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

Tumorigenesis in mice of the rat insulin promoter [RIP]-simian virus 40 tumor antigen [SV40 Tag] transgenic lineages, RIP1-Tag2 and RIP1-Tag4, is a process initiated by expression of SV40 Tag in pancreatic beta cells, evolution of islet cell hyperplasia and insulinoma appearance. Analysis of major histocompatibility complex [MHC] class I gene expression during this process revealed a normal level of MHC class I molecules at the surface of pancreatic islet cells of RIP1-Tag4 mice, while hyperplastic islets from the same mice contained cells expressing a normal level and cells expressing a low level of MHC class I antigen. Insulinomas themselves expressed very low levels or no MHC class I gene product. Thus, down-regulation of MHC class I gene appears to accompany tumor progression of SV40 Tag-transformed beta islet cells. MHC class I antigen expression in a series of clonally derived cell lines of beta cell origin from different SV40 Tag-induced insulinomas ranged from quite low to undetectable, although expression was inducible by interferon-gamma. Nuclear run-on and transient transfection analyses indicated that expression of the MHC class I gene in these cells in controlled at the transcriptional level, and that the decreased expression is paralleled by reduced binding of transcription factors to the R1 element of the H-2 enhancer.
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PMID:Down-regulation of MHC class I antigen in insulinoma cells controlled by the R1 element of the H-2 enhancer. 813 22

Tolerance to tumor cell-expressed molecules and selection of cells that evade immune surveillance during tumor progression create effective barriers to immunotherapy. We investigated the cytotoxic T-lymphocyte response to simian virus 40 (SV40) tumor (T/t) antigen in two lineages of transgenic mice bearing the same rat insulin promoter-SV40 T/t antigen (RIP Tag) hybrid gene. RIP1-Tag2 mice, which express Tag as embryos, are tolerant to Tag, whereas RIP1-Tag4 mice, which express the transgene in pancreatic islet beta cells several weeks after birth and develop insulinomas, can be immunized to generate active Tag-specific cytotoxic T lymphocytes as determined by in vitro assays. Indeed, RIP1-Tag4 mice immunized with Tag by SV40 infection prior to the time of endogenous transgene expression also mount an effective in vivo cellular immune response to the Tag-expressing pancreatic beta cells, and Tag-induced tumor growth is significantly delayed (up to 1 year). However, after the transgene is expressed, RIP1-Tag4 mice are unable to mount a tumor-inhibiting response upon immunization, although Tag-specific cytotoxic T cells can still be demonstrated in vitro. Our data suggest that Tag-specific T cells are rendered unresponsive in vivo in RIP1-Tag4 mice and that the establishment of this unresponsiveness to Tag can be prevented by SV40 immunization only before the onset of the transgene expression. In the older, successfully immunized mouse, decreased immune surveillance and selection of cells with down-regulation of major histocompatibility complex class I expression most likely set the stage for insulinoma development.
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PMID:Timely immunization subverts the development of peripheral nonresponsiveness and suppresses tumor development in simian virus 40 tumor antigen-transgenic mice. 817 Oct 12

The Eph family of receptor tyrosine kinases and their ligands, known as ephrins, play a crucial role in vascular development during embryogenesis. The function of these molecules in adult angiogenesis has not been well characterized. Here, we report that blocking Eph A class receptor activation inhibits angiogenesis in two independent tumor types, the RIP-Tag transgenic model of angiogenesis-dependent pancreatic islet cell carcinoma and the 4T1 model of metastatic mammary adenocarcinoma. Ephrin-A1 ligand was expressed in both tumor and endothelial cells, and EphA2 receptor was localized primarily in tumor-associated vascular endothelial cells. Soluble EphA2-Fc or EphA3-Fc receptors inhibited tumor angiogenesis in cutaneous window assays, and tumor growth in vivo. EphA2-Fc or EphA3-Fc treatment resulted in decreased tumor vascular density, tumor volume, and cell proliferation, but increased cell apoptosis. However, EphA2-Fc had no direct effect on tumor cell growth or apoptosis in culture, yet inhibited migration of endothelial cells in response to tumor cells, suggesting that the soluble receptor inhibited blood vessel recruitment by the tumor. These data provide the first functional evidence for Eph A class receptor regulation of pathogenic angiogenesis induced by tumors and support the function of A class Eph receptors in tumor progression.
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PMID:Soluble Eph A receptors inhibit tumor angiogenesis and progression in vivo. 1237 Aug 23

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

A major challenge in tumor immunology is how best to activate the relatively low avidity self-specific and tumor-specific T cells that are available in the self-tolerant repertoire. To address this issue, we produced a TCR transgenic mouse expressing a class I-restricted hemagglutinin (HA)-specific TCR (clone 1 TCR) derived from a mouse that expressed HA as a self-Ag in the insulin-producing beta cells of the pancreatic islets (InsHA) mice. Upon transfer of clone 1 TCR CD8(+) T cells into InsHA mice, very few cells were activated by cross-presented HA, indicating that the cells were retained in InsHA mice because they ignored the presence of Ag, and not because they were functionally inactivated by anergy or tuning. Upon transfer into recipient mice in which HA is expressed at high concentrations as a tumor-associated Ag in spontaneously arising insulinomas (RIP-Tag2-HA mice), a high proportion of clone 1 cells were activated when they encountered cross-presented tumor Ag in the pancreatic lymph nodes. However, the activated cells exhibited very weak effector function and were soon tolerized. The few activated cells that did migrate to the tumor were unable to delay tumor progression. However, when HA-specific CD4 helper cells were cotransferred with clone 1 cells into RIP-Tag2-HA recipients and the mice were vaccinated with influenza, clone 1 cells were found to exert a significant level of effector function and could delay tumor growth. This tumor model should prove of great value in identifying protocols that can optimize the function of low avidity tumor-specific T cells.
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PMID:The fate of low affinity tumor-specific CD8+ T cells in tumor-bearing mice. 1572 62

The investigation deals with the role of Fas, FasL, RIP, caspase 3, and PARP taking part in Fas-mediated apoptosis, and contributing to in vitro interaction of hepatoma MH-22a and histiocytic sarcoma J-774 in mice with syngenic splenocytes. Protein expression was identified by means of indirect immunofluorescence. There were two patterns of interaction of tumor cells and splenocytes: apoptosis occurred either in 80% or in an insignificant number of tumor cells. In the latter case, high Fas expression was identified before and when it dropped after the experiment. FasL expression in tumor cells often peaked before the experiment and then it decreased after contact with lymphocytes. That mechanism was reversed in splenocytes: contact with tumor cells boosted expression. RIP, caspase 3 and PARP expression was very low and failed to show until the experiments on both patterns of cells were undertaken. After the experiments, it either remained latent or soared up. In the latter case, simultaneous expression of all proteins took place both in tumor cells and lymphocytes. A second battery of experiments demonstrated maximum rates of apoptosis both of tumor cells and splenocytes. However, the situation was different: Fas expression intensified in both patterns of cells after their interaction which was followed by post-experimental drop in RIP, caspase 3, and PARP expression in tumor cells; hence, the importance of perforin/granzyme-mediated apoptosis which occurred at the early stages of tumor growth in the midst of interaction with immune system cells. That pattern of apoptosis was highly cytotoxic. It is suggested that Fas-mediated apoptosis or any other receptor-sensitive pathway might take place during tumor progression, i.e. at a stage when tumor is most susceptible to change.
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PMID:[Role of proteins in Fas-mediated apoptosis in tumor cells and lymphocytes co-cultured in vitro]. 1766 73

In a breast tumor xenograft model, the MCT-1 oncogene increases the in vivo tumorgenicity of MCF7 cells by promoting angiogenesis and inhibiting apoptosis. Increases in the tumor microvascular density are accompanied by a strong reduction in the levels of the angiogenesis inhibitor thrombospondin-1 (TSP1), but the mechanisms underlying this process are unknown. We show that TSP1 expression is controlled, at least in part, by post-transcriptional events. Using RNA interference to knock down the expression of the RNA-binding protein HuR in MCF7 cells as well as HuR overexpression, we demonstrate that HuR plays an important role in translation of the TSP1 mRNA. Furthermore, employing the RIP-Chip assay yielded 595 transcripts with significantly altered binding to HuR in the more tumorigenic breast cancer clones compared with the weakly tumorigenic clones. These mRNAs clustered in several pathways implicated in the transformed phenotype, such as the RAS pathway (involved in mitogenesis), the PI3K pathway (evasion of apoptosis) and pathways mediating angiogenesis and the cellular response to hypoxia. These findings demonstrate for the first time that global changes in HuR-bound mRNAs are implicated in the evolution to a more tumorigenic phenotype in an in vivo tumor model and underscore the role of global mRNA-protein interactions toward tumor progression.
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PMID:Post-transcriptional gene regulation by HuR promotes a more tumorigenic phenotype. 1864 87

Both cancer and chronic inflammatory diseases are often marked by homeostatic signal transduction pathways run amok. Cleavage of membrane-bound substrates by extracellular metalloproteinases is frequently the rate limiting step in activating many of these pathways, resulting either in liberation of active ligands (shedding) or initiating further processing into bioactive cytoplasmic domains (regulated intramembrane proteolysis or RIP). ADAM10 is a member of the ADAM (A Disintegrin And Metalloproteinase) family of transmembrane metalloproteinases implicated in the RIPing and shedding of dozens of substrates that drive cancer progression and inflammatory disease, including Notch, E-cadherin, EGF, ErbB2 and inflammatory cytokines. ADAM10's emerging role as a significant contributor to these pathologies has led to intense interest in it as a potential drug target for disease treatment. Here we discuss some of the established functions of ADAM10 and the implications of its inhibition in disease progression.
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PMID:ADAM10 as a therapeutic target for cancer and inflammation. 1960 31

The significance of angiogenesis in cancer biology and therapy is well established. In this study, we used the prototypical RIP-Tag model of multistage pancreatic islet tumorigenesis to show that the nuclear receptor COUP-TFII is essential to regulate the balance between pro- and anti-angiogenic molecules that influence the angiogenic switch in cancer. Conditional ablation of COUP-TFII in the tumor microenvironment severely compromised neoangiogenesis and lymphangiogenesis during pancreatic tumor progression and metastasis. We found that COUP-TFII plays a cell-autonomous role in endothelial cells to control blood vessel sprouting by regulating cell proliferation and migration. Mechanistic investigations revealed that COUP-TFII suppressed vascular endothelial growth factor (VEGF)/VEGF receptor-2 (VEGFR-2) signaling by transcriptionally repressing the expression of VEGFR-1, thereby curtailing a central angiogenic driver of vascular growth. Taken together, our results implicate COUP-TFII as a critical factor in tumor angiogenesis through regulation of VEGF/VEGFR-2 signaling, suggesting COUP-TFII as a candidate target for antiangiogenic therapy.
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PMID:Nuclear receptor COUP-TFII controls pancreatic islet tumor angiogenesis by regulating vascular endothelial growth factor/vascular endothelial growth factor receptor-2 signaling. 2097 3

Aberrant cholesterol homeostasis and biosynthesis has been observed in different tumour types. This paper investigates the role of the post-squalenic enzyme of cholesterol biosynthesis, oxidosqualene cyclase (OSC), in regulating tumour angiogenesis and metastasis dissemination in mouse models of cancer. We showed that Ro 48-8071, a selective inhibitor of OSC, reduced vascular density and increased pericyte coverage, with a consequent inhibition of tumour growth in a spontaneous mouse model of pancreatic tumour (RIP-Tag2) and two metastatic mouse models of human colon carcinoma (HCT116) and pancreatic adenocarcinoma (HPAF-II). Remarkably, the inhibition of OSC hampered metastasis formation in HCT116 and HPAF-II models. Ro 48-8071 induced tumour vessel normalization and enhanced the anti-tumoral and anti-metastatic effects of 5-fluorouracil (5-FU) in HCT116 mice. Ro 48-8071 exerted a strong anti-angiogenic activity by impairing endothelial cell adhesion and migration, and by blocking vessel formation in angiogenesis assays. OSC inhibition specifically interfered with the PI3K pathway. According to in vitro results, Ro 48-8071 specifically inhibited Akt phosphorylation in both cancer cells and tumour vasculature in all treated models. Thus, our results unveil a crucial role of OSC in the regulation of cancer progression and tumour angiogenesis, and indicate Ro 48-8071 as a potential novel anti-angiogenic and anti-metastatic drug.
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PMID:The cholesterol biosynthesis enzyme oxidosqualene cyclase is a new target to impair tumour angiogenesis and metastasis dissemination. 2576 81


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