Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C1519670 (tumor angiogenesis)
 6,052 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In search of biomarkers that predict of human prostate cancer progression, we hypothesized that these markers must be expressed in prostatic epithelial cells during multi-step prostate carcinogenesis. Since both genetic and epigenetic factors have been implicated in human prostate cancer development, two osseous-metastatic experimental models were developed in our laboratory, one based on gene transfection and the other on stromal-epithelial interaction studies. In the genetic model, PC-3 cells transfected with point-mutated c-erbB-2/neu oncogene subsequently acquired the potential to metastasize from the prostate to soft tissues and the skeleton. In the epigenetic model, sublines derived from the parental androgen-dependent LNCaP cell line metastasized from the primary tumor to the lymph node and bone. Cells with known lineage relationships were cloned from both the primary and the metastatic tumors and were characterized extensively using cellular, biochemical, immunohistochemical, and molecular techniques. Relevant stage-specific biomarkers associated with prostate cancer progression in these two models were defined and used to evaluate human prostate tissues obtained from the clinic. In this communication, we focused our discussion on the potential importance of c-erbB-2/neu oncogene, vimentin, hepatocyte growth factor/scatter factor and its receptor, c-met oncogene, tumor angiogenesis and neuroendocrine factors as biomarkers for human prostate cancer progression.
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PMID:Biomarkers associated with prostate cancer progression. 752 53

Endocrine organs, such as the pancreatic islets of Langerhans, contain permeable, fenestrated endothelium that allows direct access of endocrine cells to the blood stream. Factors that control differentiation and maintenance of this highly specialized endothelium remain unknown. Vascular endothelial growth factor (VEGF) is a multifunctional growth factor that may be responsible for the homeostasis of endocrine endothelium; it is a selective mitogen for endothelial cells and is able to permeabilize endothelium. We have analyzed the expression of VEGF mRNA and protein in pancreatic islet cells of normal mice and during the different stages of tumor progression in a transgenic mouse model of beta-cell carcinogenesis. The 120-amino acid and the 164-amino acid isoforms of VEGF are expressed in normal islets of Langerhans and are moderately up-regulated during the stages of tumor development. Two high-affinity receptors for VEGF, flt-1 and flk-1, are expressed by endothelial cells both in normal islets and in the stages of tumorigenesis; these receptors are not up-regulated during this process. Our data raise the possibility that VEGF is involved in the maintenance of permeable endothelium in islets of Langerhans, an observation that may have implications for islet cell physiology and diabetes. While VEGF may also play an important role in the growth of new blood vessels during islet cell tumorigenesis, it cannot be the only factor required for the activation of tumor angiogenesis.
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PMID:Vascular endothelial growth factor and its receptors, flt-1 and flk-1, are expressed in normal pancreatic islets and throughout islet cell tumorigenesis. 861 12

There are two distinct phases during prostatic carcinogenesis with regard to tumor blood vessel development. During the first or prevascular phase, which may persist for years, cells that have undergone some but not all of the transformation steps undergo a limited amount of net growth, producing premalignant prostatic intraepithelial neoplastic (PIN) lesions. Most of these PIN lesions do not continue net growth and do not progress to produce histologically detectable cancer. Even the PIN lesions that do progress to cancer remain of limited virulence unless they undergo conversion to the second or angiogenic phase. Once this angiogenic phase is reached, new blood vessel development is greatly enhanced within the cancer. It is this enhanced tumor angiogenesis which allows these cancers both to grow continuously and to metastasize. Thus, inhibition of angiogenesis should be an effective chemopreventive approach for prostatic carcinogenesis. Linomide is a low molecular weight, water-soluble agent with excellent p.o. absorption and bioavailability. We have previously demonstrated that daily p.o. treatment with Linomide has antiangiogenic abilities against a series of rat and human prostatic cancer xenografts growing in vivo. In the present studies, we have demonstrated using Matrigel in in vivo angiogenesis assays that daily p.o. Linomide at 25 mg/kg/day inhibits angiogenesis induced by tumor necrosis factor alpha, acidic fibroblast growth factor, basic fibroblast growth factor, and vascular endothelial growth factor. Using an N-methylnitrosourea initiation-androgen promotion model, Linomide was given p.o. at a daily dose as high as 25 mg/kg/day for at least 1 year without major toxicity while inhibiting the development of seminal vesicle/prostate cancers in male rats by >50%. Dose-response analysis demonstrated that a Linomide blood level of 50-100 microM is optimal for such chemoprevention. In addition, Linomide treatment at a dose of 25 mg/kg/day was able to inhibit by approximately 60% the incidence of N-methylnitrosourea and approximately 50% of 7,12-dimethyl-benz(a)anthracine-induced mammary carcinogenesis in female rats.
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PMID:Antiangiogenic treatment with linomide as chemoprevention for prostate, seminal vesicle, and breast carcinogenesis in rodents. 875 2

A malignant cell population needs the development of microvessels in order to grow and metastasize. Recently, a role for the p53 gene in the regulation of this angiogenic process has been suggested. Wild-type p53 is involved in the secretion of Trombospondin-1 (TSP-1), an angiogenesis inhibitor. Mutations of the p53 gene cause a downregulation of TSP-1 mRNA in cell lines. Mutant p53 also upregulates the expression of vascular endothelial cell growth factor, a potent angiogenic factor. Together with the reported association of p53 protein overexpression and microvessel density (MVD) in head-and-neck squamous-cell carcinoma, these in vitro findings led us to investigate whether this association would also apply in colorectal adenocarcinomas. Structural changes of the p53 gene are the most frequent observed mutations in colorectal carcinoma and are suspected to be involved in the carcinogenesis at a relatively early stage. Parallel tissue sections from primary colorectal adenocarcinomas were immunostained for CD31, an endothelial cell marker, and with DO7, recognizing both mutant and wild-type p53 protein overexpression. The presence of p53 protein overexpression was found to be significantly associated with high MVD in the vascular hot spots. Our results are in accordance with the in vitro studies on the involvement of p53 in angiogenesis. Mutant p53 might stimulate tumor angiogenesis both indirectly, by augmenting the tumor cell proliferation, and directly, by upregulating angiogenic factors and downregulating angiogenic inhibitors.
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PMID:Correlation of intratumoral microvessel density and p53 protein overexpression in human colorectal adenocarcinoma. 877 72

Angiogenesis is an essential component of multifactorial carcinogenesis and thus a potential target of therapeutic intervention. To develop a novel cancer gene therapy strategy based on suppression of tumor angiogenesis, we examined the feasibility of targeting and preferential killing of proliferating endothelial cells by use of the von Willebrand factor (vWf) promoter and herpes simplex virus thymidine kinase gene (HSV-TK). Based on previous reports on the vWf promoter, we tested two putative vWf promoter regions. The luciferase assay showed that the shorter region, which encompasses most of the first noncoding exon, had stronger activity in endothelial cells. Although the promoter activity was low when employed as an internal promoter for retroviral and adenoviral vectors, endothelial cell specificity was suggested; the promoter, when used to drive the HSV-TK gene, could preferentially suppress endothelial cell growth in the presence of prodrug ganciclovir, suggesting the feasibility of designing an anti-angiogenesis gene therapy using the vWf promoter and the suicide gene/prodrug strategy.
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PMID:Use of von Willebrand factor promoter to transduce suicidal gene to human endothelial cells, HUVEC. 886 49

Previous studies have shown that reduced glutathione (GSH) inhibits experimental oral carcinogenesis in the hamster buccal pouch model. To gain further understanding of molecular mechanisms in the anticancer effect of GSH, these studies examined levels of p53 protein expression. 7,12-Dimethylbenz[a]anthracene (DMBA) was applied to the buccal pouches of 20 Syrian Golden hamsters (Mesocricetus auratus) in a 0.5% solution in mineral oil thrice weekly for 14 weeks. In 10 animals, 10 mg/kg reduced glutathione (GSH) in 0.5 ml of mineral oil was administered by mouth thrice weekly on days alternate to the DMBA painting. An additional 20 animals served as DMBA-untreated and GSH controls. At the termination of the experimental period, there were fewer tumors in the DMBA-GSH than in the DMBA tumor control group, and the tumors were smaller (tumor burden 315 vs. 3,040 mm3). Histologically, the DMBA-GSH group showed a marked reduction in dysplasia, carcinoma in situ, and invasive epidermoid carcinoma sites. Immunohistochemically, by use of monoclonal antibodies for wild-type p53 (PAb 246), changes were observed in protein expression levels at dysplastic sites and within the malignant tumors. Staining for p53 protein was slightly increased in dysplasia and squamous cell carcinoma in the tumor control animals (painted with DMBA) compared with the untreated controls that were free of tumors. In the GSH and DMBA treatment group, p53 protein expression levels were strongly increased in dysplastic and tumor sites. The significant inhibition of oral carcinogenesis associated with the administration of GSH was correlated with the increased levels of the wild-type p53 tumor suppressor gene, suggesting its possible use as a biomarker for GSH chemoprevention. The inhibition of oral carcinogenesis by reduced GSH was also related to a very significant inhibition of tumor angiogenesis, defined by factor VIII staining. Thus angiogenesis inhibition may be an additional mechanism for antioxidant chemoprevention, and this suggests another possible biomarker for antioxidant chemoprevention.
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PMID:Glutathione inhibits experimental oral carcinogenesis, p53 expression, and angiogenesis. 887 60

Estrogens, which have been associated with several types of human and animal cancers, can induce tumor angiogenesis in the pituitary of Fischer 344 rats. The mechanistic details of tumor angiogenesis induction, during estrogen carcinogenesis, are still unknown. To elucidate the role of estrogen in the regulation of tumor angiogenesis in the pituitary of female rats, the density of blood vessels was analysed using factor VIII related antigen (FVIIIRAg) immunohistochemistry and the expression of vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) was examined by Western blot and immunohistochemical analysis. The expression of VEGF receptor (VEGFR-2/Flk-1/KDR) was also examined by immunohistochemistry. The results demonstrated that 17beta-estradiol (E2) induces neovascularization, as well as the growth and enlargement of blood vessels after 7 days of exposure. The high tumor angiogenic potential was associated with an elevated VEGF/VPF protein expression in the E2 exposed pituitary of ovariectomized (OVEX) rats. VEGF/VPF and FVIIIRAg immunohistochemistry and endothelial specific lectin (UEA1) binding studies, indicate that the elevation of VEGF protein expression initially occurred in both blood vessels and non-endothelial cells. After 15 days of E2 exposure, VEGF/VPF protein expression, in the non-endothelial cell population, sharply declined and was restricted to the blood vessels. The function of non-endothelial-derived VEGF is not clear. Furthermore, immunohistochemical studies demonstrated that VEGFR-2 (flk-1/KDR), expression was elevated significantly in the endothelial cells of microblood vessels after 7 days of E2 exposure. These findings suggest that over expression of VEGF and its receptor (VEGFR-2) may play an important role in the initial step of the regulation of estrogen induced tumor angiogenesis in the rat pituitary.
Carcinogenesis 1997 Jun
PMID:Over expression of vascular endothelial growth factor and its receptor during the development of estrogen-induced rat pituitary tumors may mediate estrogen-initiated tumor angiogenesis. 921 97

An in vitro carcinogenesis model of human skin keratinocytes has been developed based on the spontaneously immortalized keratinocyte cell line HaCaT. Immortalization, the initial stage in human carcinogenesis in vitro, was induced by ultraviolet-type mutations in the p53 gene followed by further genetic alterations leading to the loss of senescence genes, in particular on chromosome 3p. Despite multiple genetic changes, the HaCaT cell line sustained its genomic balance up to high passage levels and maintained a non-tumorigenic phenotype. Tumorigenic transformation was induced by ras oncogene transfection but also by culture stress and elevated temperature, resulting in benign and malignant tumorigenic clones. Malignant conversion was associated with the loss of a copy of chromosome 15, leading to a decrease in thrombospondin-1 (TSP-1) expression. Heat-induced malignant conversion was associated with a gain of material on chromosome 11, including the cyclin D1 gene. The microenvironment plays a major role in tumorigenic transformation and the control of malignant cells. Overexpression of platelet-derived growth factor in HaCaT cells caused mesenchyme activation and formation of benign tumors. Halting tumor angiogenesis completely prevented invasion of malignant cells and induced a benign tumor phenotype. Transfer of a normal chromosome 15 or TSP-1 transfection into a skin carcinoma line resulted in tumor suppression due to TSP-1-blocked tumor vascularization. Because of the reduced TSP-1 expression, blood vessels infiltrated the tumor, and it expanded. Progression to more aggressive tumor phenotypes required the in vivo environment and was caused by selection of a subpopulation and further genetic modifications. The improved autonomous growth of these cells was associated with new expression of granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor, which acted in an autocrine manner to stimulate proliferation and migration. With this in vitro skin carcinogenesis model we were able to demonstrate multiple stages in the transformation process that were associated with different genetic and phenotypic characteristics. In addition, we documented that modulation of the tumor stroma plays an important and decisive role in tumor development and progression. From this we hypothesize that the growth restraints of the microenvironment are increasingly lost with advancing stages of carcinogenesis but can be restored by modulation of the tumor stroma.
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PMID:Multiple stages and genetic alterations in immortalization, malignant transformation, and tumor progression of human skin keratinocytes. 983 75

The induction of tumor angiogenesis is mediated in particular by an increased production of VEGF. As ras oncogene is implicated in tumorigenesis, the inhibition of farnesyl transferase activity has recently been developed. The purpose of this study was to evaluate whether expression of mutated Ha-ras oncogene is associated with an altered expression of VEGF in an in vitro model of human skin carcinogenesis and to appreciate the effect of a new farnesyl transferase inhibitor on this VEGF expression. The amounts of VEGF secreted by an HaCaT cell line and two cell clones (metastatic or not) obtained after mutated c-Ha-ras transfection were compared. Our findings showed that the release of VEGF is greater for HaCaT-ras than for HaCaT cells and could be down-regulated using a protein farnesyl transferase inhibitor, in a reversible and dose-dependent manner. These results confirm that the Ha-ras oncogene can contribute to tumor development and progression of epidermal tumors through neoangiogenesis and that farnesyl transferase inhibitors as anticancer drugs may be efficient for the reduction of skin tumor growth.
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PMID:The up-regulation of vascular endothelial growth factor in mutated Ha-ras HaCaT cell lines is reduced by a farnesyl transferase inhibitor. 1022 98

Decorin is a member of the small leucine-rich proteoglycan (SLRP) gene family that has recently become a focus in various areas of cancer research. The decorin protein consists of a core protein and a covalently linked glycosaminoglycan chain. Decorin binds to collagens type I, II and IV in vivo and promotes the formation of fibers with increased stability and changes in solubility. Further, the decorin core protein binds to growth factors, including transforming growth factor-beta (TGF-beta), to other intercellular matrix molecules such as fibronectin and thrombospondin, and to the decorin endocytosis receptor. Decorin may directly interfere with the cell cycle via the induction of p21WAF1/CIP1 (p21), a potent inhibitor of cyclin-dependent kinases (CDKs). Here, we discuss interactions of decorin with TGF-beta and with p21, both of which are relevant to carcinogenesis and tumor progression. TGF-beta is released by tumors of various histogenetic origins and promotes immunosuppression in the host and tumor immune escape by induction of growth arrest and apoptosis in immune cells, by downregulation of MHC II antigen expression and by changes in the cytokine release profiles of immune and tumor cells. Moreover, TGF-beta may modulate tumor growth in an autocrine and paracrine fashion, may mediate drug resistance, and may facilitate tumor angiogenesis. Decorin binds to TGF-beta, thus inhibiting its bioactivity, and is a direct or indirect negative modulator of TGF-beta synthesis. Ectopic expression of decorin results in the regression of rat C6 gliomas, an antineoplastic effect attributed to the reversal of TGF-beta-induced immunosuppression. On the other hand, de novo expression of decorin in colon cancer cells and some other tumor cells, even though not in glioma cells, results in an upregulation of p21 expression and a cell cycle arrest, presumably in a TGF-beta-independent manner. Decorin expression is downregulated in many tumors but upregulated in the peritumoral stroma. By virtue of its growth regulatory and immunomodulatory properties, decorin promises to become a novel target for the experimental therapy of human cancers.
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PMID:Transforming growth factor-beta and p-21: multiple molecular targets of decorin-mediated suppression of neoplastic growth. 1038 66


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