Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of ultrasonic shock waves (SW), recombinant interleukin-12 (rIL-12) protein and DNA plasmids coding for interleukin-12 (pIL-12) were investigated on progression of mouse B16 melanoma and RENCA renal carcinoma tumors. Tumor cells were implanted and grown on the hind legs of syngeneic mice. Before treatment, mice were anesthetized and the tumor region was shaved and depilated. Air bubbles at 10% of tumor volume and an equal volume of phosphate buffered saline (PBS), either with rIL-12 or pIL-12 were injected into the tumor. SW treatment consisted of 500 SWs (7.4-MPa peak negative pressure) from a spark-gap lithotripter. Tumor volume was measured every other day and tumor growth was statistically modeled. SW treatment augmented by air injection induced a tumor growth delay for a few days immediately after exposure. Intratumor rIL-12 injection enhanced the SW effect on tumor progression, to the extent that a statistically significant increase in survival was realized in both tumor models. pIL-12 injection alone, which is known to produce some gene transfer, provided no detectable tumor-growth reduction. The combination of SW and pIL-12 injection provided a statistically significant reduction in tumor growth relative to SW alone for both tumor models. IL-12 expression due to SW-induced gene transfer was confirmed in ELISA assays. This research demonstrates a potentiality for further development of ultrasound (US)-enhanced cancer gene therapy.
 ...
PMID:Combined shock-wave and immunogene therapy of mouse melanoma and renal carcinoma tumors. 1220 40

The sphingolipid metabolites ceramide (Cer), sphingosine (Sph), and sphingosine-1-phosphate (S1P) play an important role in the regulation of cell proliferation, survival, and cell death. Cer and Sph usually inhibit proliferation and promote apoptosis, while the further metabolite S1P stimulates growth and suppresses apoptosis. Because these metabolites are interconvertible, it has been proposed that it is not the absolute amounts of these metabolites but rather their relative levels that determines cell fate. The relevance of this "sphingolipid rheostat" and its role in regulating cell fate has been borne out by work in many labs using many different cell types and experimental manipulations. A central finding of these studies is that Sph kinase (SphK), the enzyme that phosphorylates Sph to form S1P, is a critical regulator of the sphingolipid rheostat, as it not only produces the pro-growth, anti-apoptotic messenger S1P, but also decreases levels of pro-apoptotic Cer and Sph. Given the role of the sphingolipid rheostat in regulating growth and apoptosis, it is not surprising that sphingolipid metabolism is often found to be disregulated in cancer, a disease characterized by enhanced cell growth, diminished cell death, or both. Anticancer therapeutics targeting SphK are potentially clinically relevant. Indeed, inhibition of SphK has been shown to suppress gastric tumor growth [Cancer Res. 51 (1991) 1613] and conversely, overexpression of SphK increases tumorigenicity [Curr. Biol. 10 (2000) 1527]. Moreover, S1P has also been shown to regulate angiogenesis, or new blood vessel formation [Cell 99 (1999) 301], which is critical for tumor progression. Furthermore, there is intriguing new evidence that S1P can act in an autocrine and/or paracrine fashion [Science 291 (2001) 1800] to regulate blood vessel formation [J. Clin. Invest. 106 (2000) 951]. Thus, SphK may not only protect tumors from apoptosis, it may also increase their vascularization, further enhancing growth. The cytoprotective effects of SphK/S1P may also be important for clinical benefit, as S1P has been shown to protect oocytes from radiation-induced cell death in vivo [Nat. Med. 6 (2000) 1109]. Here we review the growing literature on the regulation of SphK and the role of SphK and its product, S1P, in apoptosis.
 ...
PMID:Sphingosine kinase, sphingosine-1-phosphate, and apoptosis. 1253 54

Cancer development results from the interaction between genetic factors, the environment, and dietary factors have been identified as modulators of carcinogenesis process. The formation of DNA adducts is recognized as the initial step in chemical carcinogenesis. Accordingly, blocking DNA adducts formation would be the first line of defense against cancer caused by carcinogens. Glutathione-S-transferases inactivate chemical carcinogens into less toxic or inactive metabolite through reduction of DNA adducts formation. There are many different types of glutathione S-transferase isozymes. For example, GST delta serves as a marker for hepatotoxicity in rodent system, and also plays an important role in carcinogen detoxification. Therefore, inhibition of GST activity might potentiate the deleterious effects of many environmental toxicants and carcinogens. In addition, approximately half of the population lacks GST Mu expression. Epidemiological evidence showed that persons possessing this genotype are predisposed to a number of cancers including breast, prostate, liver and colon cancers. In addition, individual risk of cancer depends on the frequency of mutational events in target oncogenes and tumor suppressor genes which could lead to loss of chromosomal materials and tumor progression. The most frequent genetic alteration in a variety of human malignant tumors is the mutation of the coding sequence of the p53 tumor suppressor gene. O(6)-alkylguanine in DNA leads to very high rates of G:C deltaA:T transitions in p53 gene. These alterations will modulate the expression of p53 gene and consequently change DNA repair, cell division, and cell death by apoptosis. Also, changes in the expression of BcI-2 gene results in extended viability of cells by over-riding programmed cell death (apoptosis) induced under various conditions. The prolonged life-span increases the risk of acquiring genetic changes resulting in malignant transformation. In addition, a huge variety of food ingredients have been shown to affect cell proliferation rates. They, therefore, may either reduce or increase the risk of cancer development and progression. For example, it has been found that a high intake of dietary fat accelerates the development of breast cancer in animal models. Certain diets have been suggested to act as tumor promoters also in other types of cancer such as colon cancer, where high intake of fat and phosphate have been linked to colonic hyper-proliferation and colon cancer development. Different factors such as oncogenes, aromatic amines, alkylating agents, and diet have a significant role in cancer induction. Determination of glutathione S-transferase isozymes in plasma or serum could be used as a biomarker for cancer in different organs and could give an early detection.
 ...
PMID:Cancer and phase II drug-metabolizing enzymes. 1257 Jul 45

Cystatins constitute a superfamily of cysteine protease inhibitors. A member of the type II secreted cystatin family, cystatin F, has been identified through different gene array experiments to be specifically expressed in hematopoietic cells as well as to be associated with several malignant tumors, suggesting a role in immunity or cancer progression. Cystatin F specificity as a protease inhibitor is still elusive, and understanding the cellular traffic of this molecule is therefore a major step in its characterization. Although the mannosylation-6 phosphate of cystatin F has been suggested, no conclusive evidences of its endosomal targeting have been reported. Here we show using U937 cells that cystatin F is secreted as a disulfide bridge-linked dimer and is not associated with endosomes intracellularly. Interestingly, although cystatin F targeting to endosomes or lysosomes is not observed in U937, modification of its C-terminal end by the addition of several amino acids promotes its accumulation in the lysosomes of transfected HeLa cells. This observation suggests that cystatin F can be targeted to the endocytic pathway under specific conditions and its C-terminal domain might contribute to this event.
 ...
PMID:Cystatin F is secreted, but artificial modification of its C-terminus can induce its endocytic targeting. 1521 60

Lipid phosphates initiate key signaling cascades in cell activation. Lysophosphatidate (LPA) and sphingosine 1-phosphate (S1P) are produced by activated platelets. LPA is also formed from circulating lysophosphatidylcholine by autotaxin, a protein involved tumor progression and metastasis. Extracellular LPA and S1P stimulate families of G-protein coupled receptors that elicit diverse responses. LPA is involved in wound repair and tumor growth. Exogenous S1P is a potent stimulator of angiogenesis, a process vital in development, tissue repair and the growth of aggressive tumors. Inside the cell, phosphatidate (PA), ceramide 1-phosphate (C1P), LPA, and S1P act as signaling molecules with distinct functions including the stimulation of cell division, cytoskeletal rearrangement, Ca(2+) transients, and membrane movement. These observations imply that phosphatases that degrade lipid phosphates on the cell surface, or inside the cell, regulate cell signaling under physiological and pathological conditions. This occurs through attenuation of signaling by the lipid phosphates and by the production of bioactive products (diacylglycerol, ceramide, and sphingosine). Three lipid phosphate phosphatases (LPPs) and a splice variant dephosphorylate LPA, PA, CIP, and S1P. Two S1P phosphatases (SPPs) act specifically on S1P. In addition, there is family of four LPP-related proteins (LPRs, or plasticity-related genes, PRGs). PRG-1 expression in neurons has been reported to increase extracellular LPA breakdown and attenuate LPA-induced axonal retraction. It is unclear whether the LRPs dephosphorylate LPA directly, stimulate LPP activity, or bind LPA and S1P. Also, the importance of extra- versus intra-cellular actions of the LPPs and SPPs, and the individual roles of different isoforms is not firmly established. Understanding the functions and regulation of the LPPs, SPPs and related proteins will hopefully contribute to interventions to correct dysfunctions in conditions such as wound repair, inflammation, angiogenesis, tumor growth, and metastasis.
 ...
PMID:Lipid phosphate phosphatases and related proteins: signaling functions in development, cell division, and cancer. 1525 14

Ranking as the fourth commonest cancer, esophageal squamous cell carcinoma (ESCC) represents one of the leading causes of cancer death in China. One of the main reasons for the low survival rate is that neoplasms in esophagus are not detected until they have invaded into surrounding tissues or spread throughout the body at advanced stages. A better understanding of the malignant mechanism and early diagnosis are important for fighting ESCC. In this study, we used proteomics to analyze ESCC tissues, aiming at defining the proteomic features implicated in the multistage progression of esophageal carcinogenesis. Proteins that exhibited significantly different expressions were identified by peptide mass fingerprinting and validated by Western blotting and reverse transcriptase-polymerase chain reaction. The protein changes were then correlated to the different grades of disease differentiation. Compared to those in adjacent normal epitheliums, the expression of 15 proteins including enolase, elongation factor Tu, isocitrate dehydrogenase, tubulin alpha-1 chain, tubulin beta-5 chain, actin (cytoplasmic 1), glyceraldehyde-3 phosphate dehydrogenase, tropomyosin isoform 4 (TPM4), prohibitin, peroxiredoxin 1 (PRX1), manganese-containing superoxide dismutase (MnSOD), neuronal protein, and transgelin was up-regulated; and the expression of five proteins including TPM1, squamous cell carcinoma antigen 1 (SCCA1), stratifin, peroxiredoxin 2 isoform a, and alpha B crystalline was down-regulated in cancer tissues with a statistical significance (p < 0.05). In addition, the differential expression of SCCA1, PRX1, MnSOD, TPM4, and prohibitin can be observed in precancerous lesions of ESCC. The expression of stratifin, prohibitin, and SCCA1 dropped with increasing dedifferentiation of ESCC. These data may suggest that these proteins contribute to the multistage process of carcinogenesis, tumor progression, and invasiveness of ESCC.
 ...
PMID:Comparative proteomic analysis of esophageal squamous cell carcinoma. 1598 32

Sphingosine-1-phosphate (S1P) is a potent lysolipid involved in a variety of biological responses important for cancer progression. Therefore, we investigated the role of sphingosine kinase type 1 (SphK1), the enzyme that makes S1P, in the motility, growth, and chemoresistance of MCF-7 breast cancer cells. Epidermal growth factor (EGF), an important growth factor for breast cancer progression, activated and translocated SphK1 to plasma membrane. SphK1 was required for EGF-directed motility. Downregulation of SphK1 in MCF-7 cells reduced EGF- and serum-stimulated growth and enhanced sensitivity to doxorubicin, a potent chemotherapeutic agent. These results suggest that SphK1 may be critical for growth, metastasis and chemoresistance of human breast cancers.
 ...
PMID:Sphingosine kinase 1 is required for migration, proliferation and survival of MCF-7 human breast cancer cells. 1619 37

Lipid phosphates are potent mediators of cell signaling and control processes including development, cell migration and division, blood vessel formation, wound repair, and tumor progression. Lipid phosphate phosphatases (LPPs) regulate the dephosphorylation of lipid phosphates, thus modulating their signals and producing new bioactive compounds both at the cell surface and in intracellular compartments. Knock-down of endogenous LPP2 in fibroblasts delayed cyclin A accumulation and entry into S-phase of the cell cycle. Conversely, overexpression of LPP2, but not a catalytically inactive mutant, caused premature S-phase entry, accompanied by premature cyclin A accumulation. At high passage, many LPP2 overexpressing cells arrested in G(2)/M and the rate of proliferation declined severely. This was accompanied by changes in proteins and lipids characteristic of senescence. Additionally, arrested LPP2 cells contained decreased lysophosphatidate concentrations and increased ceramide. These effects of LPP2 activity were not reproduced by overexpression or knock-down of LPP1 or LPP3. This work identifies a novel and specific role for LPP2 activity and bioactive lipids in regulating cell cycle progression.
 ...
PMID:Lipid phosphate phosphatase-2 activity regulates S-phase entry of the cell cycle in Rat2 fibroblasts. 1646 4

Sphingosine-1-phosphate (S1P) is a pleiotropic lipid mediator that has been shown to regulate cell growth, cell survival, cell invasion, vascular maturation, and angiogenesis, processes that are important for cancer progression. In this issue of Cancer Cell, Visentin et al. demonstrate that a monoclonal antibody that binds S1P with extremely high affinity and specificity significantly slows tumor progression and associated angiogenesis in several animal models of human cancer. Their results suggest that S1P not only affects tumor cells themselves, but also is permissive or required for the actions of angiogenic factors, and thus may be a bona fide cancer target.
 ...
PMID:Targeting sphingosine-1-phosphate: a novel avenue for cancer therapeutics. 1653 Jul 6

A series of novel, multisubstrate, bicyclic pyrimidine nucleoside inhibitors of human thymidine phosphorylase (TP) is described. Thymidine phosphorylase has been implicated in angiogenesis and plays a significant role in tumor progression and metastasis. The presence and orientation of the phosphonate moiety (acting as a phosphate mimic) in these derivatives were critical for inhibitory activity. The most active compounds possessed a phosphonate group in an endo orientation. This was consistent with molecular modeling results that showed the endo isomer protein-ligand complex to be lower in energy than the exo complex.
 ...
PMID:Synthesis and evaluation of multisubstrate bicyclic pyrimidine nucleoside inhibitors of human thymidine phosphorylase. 1718 Nov 63


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>