Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The degree of DNA instability as determined by immunohistochemical staining with anti-single-stranded DNA antibody after acid hydrolysis (the DNA instability test) was used as a marker of malignancy. The test was applied to tissues of oral leukoplakia assessed histopathologically as hyperplasia (38 cases), mild (12 cases), moderate (11 cases) and severe (8 cases) dysplasia, and invasive squamous cell carcinoma (SCC, 20 cases). Tissues were subjected to immunohistochemical staining for proliferating cell nuclear antigen (PCNA), p53, DNA-fragmentation factor 45 (DFF45), analysis of various AgNORs parameters, and triple immunostaining for vascular endothelial growth factor (VEGF), CD34, and PCNA. The DNA instability test was positive in 20 (100%) SCC cases, 8 (100%) severe dysplasia cases, 8 (72.7%) moderate dysplasia cases, 6 (50.0%) mild dysplasia cases, and 9 (23.7%) hyperplasia cases, indicating malignancy. The proportion of lesions positive for PCNA, p53, DFF45, and values of AgNORs parameters steadily increased from hyperplasia to mild, moderate and severe dysplasia, and SCC, especially in those showing positive DNA instability test, indicative of malignancy. Based on these results, 44.9% of leukoplakia were malignant tissues, namely carcinoma in situ. The proportion of PCNA-positive vascular endothelial cells in the vicinity of VEGF-positive epithelial lesion was significantly higher than that of negative DNA instability lesions, as revealed by immunohistochemical triple staining for VEGF, CD34, and PCNA. Our results suggest that increased DNA instability, enhanced proliferative activity, p53 mutation, and induction of DFF45 and VEGF may allow cancer cell proliferation, enhance their survival by escaping apoptosis, and provide abundant nutrients during early-stage carcinogenesis of oral leukoplakia.
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PMID:Immunohistochemical detection of early-stage carcinogenesis of oral leukoplakia by increased DNA-instability and various malignancy markers. 1184 1

The distinct roles of angiopoietin (Ang)-1 and Ang2, counteracting ligands for the endothelium-specific Tie2 receptor, in tumor development and progression have remained poorly understood. We investigated the expression of Ang1 and Ang2 during multistep mouse skin carcinogenesis and in human squamous cell carcinoma (SCC) xenografts. Expression of Ang2, but not of Ang1, was up-regulated in angiogenic tumor vessels already in early stages of skin carcinogenesis and was also strongly increased in SCCs. Stable overexpression of Ang1 in human A431 SCCs resulted in a more than 70% inhibition of tumor growth, associated with enhanced Tie2 phosphorylation levels, as compared with low levels in control transfected tumors. No major changes in the vascular density, vascular endothelial growth factor mRNA and protein expression, and vascular endothelial growth factor receptor-2 phosphorylation levels were observed in Ang1-expressing tumors. However, the fraction of tumor blood vessels with coverage by alpha-smooth muscle actin-positive periendothelial cells was significantly increased, indicative of an increased vascular maturation status. These findings identify an inhibitory role of Ang1/Tie2 receptor-mediated vessel maturation in SCC growth and suggest that up-regulation of its antagonist, Ang2, during early-stage epithelial tumorigenesis contributes to the angiogenic switch by counteracting specific vessel-stabilizing effects of Ang1.
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PMID:Activation of the tie2 receptor by angiopoietin-1 enhances tumor vessel maturation and impairs squamous cell carcinoma growth. 1194 23

Cyclooxygenase-2 (COX-2) and peroxisome proliferator-activated receptor-gamma (PPARgamma) have emerged as candidate molecules that hold great promise for cancer chemoprevention. COX-2 increased expression and PPARgamma inactivation occur during mammary gland carcinogenesis. COX-2 and PPARgamma may contribute to breast cancer induction either directly or via their effects on factors known to influence tumor development, e.g., nuclear factor-kappaB and vascular endothelial growth factor. Inhibition of COX-2 or activation of PPARgamma prevents mammary carcinomas in experimental animals with little toxicity. Combinational treatment with COX-2 inhibitor and PPARgamma agonists may produce synergistic anti-tumorigenic effects without significant toxicity and, therefore, be an effective strategy to prevent human breast cancer. Establishing a relationship between COX-2 and PPARgamma in this malignancy may provide the basis for a novel chemopreventive strategy based on the modulation of both molecules simultaneously. This review evaluates experimental and epidemiological findings suggesting a possible role of COX-2 and PPARgamma in the development of human breast cancer and presents evidence substantiating their coordinated action in carcinogenesis and finally develops a rationale for the simultaneous targeting of both molecules as a potentially effective strategy to prevent breast malignancy.
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PMID:Chemoprevention of breast cancer by targeting cyclooxygenase-2 and peroxisome proliferator-activated receptor-gamma (Review). 1201 87

Sodium butyrate (NaB), a short-chain fatty acid naturally present in the human colon, is able to induce cell cycle arrest, differentiation and apoptosis in colon cancer cells. In addition to these effects, we investigated the effect of NaB on two angiogenesis-related proteins in a colon carcinoma cell line (HT29): vascular endothelial growth factor (VEGF), the most potent angiogenic factor, and hypoxia-inducible factor (HIF)-1alpha, the main transcription activator of the VEGF gene, which are both constitutively expressed at high levels in HT29 also in normoxic conditions. NaB treatment had a different effect on VEGF165 and HIF-1alpha expression. In fact, it induced a dose-dependent down regulation of the VEGF165 protein level that was not paralleled by a concomitant down regulation of the corresponding mRNA, suggesting a post-translational regulation of the factor. Conversely, after 24 h of treatment all the tested NaB concentrations reduced the HIF-1alpha protein level, whereas after a longer time of exposure HIF-1alpha level increased in the presence of a high NaB concentration (2 mM) with a concomitant increase in HIF-1alpha mRNA. These results indicate that NaB, besides regulating other fundamental cellular processes, is able to modulate the expression of two important angiogenesis-related molecules and suggested a further possible clinical application of this short-chain fatty acid as an anti-angiogenic compound in association with conventional chemotherapeutic agents.
Carcinogenesis 2002 May
PMID:Modulation of angiogenesis-related proteins synthesis by sodium butyrate in colon cancer cell line HT29. 1201 45

Cyclooxygenase (COX)-2 and vascular endothelial growth factor (VEGF) have been reported to be significantly related to carcinogenesis or progression of various cancers. However, there has been no report on the relation between COX-2 and VEGF overexpression in pancreatic tumors. We investigated the overexpression of COX-2 and VEGF immunohistochemically in intraductal papillary-mucinous tumors (IPMT) and invasive ductal carcinoma (IDC) and examined the relationship with clinicopathological factors and the correlation between these immunoactivities in IPMT and IDC. In IPMT, the positive rates of COX-2 overexpression were 0% in 10 areas of hyperplasia, 54.5% of adenoma, 83.3% of intraductal areas of adenocarcinoma, and 66.7% of invasive areas of adenocarcinoma. On the contrary, 47.8% of IDC were positive for COX-2 overexpression. The positive rates of VEGF in IPMT were 10% in areas of hyperplasia, 54.5% of adenoma, 66.7% of intraductal areas of adenocarcinoma and 66.7% of invasive areas of adenocarcinoma. However, in IDC it was 47.8%. Only lymph node metastasis correlated significantly with VEGF overexpression (p=0.04), while the other factors had no significant relationships with either COX-2 or VEGF overexpression. There was a statistically significant correlation between COX-2 and VEGF overexpression in IPMT (p<0.001), in 5 patients with adenoma of which both COX-2 and VEGF were stained in almost exactly the same locations. On the contrary, COX-2 and VEGF overexpression had no statistically significant relationship in IDC. In conclusion, we demonstrate evidence of COX-2 and VEGF overexpression in human pancreatic tumors. Chemoprevention via the suppression of angiogenesis by means of COX-2 inhibitor may be more effective in IPMT than in IDC, because of the strong correlation of both factors especially in IPMT.
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PMID:Expression of cyclooxygenase-2 and vascular endothelial growth factor in pancreatic tumors. 1206 5

Epidermal growth factor receptor (EGFR) plays a critical role in epidermal biology. Abnormal EGFR function has been described in epithelial tumors including those induced by two-stage chemical carcinogenesis in mouse skin. A large body of evidence indicates that in this model, activation of Ha-ras is the critical event in papilloma formation, a process that involves epidermal proliferation and stroma remodeling, which includes angiogenesis. This study reports that activated Ha-ras results in a dramatic induction of EGFR in epidermal tumor cells and provides experimental evidence that EGFR signaling is responsible for Ha-ras-dependent vascular endothelial growth factor (VEGF) induction, as well as for the repression of other angiogenic factors such as angiopoietin 1. The pivotal role of functional EGFR in throwing the angiogenic switch necessary for tumor growth was confirmed by s.c. injection of immunodeficient mice with epidermal tumor cells carrying a dominant negative (dn) EGFR and by in vivo chemical skin carcinogenesis assays in transgenic mice expressing the same dn EGFR form in the epidermis. Immunohistochemical analysis of the tumors obtained by both ex vivo and in vivo approaches showed that dn EGFR expression abolished the changes in blood vessels that occurred during tumor progression. A strong reduction of VEGF expression in dn EGFR tumors appears to be the key event responsible for angiogenesis and tumor growth suppression. The apoptotic rate was increased, and Akt activity was decreased, suggesting that impaired nutrient and oxygen supply might contribute to diminished cell survival in dn EGFR tumors. Support for this mechanism is provided by the fact that the ectopic expression of VEGF in dn EGFR-expressing tumor cell lines restored tumor growth capacity. Although ras activation might suffice for epidermal transformation and the stroma-remodeling events of tumor induction, such effects may not be operative without a functional upstream EGFR. It is tempting to speculate that EGFR family members may function as angiogenic regulators in other epithelial tumors such as those of the colon, breast, and prostate, reinforcing their value as targets for therapeutic intervention.
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PMID:A critical role for ras-mediated, epidermal growth factor receptor-dependent angiogenesis in mouse skin carcinogenesis. 1206 82

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

In the RIP1-Tag2 mouse model of pancreatic islet carcinoma, angiogenesis is switched on in a discrete premalignant stage of tumor development, persisting thereafter. Signaling through VEGF receptor tyrosine kinases is a well-established component of angiogenic regulation. We show that five VEGF ligand genes are expressed in normal islets and throughout islet tumorigenesis. To begin dissecting their contributions, we produced an islet beta cell specific knockout of VEGF-A, resulting in islets with reduced vascularity but largely normal physiology. In RIP1-Tag2 mice wherein most oncogene-expressing cells had deleted the VEGF-A gene, both angiogenic switching and tumor growth were severely disrupted, as was the neovasculature. Thus, VEGF-A is crucial for angiogenesis in a prototypical model of carcinogenesis, whose loss is not readily compensated.
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PMID:VEGF-A has a critical, nonredundant role in angiogenic switching and pancreatic beta cell carcinogenesis. 1208 77

Prostatic intraepithelial neoplasia (PIN) is composed of dysplastic cells with a luminal cell phenotype, expressing the androgen receptor as well as prostate specific antigen. PIN is characterized by progressive abnormalities of phenotype which are intermediate between normal prostatic epithelium (NP) and cancer, indicating impairment of cell differentiation and regulatory control with advancing stages of carcinogenesis. High-grade PIN is considered the most likely precursor of prostatic carcinoma (PCa), according to virtually all available evidence. Androgen deprivation decreases the prevalence and extent of PIN and the degree of capillary vascularization (e.g., angiogenesis) in the surrounding stroma via the suppression of vascular endothelial growth factor (VEGF) production. It is likely that PCa might also arise from precursor lesions other than high-grade PIN (low-grade PIN, atypical adenomatous hyperplasia, malignancy-associated foci, and atrophy).
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PMID:Prostatic intraepithelial neoplasia and prostate cancer. 1209 35

Prostatic intraepithelial neoplasia (PIN) is composed of dysplastic cells with a luminal cell phenotype, expressing the androgen receptor as well as prostate-specific antigen. PIN is characterized by progressive abnormalities of phenotype that are intermediate between normal prostatic epithelium and cancer, indicating impairment of cell differentiation and regulatory control with advancing stages of carcinogenesis. High-grade PIN is considered the most likely precursor of prostatic carcinoma, according to virtually all available evidence. Androgen deprivation decreases the prevalence and extent of PIN and the degree of capillary vascularization (e.g., angiogenesis) in the surrounding stroma via suppression of vascular endothelial growth factor production. Prostatic carcinoma is also likely to arise from precursor lesions other than high-grade PIN such as low-grade PIN, atypical adenomatous hyperplasia, malignancy-associated foci, and atrophy.
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PMID:Precancerous lesions and conditions of the prostate: from morphological and biological characterization to chemoprevention. 1209 42


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