Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P43146 (tumour suppressor)
 5,935 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) are two important determinants of angiogenesis in human cancers. Expression of VEGF and bFGF was examined by immunohistochemistry in 120 colorectal cancers. Neoplasms were classified according to the presence or absence of microsatellite instability determined at six microsatellite loci and labelled as a high microsatellite instability (MSI-H), low microsatellite instability (MSI-L) or microsatellite stable (MSS). Only 4/30 MSI-H cancers expressed VEGF (13 per cent), compared with 24/64 MSS cancers (38 per cent; p< 0.01). Fewer MSI-H cancers showed bFGF expression (38 per cent) than MSS cancers (53 per cent; p< 0.09). MSI-L cancers showed the same pattern as MSS cancers. Western blotting and immunohistochemistry showed that the tumour suppressor gene p53 was mutated infrequently in MSI-H cancers (8 per cent; p< 0. 001). Microvessel density counts using CD31 and UEA-1 demonstrated no difference in the number of blood vessels in MSI-H and MSS cancers. Although these results are consistent with the known role of wild-type p53 in down-regulating VEGF, no association was found between a mutation in p53 and VEGF or bFGF levels in all colonic neoplasms. This is the first evidence that MSI-H cancers may follow a different pathway to angiogenesis. The low frequency of VEGF expression amongst MSI-H cancers may partially explain why these cancers are less aggressive, with a better overall prognosis.
 ...
PMID:Angiogenic factor VEGF is decreased in human colorectal neoplasms showing DNA microsatellite instability. 1054 92

The accuracy and reliability of in situ studies may be compromised by qualitative interpretations. Quantitation imposes a greater degree of objectivity, is more reproducible, and facilitates the clarity of definitions. The aim of this study was to validate the utility of laser imaging systems for the in situ quantitative analysis of gene expression in tissue microarrays. Immunofluorescence was employed to quantify the expression of the tumour suppressor p53, a marker of proliferation (Ki67), an endothelial cell marker (CD31), and the mismatch repair proteins human Mut L homologue 1 and human Mut S homologue 2 in an arrayed series of colorectal tissues (n = 110). Quantitative data on this panel of antigens were compared objectively with qualitative scoring of immunohistochemical chromogen deposition. In addition, the expression of vascular endothelial growth factor (VEGF)-A, placental growth factor, hepatocyte growth factor, and c-Met mRNA was quantified by phosphor image analysis of in situ hybridization reactions. The quantified data on p53, Ki67, and CD31 expression were significantly associated with the pathologist's score (p < or = 0.001). While hepatocyte growth factor and placental growth factor were not up-regulated, c-Met expression was increased up to 2.5-fold and the median VEGF-A expression was elevated 4-fold (p = 0.003) in this series of colorectal tumours. Laser imaging systems are therefore feasible for high-throughput, quantitative profiling of tissue microarrays.
 ...
PMID:Quantitative analysis of colorectal tissue microarrays by immunofluorescence and in situ hybridization. 1289 93

The p53 tumour suppressor protein has long been recognized as the central factor protecting humans from cancer. In this study we evaluated the associations of p53 status and vessel density (angiogenesis) in a set of diffuse low-grade astrocytomas. Immunohistochemistry was performed on 23 diffuse low-grade astrocytomas for CD31 and p53. Mutations in the TP53 gene were identified by PCR amplification of genomic DNA extracted from the indicated tumour tissues. Microvessel counts were done by computer analyses. Intratumoural or peritumoural microvascular hot spots were assessed and analysed from an image taken with a 200x fold magnification. Statistical analysis was performed with Pearson correlation coefficient and Student's t-test. We found that 9/23 (39%) of the astrocytomas stained positive for p53 in the immunohistochemistry. We identified TP53 mutations in 11/23 (47%) of the astrocytomas. No association between micro vessel density (MVD) and p53 immunohistochemical status was found. However, the MVD was significantly increased in p53 mutated low-grade astrocytomas. Furthermore, the absolute vessel number was significantly higher in p53 mutated than in p53 wild-type low-grade astrocytomas. To analyse the molecular background for that epiphenomenon LN229 glioma cells which harbour a TP53 mutation were transfected with a plasmid encoding p53 wild-type and an angiogenesis protein array was performed. We detected a significant increase for thrombospondin-1, coagulation factor III and serpin E1 and a significant decrease of MMP-9 in wild-type p53 transfected LN229 cells. The higher microvessel density and the increased absolute vessel number in p53 mutated tumours supports the importance of p53 for tumour angiogenesis in diffuse low-grade astrocytomas. Our results support the hypothesis that p53 regulates angiogenesis in low-grade astrocytomas.
 ...
PMID:p53-mediated inhibition of angiogenesis in diffuse low-grade astrocytomas. 1942 89

Abnormal DNA methylation orchestrates many of the cancer-related gene expression irregularities such as the inactivation of tumour suppressor genes through hypermethylation as well as activation of prometastatic genes through hypomethylation. The fact that DNA methylation abnormalities can be chemically reversed positions the DNA methylation machinery as an attractive target for anti-cancer drug development. However, although in vitro studies suggested that targeting concordantly hypo- and hypermethylation is of benefit in suppressing both oncogenic and prometastatic functions of breast cancer cells, this has never been tested in a therapeutic setting in vivo. In this context, we investigated the combined therapeutic effects of an approved nutraceutical agent S-adenosylmethionine (SAM) and FDA-approved hypomethylating agent decitabine using the MDA-MB-231 xenograft model of breast cancer and found a pronounced reduction in mammary tumour volume and lung metastasis compared to the animals in the control and monotherapy treatment arms. Immunohistochemical assessment of the primary breast tumours showed a significantly reduced expression of proliferation (Ki-67) and angiogenesis (CD31) markers following combination therapy as compared to the control group. Global transcriptome and methylome analyses have revealed that the combination therapy regulates genes from several key cancer-related pathways that are abnormally expressed in breast tumours. To our knowledge, this is the first preclinical study demonstrating the anti-cancer therapeutic potential of using a combination of methylating (SAM) and demethylating agent (decitabine) in vivo. Results from this study provide a molecularly founded rationale for clinically testing a combination of agents targeting the epigenome to reduce the morbidity and mortality from breast cancer.
 ...
PMID:S-adenosylmethionine in combination with decitabine shows enhanced anti-cancer effects in repressing breast cancer growth and metastasis. 3272 Apr 67