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)

In breast cancer, vascular endothelial growth factor (VEGF) is a prognostic factor, but the relationship of VEGF mRNA levels with various parameters or tumor progression is unclear. VEGF mRNA levels were measured in 48 cases of invasive ductal carcinoma by using laser capture microdissection and quantitative reverse transcription-polymerase chain reaction (RT-PCR). The mean VEGF mRNA levels were compared among different histological types and grades in 41 and 29 samples of invasive and intraductal components, respectively. VEGF mRNA levels were always higher in cancerous cells than in non-cancerous cells, but mean VEGF mRNA levels were not significantly different between invasive component (3.24 +/- 3.18-fold the value of non-cancerous tissue) and intraductal component (4.14 +/- 4.43-fold). They were higher in papillotubular type than in other types, and higher in grade 2 carcinomas than in grade 3 carcinomas of invasive component, and higher in comedo type than in other types of intraductal component. Mean VEGF mRNA levels were higher in the VEGF-immunopositive group than in the VEGF-immunonegative group. There was no correlation between VEGF mRNA levels and tumor size, nodal status, or hormone receptor status. VEGF expression may play an important role in the development of both invasive and intraductal carcinoma components, especially those carcinoma components of less aggressive histological features.
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PMID:Vascular endothelial growth factor mRNA levels quantified by reverse transcription-polymerase chain reaction in microdissected breast carcinoma tissues are correlated with histological type and grade of both invasive and intraductal components. 1587 23

Maspin, a novel serine protease inhibitor, suppresses tumor progression in several cancer models, including an in vivo model for prostate cancer bone metastasis. However, the molecular mechanism of maspin remains illusive, primarily because its molecular targets are unknown. To this end, we used a full-length maspin cDNA bait to screen against both a primary prostate tumor cDNA prey library and a HeLa cDNA prey library by the yeast two-hybrid method. We found that heat shock protein 90, glutathione S-transferase (GST), and heat shock protein 70 interacted with maspin with the highest frequencies. We confirmed the maspin/GST interaction using purified proteins, human epithelial cell lines, and human prostate tissues. A maspin variant that has a point mutation of Arg(340) to Ala (Mas(R340A)) showed a significantly decreased affinity for GST. Although purified maspin had no effect on the activity of purified GST in vitro, intracellular interaction between endogenous maspin and GST correlated with an elevated total GST activity in both MDA-MB-435- and DU145-derived stably transfected cells. Consistently, tumor cells treated with purified wild type maspin, but not Mas(R340A), enhanced cellular GST activity. Maspin expression in cancer cell lines also correlated with decreased basal levels of reactive oxygen species (ROS). Furthermore, H(2)O(2) treatment not only induced GST expression but also increased intracellular maspin/GST interaction, which was inversely correlated with the level of ROS generation. Conversely, maspin knockdown by small interfering RNA increased the basal, as well as H(2)O(2)-induced, ROS generation. Furthermore, the maspin effect on ROS generation was completely abolished by a GST inhibitor, indicating an essential role of GST in maspin-mediated cellular response to oxidative stress. Consistently, oxidative stress-induced vascular endothelial growth factor A expression was significantly inhibited in maspin-expressing cells. Together, our data suggest a new mechanism by which maspin, through its direct interaction with GST, may inhibit oxidative stress-induced ROS generation and vascular endothelial growth factor A induction, thus preventing further adverse effects on tumor genetics and stromal reactivity.
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PMID:Tumor-suppressive maspin regulates cell response to oxidative stress by direct interaction with glutathione S-transferase. 1604 7

The identification of small molecules that inhibit the sequence-specific binding of transcription factors to DNA is an attractive approach for regulation of gene expression. Hypoxia-inducible factor-1 (HIF-1) is a transcription factor that controls genes involved in glycolysis, angiogenesis, migration, and invasion, all of which are important for tumor progression and metastasis. To identify inhibitors of HIF-1 DNA-binding activity, we expressed truncated HIF-1alpha and HIF-1beta proteins containing the basic-helix-loop-helix and PAS domains. Expressed recombinant HIF-1alpha and HIF-1beta proteins induced a specific DNA-binding activity to a double-stranded oligonucleotide containing a canonical hypoxia-responsive element (HRE). One hundred twenty-eight compounds previously identified in a HIF-1-targeted cell-based high-throughput screen of the National Cancer Institute 140,000 small-molecule library were tested in a 96-well plate ELISA for inhibition of HIF-1 DNA-binding activity. One of the most potent compounds identified, echinomycin (NSC-13502), a small-molecule known to bind DNA in a sequence-specific fashion, was further investigated. Electrophoretic mobility shift assay experiments showed that NSC-13502 inhibited binding of HIF-1alpha and HIF-1beta proteins to a HRE sequence but not binding of the corresponding proteins to activator protein-1 (AP-1) or nuclear factor-kappaB (NF-kappaB) consensus sequences. Interestingly, chromatin immunoprecipitation experiments showed that NSC-13502 specifically inhibited binding of HIF-1 to the HRE sequence contained in the vascular endothelial growth factor (VEGF) promoter but not binding of AP-1 or NF-kappaB to promoter regions of corresponding target genes. Accordingly, NSC-13502 inhibited hypoxic induction of luciferase in U251-HRE cells and VEGF mRNA expression in U251 cells. Our results indicate that it is possible to identify small molecules that inhibit HIF-1 DNA binding to endogenous promoters.
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PMID:Echinomycin, a small-molecule inhibitor of hypoxia-inducible factor-1 DNA-binding activity. 1620 79

Vascular endothelial growth factor A (VEGF-A) plays an essential role in tumor progression through stromal neovascularization in malignant solid tumors. Neuropilin (NRP) is considered to be the specific receptor for limited types of VEGF-A isoform, VEGF165. The clinicopathological implications of NRP are not well understood in colon cancer, while almost all colon cancers overexpressed VEGF-A. We examined the expression levels of NRP1 and NRP2 genes in 54 colon cancer cases and paired extraneoplastic tissue with quantitative real-time polymerase chain reaction. The gene expression levels of NRP1 in the tumor (0.431+/-0.583) were significantly decreased compared to those in the extraneoplastic tissue (0.754+/-0.799) (paired t-test, p=0.0208). On the other hand, the gene expression levels of NRP2 in the tumor (0.763+/-0.791) were not decreased compared to those in the extraneoplastic tissue (0.508+/-0.386) (paired t-test, p=0.0511). Twenty cases, with preserved expression of the NRP1 gene in the tumor, showed a better prognosis as compared to the 34 cases with decreased NRP1 expression (p=0.0258, log-rank test). No significant relationship was noted between NRP2 gene expression and prognosis. The results suggested that preserved NRP1 expression provides colon cancer patients with a better prognosis.
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PMID:The preserved expression of neuropilin (NRP) 1 contributes to a better prognosis in colon cancer. 1639 56

The Wilms' tumor suppressor gene product (WT1) regulates expression of growth control genes. Microarray analysis of gene expression profiles of hormone-treated LNCaP prostate cancer cell lines transfected with either wild-type WT1 or a zinc finger mutant form, DDS (R394W), revealed significantly altered patterns of expression. Validation studies using quantitative real-time PCR confirmed the differential expression of the tumor progression gene, vascular endothelial growth factor (VEGF). WT1-LNCaP cells had significantly reduced levels of VEGF mRNA when compared to vector control cells; in contrast, DDS-LNCaP cells showed elevated levels of VEGF transcripts. To address a functional role for WT1 overexpression, we investigated whether induction of VEGF expression, by the synthetic androgen R1881, would be disrupted in wild-type or mutant WT1-transfected LNCaP cells. Hormone treatment failed to elevate VEGF transcript levels above uninduced baseline levels in WT1-LNCaP cells, despite 48 h of treatment with 5 nM R1881. Consistent with our quantitative real-time PCR analysis, immunofluorescent staining of VEGF protein was reduced in WT1-LNCaP cells in both the presence and absence of R1881 treatment. Conversely, VEGF levels increased in vector control and DDS-LNCaP cells treated with 5 nM R1881. Not only do these studies point out the regulatory potential of WT1 for VEGF, but they also indicate an altered function for the mutant DDS isoform. Because VEGF is associated with neovascularization and promotion of metastasis in a variety of solid tumors including prostate cancer, a better understanding of the regulation of VEGF expression by transcription factors, such as WT1, is important for halting disease progression.
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PMID:Vascular endothelial growth factor (VEGF) is suppressed in WT1-transfected LNCaP cells. 1657 86

Lung cancer is the leading cause of cancer death worldwide, and most patients die of metastatic disease. Angiogenesis, namely, neovascularization from preexisting vasculature, is necessary for tumor growth in both primary and distant organs to supply oxygen and nutrition. Angiogenesis consists of sprouting and nonsprouting (the enlargement, splitting, and fusion of preexisting vessels) processes, and both can occur concurrently. The growth of non-small cell lung cancer (NSCLC), which accounts for more than 80% of all lung cancers, is usually dependent on angiogenesis, which is regulated by complex mechanisms in the presence of various angiogenesis-related molecules. Vascular endothelial growth factor (VEGF), also known as vascular permeability factor (VPF), is one of the most potent angiogenic molecules, while also regulating both angiogenesis and vascular permeability and hence promoting tumor progression and the development of malignant pleural effusions in NSCLC. Recent clinical trials showed that the anti-VEGF antibody bevacizumab, combined with standard first-line chemotherapy, provided a statistically and clinically significant survival advantage with tolerable toxicity. In addition, the combined use of the anti-VEGF antibody with an inhibitor of epidermal growth factor receptor (EGFR) has also shown favorable antitumor efficiency. These successes proved the validity of an antivasculature strategy for NSCLC. Furthermore, a large number of antivasculature agents have been shown to be effective against multiple targets. The efficiency of these compounds is currently being investigated in clinical trials for NSCLC.
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PMID:Current status and perspective of angiogenesis and antivascular therapeutic strategy: non-small cell lung cancer. 1662 42

Epidemiological and experimental animal data indicate that exposure to both metals and metalloid species exacerbates the risk of human diseases, particularly cancers. Vascular endothelial growth factor (VEGF), which performs a primary function in both tumor progression and angiogenesis, is up-regulated due to exposure to an array of carcinogenic metals, but the mechanisms responsible for the metal activation remain somewhat poorly understood. Recently, we demonstrated that AMP-activated protein kinase (AMPK), which acts as an energy sensor, providing metabolic adaptation effects under ATP-deprived conditions, is critical for the expression of VEGF under oxygen- and glucose-deprived conditions. As carcinogenic metals are potent VEGF expression inducers, we hypothesized that AMPK would also play a crucial role in metal-induced VEGF expression. Here, we present evidence that carcinogenic metals such as arsenite, vanadate, and cobalt, induce AMPK activation and VEGF expression via several different mechanisms, and that AMPK is able to regulate the expression of VEGF mRNA in a hypoxia-inducible factor-1-dependent or -independent manner, depending on the metal applied. We also attempted to characterize the relevant signal transduction pathways in metal-induced VEGF expression and AMPK activation, as well as the role of reactive oxygen species within this context. Overall, our data suggest that AMPK is a critical regulatory component in metal-induced VEGF expression, which further implies its intrinsic involvement in metal-induced carcinogenesis.
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PMID:Critical roles of AMP-activated protein kinase in the carcinogenic metal-induced expression of VEGF and HIF-1 proteins in DU145 prostate carcinoma. 1667

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

CXC chemokine receptor 4 (CXCR4) has been shown to play a critical role in chemotaxis and homing, which are key steps in cancer metastasis. There is also increasing evidence that links this receptor to angiogenesis; however, its molecular basis remains elusive. Vascular endothelial growth factor (VEGF), one of the major angiogenic factors, promotes the formation of leaky tumor vasculatures that are the hallmarks of tumor progression. Here, we investigated whether CXCR4 induces the expression of VEGF through the PI3K/Akt pathway. Our results showed that CXCR4/CXCL12 induced Akt phosphorylation, which resulted in upregulation of VEGF at both the mRNA and protein levels. Conversely, blocking the activation of Akt signaling led to a decrease in VEGF protein levels; blocking CXCR4/CXCL12 interaction with a CXCR4 antagonist suppressed tumor angiogenesis and growth in vivo. Furthermore, VEGF mRNA levels correlated well with CXCR4 mRNA levels in patient tumor samples. In summary, our study demonstrates that the CXCR4/CXCL12 signaling axis can induce angiogenesis and progression of tumors by increasing expression of VEGF through the activation of PI3K/Akt pathway. Our findings suggest that targeting CXCR4 could provide a potential new anti-angiogenic therapy to suppress the formation of both primary and metastatic tumors.
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PMID:CXCR4/CXCL12 axis promotes VEGF-mediated tumor angiogenesis through Akt signaling pathway. 1755 6

Genetic depletion of macrophages in Polyoma Middle T oncoprotein (PyMT)-induced mammary tumors in mice delayed the angiogenic switch and the progression to malignancy. To determine whether vascular endothelial growth factor A (VEGF-A) produced by tumor-associated macrophages regulated the onset of the angiogenic switch, a genetic approach was used to restore expression of VEGF-A into tumors at the benign stages. This stimulated formation of a high-density vessel network and in macrophage-depleted mice, was followed by accelerated tumor progression. The expression of VEGF-A led to a massive infiltration into the tumor of leukocytes that were mostly macrophages. This study suggests that macrophage-produced VEGF regulates malignant progression through stimulating tumor angiogenesis, leukocytic infiltration and tumor cell invasion.
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PMID:Vascular endothelial growth factor restores delayed tumor progression in tumors depleted of macrophages. 1850 9


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