was observed in normal bronchiolar and alveolar epithelia, alveolar macrophages and bronchiolar smooth muscle. This is the first report of the cellular distribution of COX-1 and COX-2 in murine lungs and the first in any species to demonstrate their co-localization. COX content in isolated bronchiolar Clara cells, a putative cell of tumor origin, was equal to that found in tumors, suggesting that the high enzyme content in neoplasms is due to their proportionally high concentration of these tumor precursor cells. Different patterns of COX-1 and COX-2 expression were observed in tumors of different growth patterns; only occasional small foci stained in solid adenomas, while most cells in papillary adenomas were immunoreactive. This staining pattern was also seen in adenocarcinomas, but some of the papillary portions also included focally stained and unstained regions. The continued expression during neoplastic progression of these specialized enzymes present in normal cells of tumor origin suggests their function in maintenance of the neoplastic state.
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PMID:High cyclooxygenase 1 (COX-1) and cyclooxygenase 2 (COX-2) contents in mouse lung tumors. 1075 83

Investigations on the influence of the parasympathetic nervous system via muscarinic signaling in tumor progression have produced contradictory evidence. We investigated the expression of muscarinic acetylcholine receptors (mAchR) and their intracellular transduction pathways, in two murine mammary adenocarcinoma cell lines, LM3 and LM2 in comparison with the normal murine mammary epithelial cell line: NMuMG. Saturation binding assays with the tritiated muscarinic antagonist quinuclidinyl benzilate ([3H]-QNB) indicate that LM3 cells express higher amounts of mAchR than LM2 cells. Muscarinic receptor activation with carbachol (CARB) enhanced basal production of citrulline to a greater extent in LM3 cells than in LM2 cells. The nitric oxide synthase (NOS) inhibitor, NGmono-methyl-L-arginine (L-NMMA), blunted this effect only in LM3 cells while in LM2 cells the action of CARB was blocked by Nomega hydroxy-L-arginine (L-OH-Arg), which is known to inhibit the arginase pathway. Atropine blocks the action of CARB in both cell lines. Additionally, mAchR activation stimulates prostaglandin E2 (PGE2) synthesis only in LM2 cells. NMuMG cells show detectable basal amounts of nitric oxide and PGE2, but they did not respond to CARB. Binding experiments confirm the absence of mAchR in these cells. The findings indicate that mAchR expression in tumor cells, and its control on arginine metabolism, via NOS/arginase, and on PGE2 synthesis by COX activation, could be a switch on mechanism that might lead mammary cells from normal to malignant phenotype. Moreover, mAchR coupling to distinct effectors might be associated with differences in aggressiveness of tumor cells.
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PMID:Nitric oxide synthase, arginase and cyclooxygenase are involved in muscarinic receptor activation in different murine mammary adenocarcinoma cell lines. 1201 84

Cells that have acquired a proliferative advantage form islets of hyperplasia during the initial stages of tumor development. Like normal cells, they require oxygen and nutrients to survive and proliferate. The centre of the islets is characterized by low oxygen pressure and low pH, conditions that stimulate the sprouting of new capillaries from nearby vascular beds. It is now well established that neovascularisation (angiogenesis) of the hyperplasias is essential for further development of the tumor. The family of ras oncogenes promotes the initiation of tumor growth by stimulating tumor cell proliferation, but also ensures tumor progression by stimulating tumor-associated angiogenesis. Oncogenic Ras proteins stimulate a number of effector pathways that culminate in the transcriptional activation of genes that control angiogenesis. Moreover, Ras signaling leads to stabilization of the produced mRNAs and, possibly, to enhanced initiation of their translation. In this review we describe the mechanisms that underlie Ras regulation of vascular endothelial growth factor (VEGF), cyclooxygenases (COX-1/-2), thrombospondins (TSP-1/-2), urokinase plasminogen activator (uPA) and matrix metalloproteases-2 and -9 (MMP-2/-9). As a result of these Ras-regulated changes in gene expression, the tumor cells cause stimulation of endothelial cells in nearby vascular beds (directly via VEGF, and indirectly via COX-produced prostaglandins) and promote remodeling of the extracellular matrix (by lowering TSP and increasing uPA/MMPs). The latter effect makes growth factors available for endothelial cell activation and migration. In addition, tumor cell-activated stromal cells also contribute to the stimulation of angiogenesis by further enhancing the production and secretion of pro-angiogenic factors into the tumor stroma.
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PMID:Stimulation of angiogenesis by Ras proteins. 1498 65

Mice bearing LP07 lung adenocarcinoma show some characteristics that are similar to those present in patients with NSCLC. LP07 tumor-bearing mice develop the paraneoplastic syndromes of cachexia, leukocytosis and hypercalcemia. These symptoms may be partly due to a systemic inflammatory response. Our aim was to determine if treatment with NSAIDs would lower tumor and metastasis growth and their accompanying syndromes. The nonselective COX inhibitor indomethacin and the selective COX-2 inhibitor celecoxib reduced tumor growth and metastasis outcome in s.c. LP07 tumor-bearing mice. Both drugs also inhibited the development of leukocytosis and the weight loss associated with LP07 progression. Serum levels of the inflammatory cytokines IL-1beta and IL-6, mediators of cachexia, were modulated by NSAIDs. Inhibition of in vitro migration and invasion and reduction in angiogenesis were attained when cells were treated with either indomethacin or celecoxib. MMP-9 activity was also reduced in conditioned media from LP07 cells treated with celecoxib. These data suggest that several processes implicated in tumor progression can be modulated with NSAID treatment. Improvement in performance status through modulation of cachexia may offer a possibility for combining anti-inflammatory treatments with more aggressive therapies.
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PMID:Reduction of tumor progression and paraneoplastic syndrome development in murine lung adenocarcinoma by nonsteroidal antiinflammatory drugs. 1517 Jun 63

Preclinical and clinical studies in our laboratory have suggested that prostaglandin (PG) E2 is involved in anorexia and cachexia development, although the role of COX pathways on the pathogenesis of cancer cachexia remains to be clarified. Expressions of PGE (EP1, EP2, EP3alpha,beta,gamma and EP4) and PGI (IP) receptors in the central nervous system (brain cortex, hypothalamus and brain stem), in peripheral (liver, white adipose tissue and skeletal muscle) and tumor tissue from MCG-101-bearing mice with and without indomethacin treatment were investigated by RT-PCR and immunohistochemistry. Expression of EP1 in the liver and EP4 receptor in white adipose tissue were upregulated and responded to indomethacin treatment, while downregulated expression of EP3 in skeletal muscle from tumor-bearing mice was unresponsive to indomethacin treatment despite improved carcass weight. Expression of EP and IP receptors in brain and tumor tissue from tumor-bearing mice were neither related nor responsive to systemic PGE2 levels including increased IL-1beta, IL-6 and TNF-alpha host activities. The expression IP receptor in CNS, peripheral tissue and tumor tissue was unchanged by cachexia development. Our results suggest that transcription of EP receptors in liver, fat and skeletal muscle tissue may be a control level for host metabolic alterations during tumor progression, while overall EP and IP receptor expression in CNS did not indicate an important control level for appetite regulation in MCG 101-bearing mice despite prostanoid related anorexia.
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PMID:Prostaglandin E and prostacyclin receptor expression in tumor and host tissues from MCG 101-bearing mice: a model with prostanoid-related cachexia. 1570 39

Antitumor antigen antibodies are promising tools for cancer therapy, under the judgment of achieving targeted cell destruction. However, antibodies can not only kill tumor cells, but also trigger inflammation in the core of the tumor. Inflammation and cancer have been firmly associated for the last 10 years. Even if this connection was known by intuition since the late 1800s, solid demonstrations of molecular mechanisms behind it have been reported only recently. Nevertheless, basic antiinflammatory factors such as aspirin, and other COX inhibitors, all act somehow as good preventive drugs, but not as therapeutic agents. We have studied the inflammatory pathways associated with tumor cell invasion and metastasis, by analyzing triggers and brittle links in the chain of inflammatory events that promote cancer recurrence and metastasis. In our experiments we observed that signals through TNFalpha and lymphotoxin-alpha (LTalpha) constitute weak links in the tumor-promoting inflammatory scenario. Using gene-targeted mutations, we demonstrated that p55TNF-R blockade could reduce metastasis outcome in mice up to 50%. Likewise, LTalpha blockade reduces mortality in tumor-challenged and untreated mice by 10%, and 54% in mice treated with simple surgical tumor ablation. Conversely, p75TNF-R blockade increases metastasis outcome up to 200%. All taken together these results demonstrate that protumor inflammatory signals transmitted through TNF receptors are not complementary, but opposed: p55TNF-R mediates promalignancy inflammation and p75TNF-R quenches that pathway. Among the triggers of promalignancy inflammatory mechanisms, we demonstrated, that IgGs developed against soluble and shed tumor associated antigens (sTTA) are a major trigger of protumor inflammation. We also demonstrated that by knocking out the B cell receptor (BCR), mice do not develop anti-sTTA IgGs, 90% of mice reject the tumor challenge entirely, and from the 10% that develop tumor, only 20% recur after tumor ablation. Cloning and investigating the IgG-VH sequences, transcribed in lymphocytes and plasma cells, from bone marrow, spleen, and tumor stroma, we also observed that tumor infiltrating plasma cells produce a distinctive family of IgGs. The induction of random expression of these VH peptide sequences in mice, by in vivo transfection into muscle cells, with VH expressing vectors, reduced tumor progression in a significant manner. All these studies indicate that: (1) The use of TNF blockers (such as infliximab and adalimumab) and p55TNF-R blockers (such as lenercept) may have therapeutic benefit in oncology. (2) p75TNF-R blockers (such as etanercept) could be detrimental in oncology. (3) Active or passive immunization against sTAA, such as sTn and others, could be absolutely detrimental in cancer immune therapy. (4) Active or passive humoral immunization against membrane integrated tumor cell antigens should be carefully tested. (5) Investigation of IgG expressed in tumor infiltrating lymphoid cells, could convey important knowledge about the immune responsibility in tumor progression.
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PMID:Antitumor-associated antigens IgGs: dual positive and negative potential effects for cancer therapy. 1716 76

Inflammation is implicated in several medical conditions that are sexually dimorphic, including depression, cardiovascular diseases, autoimmunity, and presumably cancer progression. Here we studied the effects of the proinflammatory agent, LPS, on MADB106 lung tumor retention (LTR), and sought to elucidate underlying mechanisms and sexual dimorphism. F344 male and female rats were administered with LPS (0.001-1mg/kg i.v.) simultaneously with tumor cell inoculation, and treated with a beta-blocker (nadolol, 0.2-0.3mg/kg s.c.), a COX inhibitor (indomethacin, 4mg/kg s.c.) or both drugs. To study the role of NK cells, numbers and cytotoxicity of marginating-pulmonary NK cells were studied, and selective in vivo NK-depletion was employed. Serum levels of corticosterone, IL-6, and TNF-alpha were also assessed. The findings indicated that LPS increased LTR in both sexes, but 10-fold higher doses were needed in females to reach the increase evident in males. Additionally, nadolol and indomethacin reduced the effects of LPS, more so in males. In vivo NK-depletion and ex vivo NK activity studies suggested that LPS affected LTR through both NK-independent and NK-dependent mechanisms, the latter mediated through prostaglandin release in males. Corticosterone, IL-6, and TNF-alpha responses to LPS were sexually dimorphic, but were not associated with LPS or drugs' impacts on LTR. Overall, our findings demonstrate sexual dimorphism in LPS-induced elevated susceptibility to MADB106 experimental metastasis, and in potential humoral underlying mechanisms. Further studies are needed to elucidate additional immunological and non-immunological mediators of these dimorphisms, as well as to assess their involvement in other sexually dimorphic pathologies that are associated with inflammation.
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PMID:Metastatic-promoting effects of LPS: sexual dimorphism and mediation by catecholamines and prostaglandins. 1895 72

Although COX-dependent production of prostaglandins (PGs) is known to be crucial for tumor angiogenesis and growth, the role of PGD(2) remains virtually unknown. Here we show that PGD(2) receptor (DP) deficiency enhances tumor progression accompanied by abnormal vascular expansion. In tumors, angiogenic endothelial cells highly express DP receptor, and its deficiency accelerates vascular leakage and angiogenesis. Administration of a synthetic DP agonist, BW245C, markedly suppresses tumor growth as well as tumor hyperpermeability in WT mice, but not in DP-deficient mice. In a corneal angiogenesis assay and a modified Miles assay, host DP deficiency potentiates angiogenesis and vascular hyperpermeability under COX-2-active situation, whereas exogenous administration of BW245C strongly inhibits both angiogenic properties in WT mice. In an in vitro assay, BW245C does not affect endothelial migration and tube formation, processes that are necessary for angiogenesis; however, it strongly improves endothelial barrier function via an increase in intracellular cAMP production. Our results identify PGD(2)/DP receptor as a new regulator of tumor vascular permeability, indicating DP agonism may be exploited as a potential therapy for the treatment of cancer.
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PMID:Role of prostaglandin D2 receptor DP as a suppressor of tumor hyperpermeability and angiogenesis in vivo. 1906 Feb 14

Arachidonic acid (AA) and its metabolites have recently generated a heightened interest due to growing evidence of their significant role in cancer biology. Thus, inhibitors of the AA cascade, first and foremost COX inhibitors, which have originally been of interest in the treatment of inflammatory conditions and certain types of cardiovascular disease, are now attracting attention as an arsenal against cancer. An increasing number of investigations support their role in cancer chemoprevention, although the precise molecular mechanisms that link levels of AA, and its metabolites, with cancer progression have still to be elucidated. This article provides an overview of the AA cascade and focuses on the roles of its inhibitors and their implication in cancer treatment. In particular, emphasis is placed on the inhibition of cell proliferation and neo-angiogenesis through inhibition of the enzymes COX-2, 5-LOX and CYP450. Downstream effects of inhibition of AA metabolites are analysed and the molecular mechanisms of action of a selected number of inhibitors of catalytic pathways reviewed. Lastly, the benefits of dietary omega-3 fatty acids and their mechanisms of action leading to reduced cancer risk and impeded cancer cell growth are mentioned. Finally, a proposal is put forward, suggesting a novel and integrated approach in viewing the molecular mechanisms and complex interactions responsible for the involvement of AA metabolites in carcinogenesis and the protective effects of omega-3 fatty acids in inflammation and tumour prevention.
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PMID:Inhibition of arachidonic acid metabolism and its implication on cell proliferation and tumour-angiogenesis. 1923 26

Mitochondria encoded Cytochrome B (CYTB) gene mutations were reported in tumors of different anatomic origin but the functional significance of these mutations are not well studied. Earlier, we found a 7-amino acid deletion mutation in the CYTB gene in a primary bladder cancer patient. In the present study, we overexpressed this 7-amino acid deletion mutation of CYTB gene in SV-40 transformed human uroepithelial HUC-1 cells. The nuclear transcribed mitochondrial CYTB (mtCYTB) was targeted into the mitochondria and generated increased copies of mitochondria and mitochondrial COX-I protein in the transfected HUC-1 cells. The proapoptotic protein Bax largely remained confined to the cytoplasm of the mtCYTB transfected HUC-1 cells without release of Cytochrome C. The downstream apoptotic proteins PARP also remained uncleaved along with increased Lamin B1 in the mtCYTB transfected cells. Our results demonstrate that forced overexpression of mtCYTB in transformed human uroepithelial HUC-1 cells triggered mitochondrial proliferation and induction of an antiapoptotic signaling cascade favoring sustained cellular growth. Coding mitochondrial DNA mutations appear to have significant functional contribution in tumor progression.
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PMID:Forced cytochrome B gene mutation expression induces mitochondrial proliferation and prevents apoptosis in human uroepithelial SV-HUC-1 cells. 1956 44


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