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)

Transgenic female mice expressing the transforming rat oncogene c-erbB-2 (HER-2/neu) under the mouse mammary tumor virus (MMTV) promoter (BALB-neuT) spontaneously develop mammary carcinomas with a progression resembling that of human breast cancer. In these mice, activating antitumor immunotherapy fails to induce T cell-mediated cytotoxicity, suggesting a suppression of the immune response. We found a direct correlation between tumor multiplicity and an increased proportion of Gr-1+ (Ly6G)/Mac-1+(CD11b)/ER-MP12+(CD31) immature myeloid cells in the peripheral blood (PB) and spleen, suggesting that tumor load profoundly affects overall BALB-neuT hematopoiesis. In fact, myeloid colony formation was increased in bone marrow (BM) and spleen. The immature myeloid cells displayed suppressive activity on host T lymphocytes, which progressively failed to respond to alloantigens and CD3 triggering, while maintaining the ability to proliferate in response to nonspecific mitogens. Transplantation of normal BM into BALB-neuT mice readily resulted in hypertrophic hematopoiesis with myeloid cell expansion. This persistent influence of the tumor was mediated through the release of vascular endothelial growth factor (VEGF) but not granulocyte-macrophage colony-stimulating factor (GM-CSF), and was down-modulated when tumor load was reduced but not when BM was transplanted. Together, the data obtained in the BALB-neuT model of naturally occurring carcinogenesis show that tumor-associated immune suppression is secondary to a more general alteration of host hematopoiesis, conditioned by tumor-secreted soluble factors.
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PMID:Myeloid cell expansion elicited by the progression of spontaneous mammary carcinomas in c-erbB-2 transgenic BALB/c mice suppresses immune reactivity. 1275 Jan 71

Tumor angiogenesis is governed by a complex balance of positive and negative angiogenic factors. Development of chemically-induced mouse skin tumors appears to be highly dependent on an early burst of neovascularization. We have previously shown that Ha-ras-driven vascular endothelial growth factor (VEGF) expression plays a pivotal role in this process. However, the status of other critical positive and negative angiogenic factors throughout skin tumorigenesis has not been studied to the same extent. In the present study, we show that another VEGF family member, placenta growth factor (PlGF), was highly upregulated at all tumor stages in a ras-dependent manner. The study of angiopoietin-1 (Ang-1) and angiopoietin-2 (Ang-2), ligands of receptor tyrosine kinase 2 (Tie-2), showed that while stroma-derived Ang-2 was increased, epidermal Ang-1 expression was completely abolished at early papilloma formation. Studies using epidermal tumor cell lines suggest that the disappearance of Ang-1 also depends on ras activation, extending the plethora of events controlled by this oncogene in mouse skin carcinogenesis. Our results indicated that tumor development occurred in a strong angiogenesis-prone scenario in which PlGF and Ang-2 acted cooperatively with VEGF, whereas the negative or stabilizing effect of Ang-1 was abrogated. A time-course sequence of expression of angiogenic factors expressed throughout tumor growth, as well as the identification of key signaling molecules triggering the angiogenic response, may contribute to the development and testing of antiangiogenic therapeutic strategies with this in vivo tumor model.
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PMID:Modulation of the angiogenesis response through Ha-ras control, placenta growth factor, and angiopoietin expression in mouse skin carcinogenesis. 1276 7

The purpose of this study was to determine whether cyclooxygenase-2 (COX-2) was overexpressed in head and neck squamous cell carcinoma (HNSCC) in relation to vascular endothelial growth factor (VEGF) expression and lymph node metastasis. COX-2 has an important role in the promotion of carcinogenesis, tumor invasiveness and angiogenesis. VEGF is a proangiogenic factor that is up-regulated in various tumors. VEGF has been shown to interact with COX-derived prostaglandins in angiogenesis. To better understand the roles of these genes in HNSCC, we evaluated the immunohistochemical expression pattern of COX-2 and VEGF in relationship with histologic differentiation, clinical stage, and nodal status in 146 HNSCC. The COX-2/VEGF double immunofluorescein staining was evaluated with confocal scanning laser microscope. A positive expression was seen in 96% (140/146: 98 strong positive, 42 weakly positive) for COX-2 and in 98% (143/146: 63 strong positive, 80 weakly positive) for VEGF in HNSCC. A correlation was present in the positive expression of COX-2 with histologic differentiation, clinical stage, and nodal status. VEGF expression was also correlated with nodal status. A significant relation was observed between COX-2 and VEGF expressions. The simultaneous expression of COX-2 and VEGF was statistically significant (p<0.05). These results indicate that elevated COX-2 or VEGF expression is more common in HNSCC with poor prognostic characteristics. The present findings support the efforts to initiate clinical trials on the efficacy of COX-2 inhibitors in adjuvant treatment of HNSCC.
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PMID:Correlation of cyclooxygenase-2 pathway and VEGF expression in head and neck squamous cell carcinoma. 1288 61

The 14-3-3 family proteins are key regulators of various signal transduction pathways including malignant transformation. Previously, we found that the expression of the 14-3-3beta gene is deregulated as well as c-myc gene in aflatoxin B1 (AFB1)-induced rat hepatoma K1 and K2 cells. To elucidate the implication of 14-3-3beta in tumor cell growth, in this paper we analyzed the effect of forced expression of antisense 14-3-3beta RNA on the growth and tumorigenicity of K2 cells. K2 cells transfected with antisense 14-3-3beta cDNA expression vector diminished their growth ability in monolayer culture and in semi-solid medium. Expression level of vascular endothelial growth factor mRNA was also reduced in these transfectants. Tumors that formed by the transfectants in nude mice were much smaller and histologically more benign tumors, because of their decreased level of mitosis compared with those of the parental cells. Frequency of apoptosis detected by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay was increased in the transfectant-derived tumors accompanying the inhibition of angiogenesis. In addition, over-expression of 14-3-3beta mRNA was observed in various murine tumor cell lines. These results suggest that 14-3-3beta gene plays a pivotal role in abnormal growth of tumor cells in vitro and in vivo.
Carcinogenesis 2003 Sep
PMID:Forced expression of antisense 14-3-3beta RNA suppresses tumor cell growth in vitro and in vivo. 1289 1

Folate depletion and aging are risk factors for colorectal cancer. We investigated the effects of folate status and aging on gene expression in the rat colon. Young (weanling) and older (12 month) rats were fed folic acid depleted (0 mg/kg) and supplemented (8 mg/kg) diets for 20 weeks. Gene expression was measured in colonic mucosal scrapings (n = 3 per group) using oligonucleotide arrays (Affymetrix U34A). Folate depletion induced the up-regulation of immune-related genes, urokinase and inducible nitric oxide synthase and the down-regulation of adhesion molecules (protocadherin-4, nidogen and integrin alphaV) and vascular endothelial growth factor in young rats. The abbreviated response to depletion in old rats (62 changes versus 136 in the young) included up-regulation of caspase-2 and deleted in colon cancer. Gene expression changes due to aging were more abundant in folate depleted than supplemented rats (38 versus 119 genes, respectively). In folate-deficient rats, aging induced the down-regulation of immune-related genes, urokinase, p53, insulin-like growth factor binding protein-3 and vav-1 oncogene. In folate supplemented rats, aging induced the down-regulation of vascular endothelial growth factor and caspase-2. Lower expression of adhesion molecules and higher expression of urokinase with folate depletion in young rats may indicate that cell detachment and migration, cancer-related processes, may be modulated by folate status. An age-related decline in p53 and IGF-BP3 expression was only observed in folate depleted animals, indicating that folate supplementation may reduce the risk for age-associated cancers by suppressing deleterious changes in the expression of certain genes.
Carcinogenesis 2004 Jan
PMID:Effects of dietary folate and aging on gene expression in the colonic mucosa of rats: implications for carcinogenesis. 1297 65

Conjugated linoleic acid (CLA), found naturally in dairy products and ruminant meats, refers to isomers of octadecadienoic acid with conjugated double bonds. CLA inhibits both DMBA- and NMU-induced rat mammary carcinogenesis, and its antitumor efficacy is similar whether it is fed only during puberty, or continuously during promotion. Pubertal feeding is associated with a reduced proliferation of the epithelial cells within the terminal end buds (TEBs) and lobular epithelium, and results in a decrease in the epithelial density, suggesting a reduction in the carcinogen-sensitive target population. During promotion, CLA feeding induces apoptosis of preneoplastic lesions. The effects of CLA are mediated by a direct action on the epithelium, as well as by an indirect effect through the stroma. CLA is incorporated into the neutral lipids of mammary adipocytes, where it can serve as a local reservoir of CLA. Additionally, CLA induces the adipogenic differentiation of multipotent mammary stromal cells in vitro, and inhibits their development into three-dimensional capillary networks. This suggested that CLA might inhibit angiogenesis in vivo, a hypothesis that was subsequently confirmed. The antiangiogenic effect is mediated, in part, through a CLA-induced decrease in serum VEGF (vascular endothelial growth factor) and mammary gland VEGF and flk-1. Together, the data suggest that CLA may be an excellent candidate for prevention of breast cancer.
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PMID:Prevention of mammary cancer with conjugated linoleic acid: role of the stroma and the epithelium. 1458 66

Elevated expression of Eph receptors has long been correlated with the growth of solid tumors. However, the functional role of this family of receptor tyrosine kinases in carcinogenesis and tumor angiogenesis has not been well characterized. Here we report that soluble EphA receptors inhibit tumor angiogenesis and tumor progression in vivo in the RIP-Tag transgenic model of vascular endothelial growth factor (VEGF)-dependent multistage pancreatic islet cell carcinoma. Soluble EphA receptors delivered either by a transgene or an osmotic minipump inhibited the formation of angiogenic islet, a premalignant lesion, and reduced tumor volume of solid islet cell carcinoma. EphA2-Fc or EphA3-Fc treatment resulted in decreased tumor volume but increased tumor and endothelial cell apoptosis in vivo. In addition, soluble EphA receptors inhibited VEGF and betaTC tumor cell-conditioned medium-induced endothelial cell migration in vitro and VEGF-induced cornea angiogenesis in vivo. A dominant negative EphA2 mutant inhibited--whereas a gain-of-function EphA2 mutant enhanced--tumor cell-induced endothelial cell migration, suggesting that EphA2 receptor activation is required for tumor cell-endothelial cell interaction. These data provide functional evidence for EphA class receptor regulation of VEGF-dependent tumor angiogenesis, suggesting that the EphA signaling pathway may represent an attractive novel target for antiangiogenic therapy in cancer.
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PMID:Inhibition of VEGF-dependent multistage carcinogenesis by soluble EphA receptors. 1467 Jan 82

Ovarian cancer is believed to develop from the ovarian surface epithelium through the accumulation of aberrations of oncogenes and/or tumor suppressor genes. However, it is unclear how the gene abnormalities are involved in ovarian carcinogenesis. To elucidate the process, we transfected genes reported to show their abnormalities in human ovarian cancers into human ovarian surface epithelial cells. Immortalization of the cells was achieved by the transfection of SV40 large T antigen (LT) and human telomerase reverse transcriptase (hTERT); however, the resultant cells showed no tumorigenesis. Additional transfection of either c-erbB-2 or mutant Ha-ras into the immortalized cells showed the anchorage-independent growth and tumorigenesis in mice with the incidence of 50% and 40%, respectively. Histologically, all the tumours were undifferentiated. In association with the tumorigenesis, the cells expressing c-erbB-2 or mutant Ha-ras demonstrated increased vascular endothelial growth factor secretion under hypoxia and enhanced resistance to apoptosis compared with the immortalized cells. Collectively, the introduction of either c-erbB-2 or mutant Ha-ras in the cells, which were efficiently immortalized by the transfection of LT and hTERT, showed tumorigenicity, suggesting that c-erbB-2 or mutant Ha-ras genes might be involved in ovarian carcinogenesis.
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PMID:C-erbB-2 or mutant Ha-ras induced malignant transformation of immortalized human ovarian surface epithelial cells in vitro. 1467 9

Cyclooxygenase-2 (COX-2), vascular endothelial growth factor (VEGF), and microvessel density (MVD) have been reported to be significantly related to carcinogenesis and to tumoral progression. The aim of the study was to analyse immunohistochemically the overexpression of COX-2 and VEGF, and the MVD between one another, and also in relation with clinical outcome in ovarian carcinoma. We selected 52 patients with ovarian carcinoma homogeneous by stage, type and histological grade, surgical and chemotherapeutic treatment. Of these, 28 patients had died of progression of their disease within 2 years of their primary surgical treatment, while 24 patients were alive with no evident disease at 5 years from the primary surgical treatment. The differences of the COX-2 status, the MVD and the VEGF expression in the two groups of ovarian carcinoma patients with low and high survival rate, respectively, were calculated according to the Fisher's exact test and the logistic regression. The shift in location of MVD in the two groups of patients was calculated according to the Wilcoxon Mann-Whitney test. MVD was correlated with COX-2 and VEGF overexpression (P=0.009 and P=0.003, respectively), COX-2 and VEGF were correlated to one another (P=0.044). In logistic regression analysis, COX-2, VEGF, and MVD were significant (P=0.017, P=0.008, P<0.0005, respectively). In the cases with low survival rate, the average MVD was 102, while in the cases with high survival rate the average MVD was 40.5 (P<0.0005). The evaluation of the COX-2, the VEGF and the MVD may give additional prognostic information for first-line chemotherapy and clinical outcome of patients with ovarian carcinoma and may encourage selection of more tailored therapies. Angiogenesis inhibitors or COX-inhibitors probably can have synergistic effects with chemotherapy.
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PMID:COX-2 status in relation to tumor microvessel density and VEGF expression: analysis in ovarian carcinoma patients with low versus high survival rates. 1471 60

We previously reported that vascular endothelial growth factor (VEGF) expression correlates with vessel density in human esophageal squamous cell carcinomas. However, tumor angiogenesis is not controlled simply by the presence of VEGF, and is likely regulated by several angiogenic factors produced by tumor and host cells. The goal of the present study was to determine the angiogenic profile of precancerous and cancerous lesions of the esophagus. Expression of mRNAs for VEGF, platelet derived endothelial cell growth factor (PD-ECGF), basic fibroblast growth factor (bFGF), and interleukin (IL)-8 was examined in six esophageal carcinoma cell lines and fresh biopsy specimens from 16 patients with invasive esophageal carcinoma by RT-PCR. Immunohistochemical analyses with antibodies against VEGF, PD-ECGF, bFGF, and IL-8 were performed on archival specimens of 60 normal esophageal mucosa, 11 dysplasias and 49 carcinomas of the esophagus. Microvessels were stained with anti-CD34 antibody and quantified by counting the number of vessels in a x200 field in the most vascularized areas of the tumor. Esophageal carcinoma cell lines and tumor tissues expressed mRNAs for one or more these angiogenic factors at various levels. An initial increase in vessel density and enhanced expression of PD-ECGF and VEGF were observed in dysplastic epithelium. Vessel density was significantly higher in more advanced lesions. bFGF and IL-8 were not expressed in dysplasias and mucosal carcinomas, but expression was increased in late stage squamous cell carcinoma. These findings suggest that the angiogenic switch is a very early event in the development of invasive carcinoma. Several different angiogenic factors produced by tumor cells and host cells may regulate angiogenesis during different steps of esophageal carcinogenesis.
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PMID:Angiogenic switch occurs during the precancerous stage of human esophageal squamous cell carcinoma. 1471 61


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