UMLS:C0178874 - FACTA Search

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Query: UMLS:C0178874 (tumor progression)
40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tumor-stroma interactions are of primary importance in determining the pathogenesis of metastasis. Here, we describe the application of sensitive competitive polymerase chain reaction (PCR) techniques for detection and quantitation of human breast cancer cells (MDA-MB-231) in an in vivo mouse model of experimental metastasis. Human-specific oligonucleotide primers in competitive PCR reactions were used to quantify the amount of MDA-MB-231 cells per tissue per organ. Using this species-specific (semi)quantitative PCR approach, gene expression patterns of (human) tumor cells or (mouse) stromal cells in metastatic lesions in the skeleton or soft tissues were investigated and compared. In all metastatic lesions, MDA-MB-231 cells express angiogenic factors (vascular endothelial growth factors [VEGFs]; VEGF-A, -B, and -C) and bone-acting cytokines (parathyroid hormone-related protein [PTHrP] and macrophage colony-stimulating factor [M-CSF]). In these metastases, PECAM-1-positive blood vessels and stromal cells of mouse origin are detected. The latter express angiogenic factors and markers of sprouting vessels (VEGF receptors flt-1/flk - 1/flk-4 and CD31/PECAM-1). Strikingly, steady-state messenger RNA (mRNA) levels of VEGF-A and -B and the major bone resorption stimulators PTHrP and M-CSF by tumor cells were elevated significantly in bone versus soft tissues (p < or = 0.05, p < or = 0.0001, p < or = 0.001, and p < or = 0.05, respectively), indicating tissue-specific expression of these tumor progression factors. In conclusion, MDA-MB-231 breast cancer cells express a variety of factors in vivo that have been implicated in metastatic bone disease and that correlate with poor survival of patients with breast cancer. We hypothesize that the observed up-regulated expression of angiogenic and bone-resorbing factors by the breast cancer cells in the skeleton underlie the clinically observed osteotropism of breast cancer cells and pathogenesis of osteolytic bone metastases. The application of the species-specific competitive PCR-based assay in vivo can provide new information concerning the involvement of gene families in tumor progression and metastatic disease and greatly facilitates the study of tumor-stroma interactions in cancer invasion and metastasis.
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PMID:Monitoring metastatic behavior of human tumor cells in mice with species-specific polymerase chain reaction: elevated expression of angiogenesis and bone resorption stimulators by breast cancer in bone metastases. 1139 85

CD44, a hyaluronan (HA) receptor, belongs to a family of transmembrane glycoproteins which exists as several isoforms. Cell surface expression of certain CD44 isoforms is closely correlated with the progression and prognosis of breast cancers. A number of angiogenic factors (e.g., VEGF and FGF-2) and matrix degrading enzymes (MMPs) are tightly complexed with CD44 isoforms, suggesting that they are involved in the onset of oncogenic signals required for breast tumor cell invasion and migration. Most importantly, interaction of extracellular matrix components (e.g., HA) with cells triggers the cytoplasmic domain of CD44 isoforms to bind its unique downstream effectors (e.g., the cytoskeletal protein ankyrin or various oncogenic signaling molecules-Tiam1, RhoA-activated ROK, c-Src kinase and p185HER2) and to coordinate intracellular signaling pathways (e.g., Rho/Ras signaling and receptor-linked/non-receptor-linked tyrosine kinase pathways), leading to a concomitant onset of multiple cellular functions (e.g., tumor cell growth, migration and invasion) and breast tumor progression.
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PMID:CD44-mediated oncogenic signaling and cytoskeleton activation during mammary tumor progression. 1154 98

Factors that govern host-tumor interaction play a critical role in tumor progression. In previous studies we have shown that oncogenic Ras inhibits the expression of Fas (CD95) and renders Ras-transformed cells resistant to Fas-induced death. We now demonstrate that culture of Ras-transformed cells in the presence of the farnesyltransferase inhibitor (FTI) LB42722 leads to up-regulation of Fas expression, both under basal growth conditions and in the presence of the inflammatory cytokines IFN-gamma and tumor necrosis factor alpha. This is manifested by an increase in fas mRNA, Fas cell surface expression, and Fas-induced apoptosis. Whereas FTI up-regulates expression of FAS in Ras-transformed cells, it inhibits the expression of vascular endothelial growth factor. Culture of Ras-transformed cells in the presence of the histone deacetylase inhibitor trichostatin A resulted in morphological reversion and G(1) arrest (as observed with FTI); however, no induction of Fas was observed. Furthermore, the effects of FTI on Fas-induced death were shown to be independent of RhoB. Therefore, inhibition of oncogenic Ras by FTI can result in two events that alter host-tumor interactions: up-regulation of Fas, rendering tumors more sensitive to immune cytotoxic effector cells, and down-reglation of VEGF, which may inhibit tumor angiogenesis.
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PMID:Farnesyltransferase inhibitors reverse Ras-mediated inhibition of Fas gene expression. 1180 95

The pivotal role of vascular endothelial growth factor (VEGF-A) in the regulation of angiogenesis, in particular in the onset and maintenance of tumor angiogenesis, has been demonstrated repeatedly in experimental model systems and, more recently, in clinical trials. Experimental evidence has also suggested that up-regulated expression of VEGF-A may cooperate with other genetic or epigenetic changes to induce or accelerate tumor progression to invasive and metastatic cancers. Here we report the generation of transgenic mouse lines that express human VEGF-A165 under the control of the rat insulin promoter in the beta cells of pancreatic islets of Langerhans (Rip1VEGF-A). These mice do not exhibit detectable changes in islet development, vascularization, or physiology. Intercrosses of these mice with a transgenic mouse model of pancreatic beta cell carcinogenesis (Rip1Tag2) result in an earlier onset of tumor angiogenesis and with it accelerated tumor growth and mortality. The transition from benign tumors (adenoma) to malignant tumors (carcinoma) is modestly accelerated; however, tumor metastases are not observed. Our findings indicate that in beta-cell tumorigenesis, overexpression of VEGF-A165 accelerates the onset of tumor angiogenesis and with it tumor progression but is not sufficient to induce tumor metastasis.
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PMID:Overexpression of vascular endothelial growth factor-A165 enhances tumor angiogenesis but not metastasis during beta-cell carcinogenesis. 1180 16

Cyclin D1 is frequently overexpressed in human esophageal cancer. We examined the possible role of cyclin D1 overexpression on specific malignant properties of tumor cells using a series of eight human esophageal cancer cell lines that express different levels of cyclin D1. We did not find a simple correlation between levels of cyclin D1 expression and anchorage-independent growth, production of angiogenic factors, or tumorigenicity in nude mice, suggesting that other factors can influence these parameters. We did, however, obtain evidence that tumorigenicity appeared to require both the capacity for anchorage-independent growth and the production of angiogenic factors. To better assess the specific role of cyclin D1, we stably expressed an antisense cyclin D1 cDNA construct in the tumorigenic cell line TTn. This significantly decreased anchorage-independent growth and VEGF production and led to a loss of tumorigenicity in nude mice. Furthermore, these cells diplayed a marked increase in sensitivity to antitumor agents and to Fas antibody-induced apoptosis. Taken together, these findings suggest that the overexpression of cyclin D1 can confer esophageal cancer cells with enhanced malignancy through increases in anchorage-independent growth and VEGF production, and down-regulation of Fas expression, thus suggesting novel functions of the cyclin D1 protein in tumor progression.
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PMID:Overexpression of cyclin DI contributes to malignant properties of esophageal tumor cells by increasing VEGF production and decreasing Fas expression. 1201 32

Subcutaneous in vivo injections of cells of the mastocytoma line P815 in syngenic DBA/2 mice induce locally fast growing solid tumors. These have been used extensively as a cancer model to analyze and manipulate the relationship between tumor cells and host's immune defenses. We report that progression of P815 tumors in vivo was accompanied by a burst (Days 5-7) of local inflammatory cells recruitment and angiogenesis observed histologically, corroborated in vivo by MRI with gadolinium, overtranscription of macrophage activation marker genes, secretion of TNF-alpha by regional lymph node cells and concomitant systemic inflammation. No substantial overtranscriptions of either VEGF or IL-10 or TGF-beta genes were observed. Induction of COX-2 gene was a late event. To establish a possible relationship between the tumor-induced local, regional and systemic increase of pro-inflammatory mediators and progression of tumors in vivo, we carried out experiments deliberately modulating the inflammatory status of the recipient animals. Pretreatment of recipient animals by i.p. injection of thioglycolate accelerated P815 tumor growth. At the opposite, treatment of mice with either a COX-1 + COX-2 inhibitor (aspirin, 1 mg/day/mouse) or a specific COX-2 inhibitor (celecoxib, 0.13 mg/day/mouse) for 2 weeks after injection of tumor cells, significantly reduced the size and growth rate of tumors compared to control mice. Experiments carried out in vitro indicated that peritoneal macrophages from untreated animals were strongly activated by live P815 cells and by P815 membrane preparations. The tumor-induced inflammatory reaction could establish a local micro environment favoring tumor progression. The P815 tumor model might be helpful to recognize important factors controlling host/tumor relationship.
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PMID:Inflammation and cancer, the mastocytoma P815 tumor model revisited: triggering of macrophage activation in vivo with pro-tumorigenic consequences. 1212 7

Outgrowth of solid tumors requires blood supply to the tumor. Tumor angiogenesis is dependent on the interplay between tumor-derived angiogenic factors and stromal cells. Recently, it has been shown that the neurotransmitter dopamine is a potent inhibitor of VEGF-induced angiogenesis. Moreover, there is evidence that patients with schizophrenia have a hyperreactive dopaminergic system and are relatively protected from cancer. We hypothesized that hyperreactivity of the dopaminergic system is related to reduced angiogenesis and tumor development. Therefore, we investigated tumor growth and angiogenesis in two lines of Wistar rats with high (APO-SUS) or low (APO-UNSUS) dopaminergic reactivity. Subcutaneous implants of mammary adenocarcinoma cells (MADB106) in matrigel remained 35% smaller in APO-SUS rats than in APO-UNSUS rats (P<0.01). Moreover, APO-SUS rats developed less lung metastases after i.v. administration of MADB106 tumor cells. Furthermore, hemoglobin content (APO-SUS: 40.6+/-7.6; APO-UNSUS: 76.9+/-13 mg/dl, P<0.05) and expression of the endothelial determinant PECAM-1 in tumors from APO-SUS rats were reduced (APO-SUS: 37+/-18; APO-UNSUS 69+/-25 units, P<0.01), indicating that reduced angiogenesis is responsible for reduced tumor development in APO-SUS rats. These results suggest a novel link between dopaminergic reactivity, angiogenesis, and tumor development and may explain part of the individual differences in cancer progression.
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PMID:Reduced tumor growth, experimental metastasis formation, and angiogenesis in rats with a hyperreactive dopaminergic system. 1220 50

Menstrual cycle activity predisposes to ovarian epithelial tumors based on numerous epidemiological studies. We showed that the hormones involved in menstrual cycle regulation modulate cell cycle activity in these tumors in an accompanying paper. We investigated whether such hormones could also influence angiogenesis, an important determinant of tumor progression, in the same tumors. Treatment with progesterone (P4) stimulated VEGF protein secretion in 4 of 5 ovarian carcinoma cell lines examined. Northern blot analyses performed in MCV50 cells showed that this effect was accompanied by increased VEGF mRNA levels. P4 also stimulated VEGF promoter activity in these cells. Estradiol (E2) showed a similar, but substantially smaller effect on VEGF secretion which was additive to that of P4. Conditioned medium from P4-treated cells strongly stimulated angiogenesis on chicken chorio-allantoic membranes. Incubating the conditioned medium with a neutralizing anti-VEGF antibody, but not with non-specific immunoglobulins abolished this effect. Angiogenic activity was not altered by treatment of the membranes with P4 directly. We conclude that P4 can stimulate angiogenic activity via induction of VEGF secretion in some ovarian epithelial tumors. Therapeutic use of progestins may be most effective when administered in combination with an anti-angiogenic agent, at least against a subset of ovarian carcinomas.
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PMID:Effect of reproductive hormones on ovarian epithelial tumors: II. Effect on angiogenic activity. 1243 84

FGF-1 and FGF-2 are pleiotropic growth factors for many cell types, operating through the activation of specific transmembrane FGF receptors (FGFRs). The role of these factors in tumor progression was investigated, with specific discrimination between their autocrine and non autocrine cellular activity. The rat bladder carcinoma NBT-II cells were engineered to produce FGF-1 or 18 kDa FGF-2 in the presence or absence of their specific receptor. Non-autocrine cells that produced FGF-1 or FGF-2 but lacked FGFRs were epithelial and reminiscent of the parental NBT-II cells. Whilst autocrine cells, which both constitutively produced and secreted the growth factor and expressed FGFRs, had a highly invasive mesenchymal phenotype. Correspondingly, the autocrine cells were highly tumorigenic in vivo compared to the parental and non-autocrine cells, which correlated with the increased production of uPAR and active uPA and increased in vitro invasive potential. Although all cells produced VEGF, only tumors derived from cells that produced FGF-1 or FGF-2 were highly vascularized, suggesting that these two growth factors could be involved in the angiogenic process by activating host endothelial cells. As a result of activation of the FGFR in autocrine cells, changes in cell morphology and an increase in the invasive and tumorigenic properties were observed, however no in vitro or in vivo differential functions between FGF-1 and FGF-2 could be identified in this system. In conclusion, our data demonstrates that rapid tumor development is not dependent upon increased tumor vascularization, suggesting that 'basal' angiogenesis, probably mediated by VEGF, is sufficient to support tumor growth.
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PMID:Rapid tumor development and potent vascularization are independent events in carcinoma producing FGF-1 or FGF-2. 1244 48

Angiogenic factors are major causes of tumor progression in hematological malignancies, particularly multiple myeloma, as well as solid tumors. The introduction of thalidomide as an anti-angiogenic agent in myeloma treatment has demonstrated the importance of angiogenic factors in the progression of myeloma. However, the direct effects of angiogenic factors, particularly VEGFs, hypoxia, and thalidomide, on myeloma cells are not been documented. In this study, we demonstrate increased expression and production levels of VEGF in myeloma compared to non-myelomatous hematological lines, resistance to hypoxia and enhancement of VEGF-A production by hypoxia in myeloma, and direct growth inhibition of myeloma cells due to apoptosis and G1 arrest caused by TNFalpha upregulation induced by thalidomide. These findings may encourage the clinical use of anti-angiogenic agents for their cytostatic effects and the prevention of progression.
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PMID:Expression of angiogenic factors including VEGFs and the effects of hypoxia and thalidomide on human myeloma cells. 1246

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