UMLS:C0178874 - FACTA Search

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

High throughput screening (HTS) of large compound libraries for inhibitors of growth factors raises the requirement for simple yet reliable assays. Fibroblast growth factors (FGFs) play a pivotal role in the multistep pathway of malignant transformation, tumor progression, metastasis, and angiogenesis. FGF-2 (basic FGF) requires a cooperative interaction with heparin or heparan sulfate proteoglycans in order to form functional growth factor-receptor complexes that are essential for receptor binding and activation. We have developed a simple screening system, devised to identify molecules that modulate heparin-FGF-receptor interactions. The system is composed of a heparin matrix, FGF-2, and a FGF receptor-1 protein engineered by genetically fusing the extracellular domain of FGF receptor-1 to alkaline phosphatase (FRAP). The screen is conducted using 96-well plates to which heparin has been covalently attached. FGF-2 is then bound to the plates through heparin-FGF interactions, followed by the addition of FRAP and compounds to be screened for modulation of heparin-FGF, receptor-heparin, and receptor-FGF interactions. The endpoint of the assay is measured enzymatically using the alkaline phosphatase (AP)-catalyzed formation of a chromogenic product, which is directly proportional to the amount of FRAP present on the plates as a heparin-FGF-FRAP ternary complex. Reduced AP values relative to control, as measured by spectrophotometry, indicate inhibition of the formation of an active FGF-receptor-heparin complex. The simple and versatile nature of the assay makes it an attractive HTS system. The screen has identified several potent inhibitors of FGF-2 receptor binding and activation. Furthermore, secondary screening of the HTS-recognized compounds identified several compounds that have the capacity to block growth factor-mediated tumor progression and angiogenesis in vivo.
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PMID:Development of a high throughput screening assay for inhibitors of fibroblast growth factor-receptor-heparin interactions. 1168 13

NASA has established and supports a specialized center for research and training (NSCORT) to specifically address the potential deleterious effects of HZE particles on human health. The NSCORT in radiation health is a joint effort between Lawrence Berkeley National Laboratory (LBNL) and Colorado State University (CSU). The overall scope of research encompasses a broad range of subjects from microdosimetric studies to cellular and tissue responses to initial damage produced by highly energetic protons and heavy charged particles of the type found in galactic cosmic rays (GCR) spectrum. The objectives of the microdosimetry studies are to determine the response of Tissue Equivalent Proportional Counter (TEPC) to cosmic rays using ground based accelerators. This includes evaluation of energy loss due to the escape of high-energy delta rays and increased energy deposition due to the enhanced delta ray production in the wall of the detector. In this report major results are presented for 56Fe at 1000, 740, 600 and 400 MeV/nucleon. An assessment of DNA repair and early development of related chromosomal changes is extremely important to our overall understanding of enhanced biological effectiveness of high LET particle radiation. Results are presented with respect to the fidelity of the rejoining of double strand breaks and the implications of misrejoining. The relationship between molecular and cytogenetic measurements is presented by studying damage processing in highly heterochromatic supernumerary (correction of sypernumerary) X chromosomes and the active X-chromosome. One of the important consequences of cell's inability to handle DNA damage can be evaluated through mutation studies. Part of our goal is the assessment of potential radioprotectors to reduce the mutation yield following HZE exposures, and some promising results are presented on one compound. A second goal is the integration of DNA repair and mutation studies. Results are presented on a direct comparison of initial double strand breaks induction, the time course and fidelity of double strand break rejoining, cell killing and mutation induction in the same human model system. In order to understand the carcinogenic potential of protons and HZE particles, the role of damaged microenvironment in this process must be understood. In this project it has been postulated that radiation affects the microenvironment, which then modifies cell interactions in a manner conducive to neoplastic progression. Both TGF-beta and FGF-2 are important components of microenvironment. A recent result on the assessment of the role of FGF-2 and its cross-talk with TGF-beta as a function of radiation quality is presented. Theoretical modeling has so far played a central role in analyzing and integrating experimental data on repair and mutation studies and predicting new phenomena. The integrated NSCORT program also provides a broad training experience for students and postdoctoral fellows in space radiation health.
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PMID:Physical and biological studies with protons and HZE particles in a NASA supported research center in radiation health. 1177 May 39

FGF-1 and FGF-2 are pleiotropic growth factors for many cell types, operating through the activation of specific transmembrane FGF receptors (FGFRs). The role of these factors in tumor progression was investigated, with specific discrimination between their autocrine and non autocrine cellular activity. The rat bladder carcinoma NBT-II cells were engineered to produce FGF-1 or 18 kDa FGF-2 in the presence or absence of their specific receptor. Non-autocrine cells that produced FGF-1 or FGF-2 but lacked FGFRs were epithelial and reminiscent of the parental NBT-II cells. Whilst autocrine cells, which both constitutively produced and secreted the growth factor and expressed FGFRs, had a highly invasive mesenchymal phenotype. Correspondingly, the autocrine cells were highly tumorigenic in vivo compared to the parental and non-autocrine cells, which correlated with the increased production of uPAR and active uPA and increased in vitro invasive potential. Although all cells produced VEGF, only tumors derived from cells that produced FGF-1 or FGF-2 were highly vascularized, suggesting that these two growth factors could be involved in the angiogenic process by activating host endothelial cells. As a result of activation of the FGFR in autocrine cells, changes in cell morphology and an increase in the invasive and tumorigenic properties were observed, however no in vitro or in vivo differential functions between FGF-1 and FGF-2 could be identified in this system. In conclusion, our data demonstrates that rapid tumor development is not dependent upon increased tumor vascularization, suggesting that 'basal' angiogenesis, probably mediated by VEGF, is sufficient to support tumor growth.
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PMID:Rapid tumor development and potent vascularization are independent events in carcinoma producing FGF-1 or FGF-2. 1244 48

Angiogenesis, the process of new capillary formation from pre-existing vessels, has been established as an important mechanism involved in pathologic processes, such as cancer, as well as in normal physiology (Ribatti, D.; Vacca, A.; Roncali, L.; Dammacco, F. Angiogenesis under normal and pathological conditions. Haematologica 1991, 76 (4), 311-320). Basic fibroblast growth factor (FGF-2) is a critical mediator of angiogenesis that is important for normal reproduction and wound healing. FGF-2 mediates its pro-angiogenic effects by binding to heparin sulfate proteoglycan in addition to a tyrosine kinase receptor (Baird, A.; Schubert, D.; Ling, N.; Guillemin, R. Receptor and heparin-binding domain of basic fibroblast growth factor. Proc. Natl. Acad. Sci. U. S. A. 1998, 5 (7), 2324-2328; Richard, C.; Roghani, M.; Moscatelli, D. Fibroblast growth factor (FGF)-2 mediates cell attachment through interactions with two FGF receptor-1 isoforms and extracellular matrix or cell-associated heparin sulfate proteoglycans. Biochem. Biophys. Res. Commun. 2000, 276 (2), 399-405; Casu, B.; Guerrini, M.; Naggi, A.; Perez, M.; Torri, G.; Ribatti, D.; Carminati, P.; Giannini, G.; Penco, S.; Pisano, C.; Belleri, M.; Rusnati, M.; Presta, M. Short heparin sequences spaced by glycol-split urinate residues are antagonists of fibroblast growth factor 2 and angiogenesis inhibitors. Biochemistry 2002, 41 (33), 10519-10528; Murphy, P.V.; Pitt, N.; O'Brien, A.; Enright, P.M.; Dunne, A.; Wilson, S.J.; Duane, R.M.; O'Boyle, K.M. Identification of novel inhibitors of fibroblast growth factor (FGF-2) binding to heparin and endothelial cell survival from a structurally diverse carbohybrid library. Bioorg. Med. Chem. Lett. 2002, 12 (22), 3287-3290). We developed a liposomal-based peptide vaccine, L(HBD) that targets the heparin binding domain of the FGF-2 molecule. This vaccine, when inoculated into mice, inhibits angiogenesis in response to FGF-2 in a hepatic sponge model as well as tumor progression in two models of pulmonary metastatic disease. In the present studies, we further characterize the immunological and physiological responses to this vaccine. Vaccinated animals generated a specific anti-FGF-2 antibody (titer of 1:5000) that was able to inhibit FGF-2 binding to heparin sulfate in a dose dependent fashion. Cell mediated immunity was evidenced by a delayed type hypersensitivity response following challenge with the heparin binding domain peptide. Despite an immune response toward FGF-2, vaccination with L(HBD) did not result in alterations in mean time to wound healing when compared to unvaccinated animals or those treated with a liposome control. In reproductive studies, vaccinated females were not impaired in their ability to: 1) become pregnant, 2) support the growth and development of their embryos, and 3) deliver viable offspring. Furthermore, when assessed histologically, these offspring did not demonstrate any alterations in organogenesis when compared to pups born to untreated or liposome control treated females. Thus, while vaccination against FGF-2 induces a specific FGF-2 antibody response, and inhibits angiogenesis and tumor development in a pathological setting, it does not adversely alter normal physiological events dependent on FGF-2.
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PMID:Generation of a specific immunological response to FGF-2 does not affect wound healing or reproduction. 1510 30

The association between angiogenin and cancer progression and poor outcome in solid tumors has been documented, but its significance in leukemias has not been evaluated. Using an ELISA technique (Quantikine Human Angiogenin Immunoassay; R&D Systems), we measured serum angiogenin levels in 77 previously untreated Binet stage A B-cell chronic lymphocytic leukemia (CLL) patients. No difference in angiogenin serum levels could be found between patients (median: 295 ng/mL; range: 74-1700) and 15 age- and sex-matched healthy controls (median: 264 ng/mL; range: 29-1835) (P = NS; Mann-Whitney test). Increased angiogenin serum level was associated with higher LDH (P = 0.03) and beta2-m (P = 0.007) concentrations. However, angiogenin did not reflect the extent of bone marrow (BM) angiogenesis as evaluated by microvessel area (P = 0.611), circulating levels of vascular endothelial growth factor (VEGF) (P = 0.873) and basic fibroblastic growth factor (FGF-2) (P = 0.421). When the 25 patients with available data were stratified into the four major cytogenetic categories (normal karyotype, 13q as a sole aberration, 12q trisomy, 11q or 17p deletion) and aberrations were compared with angiogenin serum levels, no correlation was found (P = 0.651; Kruskall-Wallis test). A cut-off of angiogenin serum level corresponding to median (i.e. 330 ng/mL) or higher identified later upstaging and longer progression-free survival (PFS). The 5-yr PFS was 51.5% for patients with angiogenin levels lower than median and 85% for patients with higher values [P = 0.03; hazard ratio (HR) = 2.86; 95% CI: 1.08-6.72]. Although in multivariate analysis only Rai substages (P = 0.00001) and peripheral blood lymphocytosis (P = 0.009) retained their prognostic significance, angiogenin could be incorporated into the Rai substages thus leading to the identification of the following risk categories: (i) stage 0 (angionenin >330 ng/mL); (ii) stage 0 (angiogenin <330 ng/mL) + stage I-II (angiogenin >330 ng/mL); and (iii) stage I-II (angiogenin <330 ng/mL). The 40-month PFS were as follows: 85%, 65%, 25% (chi(2) for trend = 6.33; d.f. = 1; P = 0.01). In conclusion, serum angiogenin levels although not increased in comparison with healthy controls, may predict clinical outcome of patients with early CLL and help to refine Rai's stratification.
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PMID:Serum angiogenin is not elevated in patients with early B-cell chronic lymphocytic leukemia but is prognostic factor for disease progression. 1518 36

Endocan, previously called endothelial cell specific molecule-1, is a soluble proteoglycan of 50 kDa, constituted of a mature polypeptide of 165 amino acids and a single dermatan sulphate chain covalently linked to the serine residue at position 137. This dermatan sulphate proteoglycan, which is expressed by the vascular endothelium, has been found freely circulating in the bloodstream of healthy subjects. Experimental evidence is accumulating that implicates endocan as a key player in the regulation of major processes such as cell adhesion, in inflammatory disorders and tumor progression. Inflammatory cytokines such as TNF-alpha, and pro-angiogenic growth factors such as VEGF, FGF-2 and HGF/SF, strongly increased the expression, synthesis or the secretion of endocan by human endothelial cells. Endocan is clearly overexpressed in human tumors, with elevated serum levels being observed in late-stage lung cancer patients, as measured by enzyme-linked immunoassay, and with its overexpression in experimental tumors being evident by immunohistochemistry. Recently, the mRNA levels of endocan have also been recognized as being one of the most significant molecular signatures of a bad prognosis in several types of cancer including lung cancer. Overexpression of this dermatan sulphate proteoglycan has also been shown to be directly involved in tumor progression as observed in mouse models of human tumor xenografts. Collectively, these results suggest that endocan could be a biomarker for both inflammatory disorders and tumor progression as well as a validated therapeutic target in cancer. On the basis of the recent successes of immunotherapeutic approaches in cancer, the preclinical data on endocan suggests that an antibody raised against the protein core of endocan could be a promising cancer therapy.
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PMID:Endocan or endothelial cell specific molecule-1 (ESM-1): a potential novel endothelial cell marker and a new target for cancer therapy. 1616 66

Pituitary tumor transforming gene (PTTG) is a newly discovered oncogene, and serves as a marker of malignancy grades in several forms of cancer, particularly endocrine malignancies such as pituitary adenomas. PTTG appears also to have a role in the genesis of some types of cancer. Also known as a human form of securin, PTTG is an anaphase inhibitor that prevents premature chromosome separation through inhibition of separase activity; hence, its degradation is required to start anaphase. Through this important function, PTTG participates in several key cellular events such as mitosis, cell cycle progression, DNA repair and apoptosis. The physiological importance of PTTG is indicated by the study of PTTG-null mice that have cell growth abnormalities in testis and pancreatic beta cells. Overexpression of PTTG has been observed in thyroid and colon cancers. In addition, 90% of pituitary adenomas overexpress PTTG, qualifying it as the best available marker for this disease. Although the exact mechanism is unknown, PTTG participates in the pathogenesis of various tumors, including pituitary tumors, by inducing aneuploidy and upregulating FGF-2, a potent mitogenic and angiogenic factor. Various growth factors, nuclear factors and hormones regulate PTTG expression in different tumor cells, which could be important to understand in order to obtain insight into the tumorigenic and tumor progression process. Here, we review the current knowledge of the biological and pathophysiological roles of PTTG.
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PMID:The emerging role of pituitary tumor transforming gene in tumorigenesis. 1680 6

Fibroblast growth factor (FGF)-2 has been considered to play a critical role in neovascularization in several tumors; however, its precise role in tumor progression is not fully understood. In the present study, we have characterized the role of FGF-2 in B16-BL6 mouse melanoma cells, focusing on effects during the initial phase of tumor growth. FGF-2 was injected at the tumor inoculation site of dorsal skin during the initial phase. FGF-2 induced marked tumor growth and lymph node metastasis. This was well correlated with an increase in neovascularization in the host stroma. FGF-2 also recruited inflammatory and mesenchymal cells in host stroma. Marked tumor growth, pulmonary metastasis and intensive neovascularization in tumor parenchyma were also observed after a single injection of FGF-2 into the footpad inoculation site. In contrast, repeated injections of FGF-2 at a site remote from the footpad tumor were ineffective in promoting tumor growth and metastasis. These promoting activities of FGF-2 were blocked by local injections of a glucocorticoid hormone, suggesting that host inflammatory responses induced by FGF-2 are associated with FGF-2-induced tumor progression. In addition, although FGF-2 did not promote cellular proliferation and vascular endothelial growth factor A (VEGFA) mRNA expression in B16-BL6 cells in vitro, FGF-2 induced VEGFA expression in host stroma rather than tumor tissue, and local injections of a neutralizing antibody against VEGFA inhibited these activities of FGF-2 in vivo. These results indicate that abundant FGF-2 during the initial phase of tumor growth induces VEGFA-dependent intensive neovascularization in host stroma, and supports marked tumor growth and metastasis.
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PMID:Fibroblast growth factor-2-induced host stroma reaction during initial tumor growth promotes progression of mouse melanoma via vascular endothelial growth factor A-dependent neovascularization. 1735 89

Melanoma is a highly invasive tumor with elevated mortality rates. Progression and aggressiveness appear related to the achievement of an angiogenic phenotype. Melanoma cells express several angiogenic factors, including fibroblast growth factor (FGF)-1 and FGF-2. The autocrine production and release of FGFs and the subsequent activation of FGF receptors, have a central role in melanoma tumor progression. We demonstrated that FGF-1 is secreted from a human melanoma cell line, A375, under conditions of serum deprivation. The release of FGF-1 is inhibited by the copper chelator ammonium tetrathiomolybdate, suggesting a role of copper in the secretory pathway, and is triggered by activation of phosphatidylinositol 3-kinase (PI3K)/Akt intracellular signaling. Interestingly, overexpression or activation of Akt has been correlated with poor prognosis in melanoma patients. Our data indicate a novel role for Akt in supporting the progression of human melanomas and advocate the need for new treatments targeting PI3K/Akt signaling pathway, to control tumor development and progression.
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PMID:The release of fibroblast growth factor-1 from melanoma cells requires copper ions and is mediated by phosphatidylinositol 3-kinase/Akt intracellular signaling pathway. 1840 Mar 76

Mast cells affect growth in various human tumors, but their role in prostate cancer (PC) is unclear. Here, we identify mast cells as independent prognostic markers in PC using a large cohort of untreated PC patients with a long follow-up. By analyzing mast cells in different tissue compartments, our data indicate that intratumoral and peritumoral mast cells have anti- opposed to protumor properties. Intratumoral mast cells negatively regulate angiogenesis and tumor growth, whereas peritumoral mast cells stimulate the expansion of human prostate tumors. We also observed mast cell recruitment particularly to the peritumoral compartment in men during the formation of castrate-resistant prostate tumors. In our ortothopic rat model, mast cells accumulated in the peritumoral tissue where they enhanced angiogenesis and tumor growth. In line with this, prostate mast cells expressed high levels of the angiogenic factor FGF-2. Similar to the situation in men, mast cells infiltrated rat prostate tumors that relapsed after initially effective castration treatment, concurrent with a second wave of angiogenesis and an up-regulation of FGF-2. We conclude that mast cells are novel independent prognostic markers in PC and affect tumor progression in animals and patients. In addition, peritumoral mast cells provide FGF-2 to the tumor micro environment, which may contribute to their stimulating effect on angiogenesis.
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PMID:Mast cells are novel independent prognostic markers in prostate cancer and represent a target for therapy. 2061 42

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