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)

Hypoxia-inducible factor 1 (HIF-1) is a heterodimeric basic helix-loop-helix transcription factor composed of HIF-1 alpha and HIF-1 beta/aryl hydrocarbon nuclear translocator subunits. HIF-1 expression is induced by hypoxia, growth factors, and activation of oncogenes. In response to hypoxia, HIF-1 activates the expression of many genes including vascular endothelial growth factor (VEGF) and erythropoietin. HIF-1 and VEGF play an important role in angiogenesis and tumor progression. Vanadate is widely used in industry, and is a potent inducer of tumors in humans and animals. In this study, we demonstrate that vanadate induces HIF-1 activity through the expression of HIF-1alpha but not HIF-1 beta subunit, and increases VEGF expression in DU145 human prostate carcinoma cells. We also studied the signaling pathway involved in vanadate-induced HIF-1 alpha and VEGF expression and found that phosphatidylinositol 3-kinase/Akt signaling was required for HIF-1 and VEGF expression induced by vanadate, whereas mitogen-activated protein kinase pathway was not required. We also found that reactive oxygen species (ROS) were involved in vanadate-induced expression of HIF-1 and VEGF in DU145 cells. The major species of ROS responsible for the induction of HIF-1 and VEGF expression was H(2)O(2). These results suggest that the expression of HIF-1 and VEGF induced by vanadate through PI3K/Akt may be an important signaling pathway in the vanadate-induced carcinogenesis, and ROS may play an important role.
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PMID:Vanadate-induced expression of hypoxia-inducible factor 1 alpha and vascular endothelial growth factor through phosphatidylinositol 3-kinase/Akt pathway and reactive oxygen species. 1207 Jan 40

Hypoxia-inducible factor 1 (HIF-1) is a master regulator of the transcriptional response to oxygen deprivation. HIF-1 has been implicated in the regulation of genes involved in angiogenesis [e.g., vascular endothelial growth factor (VEGF) and inducible nitric oxide synthase] and anaerobic metabolism (e.g., glycolytic enzymes). HIF-1 is essential for angiogenesis and is associated with tumor progression. In addition, overexpression of HIF-1 alpha has been demonstrated in many common human cancers. Therefore, HIF-1 is an attractive molecular target for development of novel cancer therapeutics. We have developed a cell-based high-throughput screen for the identification of small molecule inhibitors of the HIF-1 pathway. We have genetically engineered U251 human glioma cells to stably express a recombinant vector in which the luciferase reporter gene is under control of three copies of a canonical hypoxia-responsive element (U251-HRE). U251-HRE cells consistently expressed luciferase in a hypoxia- and HIF-1-dependent fashion. We now report the results of a pilot screen of the National Cancer Institute "Diversity Set," a collection of approximately 2000 compounds selected to represent the greater chemical diversity of the National Cancer Institute chemical repository. We found four compounds that specifically inhibited HIF-1-dependent induction of luciferase but not luciferase expression driven by a constitutive promoter. In addition, these compounds inhibited hypoxic induction of VEGF mRNA and protein expression in U251 cells. Interestingly, three compounds are closely related camptothecin analogues and topoisomerase (Topo)-I inhibitors. We show that concomitant with HIF-1 and VEGF inhibition, the activity of the Topo-I inhibitors tested is associated with induction of cyclooxygenase 2 mRNA expression. The luciferase-based high-throughput screen is a feasible tool for the identification of small molecule inhibitors of HIF-1 transcriptional activation. In addition, our results suggest that altered Topo-I function may be associated with repression of HIF-1-dependent induction of gene expression.
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PMID:Identification of small molecule inhibitors of hypoxia-inducible factor 1 transcriptional activation pathway. 1215 35

Prostate cancer presents with a broad spectrum of biologic behavior, ranging from being an indolent, incidental finding to an aggressively invasive and metastatic disease. An improved understanding of the events involved in prostate cancer progression is critically important to its diagnosis and staging, as well as to the development of new therapies. Tumor progression, particularly in aggressive and malignant tumors, is associated with the induction of an angiogenic, gene-driven switch. In prostate cancer, one of the most powerful stimulators of angiogenesis is the vascular endothelial growth factor (VEGF). VEGF transcription can be induced by hypoxia through activation of the PI3 kinase pathway and hypoxia-inducible factor alpha. MMAC/PTEN (henceforth referred to as PTEN) is a recently identified tumor suppressor gene residing on chromosome 10q23, which is frequently inactivated in a wide range of human tumors, including advanced prostate cancer. The goal of this study was to determine whether PTEN inhibits angiogenesis by modulating VEGF activity. Our results showed that reintroduction of the PTEN gene into human prostate PC-3 and LNCaP cells decreased VEGF secretion, which was accompanied by various biologic activities, including inhibited endothelial cell growth and migration. PTEN expression also down-regulated VEGF mRNA levels, as detected by RT-PCR analysis. Concomitant with lessened VEGF expression was the reduction of VEGF promoter activity in PTEN-expressing cells. Our findings suggest that PTEN modulates angiogenesis by regulating VEGF expression.
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PMID:MMAC/PTEN tumor suppressor gene regulates vascular endothelial growth factor-mediated angiogenesis in prostate cancer. 1216 88

Angiogenic cytokines, such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and angiogenin, are candidates for the induction of pleural effusions because they have been implicated in the induction of neovascularization, vascular permeability, and hemorrhage both in the inflammatory process and in tumor progression. Thus, we hypothesized that these angiogenic factors in effusion might be involved in the clinical manifestation of malignant pleural disease. We measured the levels of VEGF, bFGF, and angiogenin in pleural effusions and sera from 40 patients. Pleural effusions due to malignancy (1,350 pg/ml) contained significantly higher levels of VEGF than effusions due to inflammatory diseases (102 pg/ml; p = 0.034). Furthermore, hemorrhagic effusions showed significantly higher VEGF levels (1,942 pg/ml) than non-hemorrhagic effusions (202 pg/ml; p = 0.016) in malignant patients. In contrast, neither bFGF nor angiogenin were correlated with any clinical manifestation of pleural effusion. Immunohistochemical study revealed that malignant cells in the pleura were stained with anti-VEGF antibody. Our data suggest that VEGF secreted from tumor cells may be involved in the accumulation of pleural effusion in malignancy, and that increased levels of VEGF may induce hemorrhagic effusion.
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PMID:High level of vascular endothelial growth factor in hemorrhagic pleural effusion of cancer. 1218 74

Cancer therapies based on the inhibition of angiogenesis by endostatin have recently been developed. We demonstrate that a mutated form of human endostatin (P125A) can inhibit the angiogenic switch in the C3(1)/Tag mammary cancer model. P125A has a stronger growth-inhibitory effect on endothelial cell proliferation than wild-type endostatin. We characterize the angiogenic switch, which occurs during the transition from preinvasive lesions to invasive carcinoma in this model, and which is accompanied by a significant increase in total protein levels of vascular endothelial growth factor (VEGF) and an invasion of blood vessels. Expression of the VEGF(188) mRNA isoform, however, is suppressed in invasive carcinomas. The VEGF receptors fetal liver kinase-1 (Flk-1) and Fms-like tyrosine kinase-1 (Flt-1) become highly expressed in epithelial tumor and endothelial cells in the mammary carcinomas, suggesting a potential autocrine effect for VEGF on tumor cell growth. Angiopoietin-2 mRNA levels are also increased during tumor progression. CD-31 (platelet-endothelial cell adhesion molecule [PECAM]) staining revealed that blood vessels developed in tumors larger than 1 mm The administration of P125A human endostatin in C3(1)/Tag females resulted in a significant delay in tumor onset, decreased tumor multiplicity and tumor burden and prolonged survival of the animals. Endostatin treatment did not reduce the number of preinvasive lesions, proliferation rates or apoptotic index, compared with controls. However, mRNA levels of a variety of proangiogenic factors (VEGF, VEGF receptors Flk-1 and Flt-1, angiopoietin-2, Tie-1, cadherin-5 and PECAM) were significantly decreased in the endostatin-treated group compared with controls. These results demonstrate that P125A endostatin inhibits the angiogenic switch during mammary gland adenocarcinoma tumor progression in the C3(1)/Tag transgenic model.
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PMID:Inhibition of the mammary carcinoma angiogenic switch in C3(1)/SV40 transgenic mice by a mutated form of human endostatin. 1220 72

Because tumor progression is angiogenesis-dependent, angiogenesis density was investigated by immunohistochemistry and computed image analysis in bone marrow (BM) biopsies of 45 newly diagnosed patients with Binet stage A B-cell chronic lymphocytic leukemia (BCLL) and correlated to upstaging and progression-free survival during a 40-month follow-up period. Their microvessel areas and counts were significantly higher than those of patients with anemia due to iron or vitamin B(12) deficiencies. A cutoff value of 0.90 mm(2) x 10(-2) or greater of the microvessel area identified patients with earlier upstaging and shorter progression-free survival. When the cutoff was applied to the Rai subclassification, both Rai 0 and Rai I-II patients who upstaged and shortened the progression-free survival were classified correctly. Information of this type was not given by the microvessel counts. The cutoff did not correlate with other predictors representative of tumor mass or disease progression. The microvessel area correlated with the expression of angiogenic vascular endothelial growth factor (VEGF) by tumor tissue, and serum levels of VEGF were found to be of prognostic value. A causal relationship between risk of progression and BM angiogenesis in BCLL is suggested. A risk stratification inside Rai is proposed. The prognostic usefulness of BM angiogenesis in patients with BCLL is envisaged.
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PMID:Prognostic value of enhanced bone marrow angiogenesis in early B-cell chronic lymphocytic leukemia. 1238 36

Among superficial esophageal carcinomas (SECs), mucosal carcinoma (m) and submucosal carcinoma (sm) markedly differ regarding the presence or absence of lymph node metastases and long-term survival. To clarify differences in the growth pattern of these two superficial carcinomas, we investigated neovascularization around the site of tumor growth and expression of vascular endothelial growth factor (VEGF) in tumor cells, in patients undergoing radical esophagectomy or endoscopic mucosal resection (EMR). Moreover, we investigated whether these factors were related to the prognosis in patients undergoing treatment of SEC. This study included 90 SEC patients undergoing radical esophagectomy (surgery group) and 35 patients undergoing EMR (EMR group). For immunohistochemical staining antibodies against factor VIII-related antigen and against VEGF were used. The microvessels around the tumor were counted to calculate the vascular index (VI). VI and VEGF expression in the tumor were compared in relation to clinicopathologic findings. In the surgery group, the VI and the percent of VEGF-positive cells were significantly higher in the case of sm carcinomas. Furthermore, tumors with a high VI showed a significantly worse prognosis. In the EMR group, the VI and percent of VEGF-positive cells increased with the depth of the tumor. The VI and VEGF expression were significantly higher in sm carcinomas. This may in part explain the difference in cancer progression between m and sm carcinomas. In patients undergoing resection or EMR, examination of neovascularization using VI may be potentially useful in evaluating the prognosis of SEC.
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PMID:Clinicopathologic study of neovascularization and VEGF expression in superficial esophageal carcinoma. 1242 66

The interaction between cancer cells and their microenvironment is a promising area for the development of novel therapeutic anti-cancer modalities. The formation of new blood vessels, angiogenesis, is an important step in cancer progression. Angiogenesis is a complex multistep process involving close orchestration of endothelial cells, extracellular matrix, and soluble factors. Essentially every step has been found to be regulated by inducers and inhibitors. Prostate cancer has the ability to produce angiogenic factors such as metalloproteinases, vascular endothelial growth factor, fibroblast growth factor 2, transforming growth factor-beta and cyclooxygenase-2. In several studies in prostate cancer an increased microvessel density is associated with poorer prognosis. On the other hand several endogenous inhibitors of angiogenesis have been described in prostate cancer e.g., angiostatin, endostatin, prostate specific antigen (PSA), thrombospondin-1, interleukin 10, interferons and retinoids. The expanding insight in the process of angiogenesis has resulted in a large number of pharmaceutical agents that have been tested in preclinical studies and are currently tested in clinical trials. These agents inhibit endothelial cell proliferation or migration and induce apoptosis. This ultimately will affect the formation of new vessels thereby inducing tumor dormancy. Because antiangiogenic treatment is cytostatic rather than cytotoxic, patients will need long-term therapy to prevent regrowth of the tumor. Prostate cancer is an ideal tumor for antiangiogenic studies because of the availability of a reliable tumor marker, PSA, the indolent clinical course of this cancer and the low rate of proliferation even in metastatic sites. Furthermore, clinical studies showed limited side effects, which is advantageous in this elderly patient group. Whether the ultimate antiangiogenic treatment is effective as a single agent or in combination with radiation therapy, chemotherapy or immunotherapy remains to be determined.
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PMID:Angiogenesis in prostate cancer: its role in disease progression and possible therapeutic approaches. 1243 18

Angiogenic factors are major causes of tumor progression in hematological malignancies, particularly multiple myeloma, as well as solid tumors. The introduction of thalidomide as an anti-angiogenic agent in myeloma treatment has demonstrated the importance of angiogenic factors in the progression of myeloma. However, the direct effects of angiogenic factors, particularly VEGFs, hypoxia, and thalidomide, on myeloma cells are not been documented. In this study, we demonstrate increased expression and production levels of VEGF in myeloma compared to non-myelomatous hematological lines, resistance to hypoxia and enhancement of VEGF-A production by hypoxia in myeloma, and direct growth inhibition of myeloma cells due to apoptosis and G1 arrest caused by TNFalpha upregulation induced by thalidomide. These findings may encourage the clinical use of anti-angiogenic agents for their cytostatic effects and the prevention of progression.
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PMID:Expression of angiogenic factors including VEGFs and the effects of hypoxia and thalidomide on human myeloma cells. 1246

Angiogenesis is required for invasive tumor growth and metastasis and constitutes an important point in the control of cancer progression. Its inhibition may be a valuable new approach to cancer therapy. Avascular tumors are severely restricted in their growth potential because of the lack of a blood supply. For tumors to develop in size and metastatic potential they must make an "angiogenic switch" through perturbing the local balance of proangiogenic and antiangiogenic factors. Frequently, tumors overexpress proangiogenic factors, such as vascular endothelial growth factor, allowing them to make this angiogenic switch. Two strategies used in the development of antiangiogenic agents involve the inhibition of proangiogenic factors (eg, anti-vascular endothelial growth factor monoclonal antibodies) as well as therapy with endogenous inhibitors of angiogenesis, such as endostatin and angiostatin. Therapy with endogenous angiogenic inhibitors such as endostatin and angiostatin may reverse the angiogenic switch preventing growth of tumor vasculature. Preclinical studies have shown that endostatin effectively inhibits tumor growth and shrinks existing tumor blood vessels. Phase 1 clinical trials of endostatin and angiostatin are ongoing, and preliminary results show minimal toxicities.
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PMID:Role of angiogenesis in tumor growth and metastasis. 1251 34


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