| 61. |
- Buckley, Patrick, et al.
(författare)
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Comprehensive DNA copy number profiling of meningioma using a chromosome 1 tiling path microarray identifies novel candidate tumor suppressor loci
- 2005
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Ingår i: Cancer Research. - 0008-5472 .- 1538-7445. ; 65:7, s. 2653-2661
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Tidskriftsartikel (refereegranskat)abstract
- Meningiomas are common neoplasms of the meninges lining of the central nervous system. Deletions of 1p have been established as important for the initiation and/or progression of meningioma. The rationale of this array-CGH study was to characterize copy number imbalances of chromosome 1 in meningioma, using a full-coverage genomic microarray containing 2,118 distinct measurement points. In total, 82 meningiomas were analyzed, making this the most detailed analysis of chromosome 1 in a comprehensive series of tumors. We detected a broad range of aberrations, such as deletions and/or gains of various sizes. Deletions were the predominant finding and ranged from monosomy to a 3.5-Mb terminal 1p homozygous deletion. Although multiple aberrations were observed across chromosome 1, every meningioma in which imbalances were detected harbored 1p deletions. Tumor heterogeneity was also observed in three recurrent meningiomas, which most likely reflects a progressive loss of chromosomal segments at different stages of tumor development. The distribution of aberrations supports the existence of at least four candidate loci on chromosome 1, which are important for meningioma tumorigenesis. In one of these regions, our results already allow the analysis of a number of candidate genes. In a large series of cases, we observed an association between the presence of segmental duplications and deletion breakpoints, which suggests their role in the generation of these tumor-specific aberrations. As 1p is the site of the genome most frequently affected by tumor-specific aberrations, our results indicate loci of general importance for cancer development and progression.
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| 62. |
- Busch, Susann, et al.
(författare)
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Loss of TGF beta Receptor Type 2 Expression Impairs Estrogen Response and Confers Tamoxifen Resistance
- 2015
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Ingår i: Cancer Research. - : American Association for Cancer Research (AACR). - 0008-5472 .- 1538-7445. ; 75:7, s. 1457-1469
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Tidskriftsartikel (refereegranskat)abstract
- One third of the patients with estrogen receptor alpha (ER alpha)-positive breast cancer who are treated with the antiestrogen tamoxifen will either not respond to initial therapy or will develop drug resistance. Endocrine response involves crosstalk between ER alpha and TGF beta signaling, such that tamoxifen non-responsiveness or resistance in breast cancer might involve aberrant TGF beta signaling. In this study, we analyzed TGF beta receptor type 2 (TGFBR2) expression and correlated it with ER alpha status and phosphorylation in a cohort of 564 patients who had been randomized to tamoxifen or no-adjuvant treatment for invasive breast carcinoma. We also evaluated an additional four independent genetic datasets in invasive breast cancer. In all the cohorts we analyzed, we documented an association of low TGFBR2 protein and mRNA expression with tamoxifen resistance. Functional investigations confirmed that cell cycle or apoptosis responses to estrogen or tamoxifen in ER alpha-positive breast cancer cells were impaired by TGFBR2 silencing, as was ER alpha phosphorylation, tamoxifen-induced transcriptional activation of TGF beta, and upregulation of the multidrug resistance protein ABCG2. Acquisition of low TGFBR2 expression as a contributing factor to endocrine resistance was validated prospectively in a tamoxifen-resistant cell line generated by long-term drug treatment. Collectively, our results established a central contribution of TGF beta signaling in endocrine resistance in breast cancer and offered evidence that TGFBR2 can serve as an independent biomarker to predict treatment outcomes in ER alpha-positive forms of this disease. (C)2015 AACR.
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| 63. |
- Caja, Laia, et al.
(författare)
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Overactivation of the MEK/ERK pathway in liver tumor cells confers resistance to TGF-{beta}-induced cell death through impairing up-regulation of the NADPH oxidase NOX4.
- 2009
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Ingår i: Cancer Research. - 0008-5472 .- 1538-7445. ; 69:19, s. 7595-7602
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Tidskriftsartikel (refereegranskat)abstract
- Transforming growth factor-beta (TGF-beta) induces apoptosis in hepatocytes, being considered a liver tumor suppressor. However, many human hepatocellular carcinoma (HCC) cells escape from its proapoptotic effects, gaining response to this cytokine in terms of malignancy. We have recently reported that the apoptosis induced by TGF-beta in hepatocytes requires up-regulation of the NADPH oxidase NOX4, which mediates reactive oxygen species (ROS) production. TGF-beta-induced NOX4 expression is inhibited by antiapoptotic signals, such as the phosphatydilinositol-3-phosphate kinase or the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathways. The aim of the present work was to analyze whether resistance to TGF-beta-induced apoptosis in HCC cells is related to the impairment of NOX4 up-regulation due to overactivation of survival signals. Results indicate that inhibition of the MAPK/ERK kinase (MEK)/ERK pathway in HepG2 cells, which are refractory to the proapoptotic effects of TGF-beta, sensitizes them to cell death through a mitochondrial-dependent mechanism, coincident with increased levels of BIM and BMF, decreased levels of BCL-XL and MCL1, and BAX/BAK activation. Regulation of BMF, BCL-XL, and MCL1 occurs at the mRNA level, whereas BIM regulation occurs post-transcriptionally. ROS production and glutathione depletion are only observed in cells treated with TGF-beta and PD98059, which correlates with NOX4 up-regulation. Targeting knockdown of NOX4 impairs ROS increase and all the mitochondrial-dependent apoptotic features by a mechanism that is upstream from the regulation of BIM, BMF, BCL-XL, and MCL1 levels. In conclusion, overactivation of the MEK/ERK pathway in liver tumor cells confers resistance to TGF-beta-induced cell death through impairing NOX4 up-regulation, which is required for an efficient mitochondrial-dependent apoptosis.
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| 64. |
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| 65. |
- Cedervall, Jessica, et al.
(författare)
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Neutrophil Extracellular Traps Accumulate in Peripheral Blood Vessels and Compromise Organ Function in Tumor-Bearing Animals
- 2015
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Ingår i: Cancer Research. - 0008-5472 .- 1538-7445. ; 75:13, s. 2653-2662
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Tidskriftsartikel (refereegranskat)abstract
- Cancer produces a variety of collateral effects in patients beyond the malignancy itself, including threats to distal organ functions. However, the basis for such effects, associated with either primary or metastatic tumors, are generally poorly understood. In this study, we show how heart and kidney vascular function is impaired by neutrophils that accumulate in those tissues as a result of tumor formation in two different transgenic mouse models of cancer (RIP1-Tag2 model of insulinoma and MMTV-PyMT model of breast cancer). Neutrophil depletion by systemic administration of an anti-Gr1 antibody improved vascular perfusion and prevented vascular leakage in kidney vessels. We also observed the accumulation of platelet-neutrophil complexes, a signature of neutrophil extracellular traps (NET), in the kidneys of tumor-bearing mice that were completely absent from healthy nontumor-bearing littermates. NET accumulation in the vasculature was associated with upregulation of the proinflammatory adhesion molecules ICAM-1, VCAM-1, and E-selectin, as well as the proinflammatory cytokines IL1 beta, IL6, and the chemokine CXCL1. Administering DNase I to dissolve NETs, which have a high DNA content, restored perfusion in the kidney and heart to levels seen in nontumor-bearing mice, and also prevented vessel leakage in the blood vasculature of these organs. Taken together, our findings strongly suggest that NETs mediate the negative collateral effects of tumors on distal organs, acting to impair vascular function, and to heighten inflammation at these sites.
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| 66. |
- Cedervall, Jessica, et al.
(författare)
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Species-specific in vivo engraftment of the human BL melanoma cell line results in an invasive dedifferentiated phenotype not present in xenografts
- 2009
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Ingår i: Cancer Research. - 0008-5472 .- 1538-7445. ; 69:9, s. 3746-3754
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Tidskriftsartikel (refereegranskat)abstract
- For clinically relevant studies on melanoma progression and invasiveness, in vivo experimental systems with a human cellular microenvironment would be advantageous. We have compared tumor formation from a human cutaneous malignant melanoma cell line (BL), after injection as conventional xenografts in the mouse, or when injected into a predominantly species-specific environment of human embryonic stem cell-derived teratoma induced in the mouse (the hEST model). The resulting melanoma histology was generally analogous, both systems showing delimited densely packed areas with pleomorphic cells of malignant appearance. A specificity of the integration process into the human embryonic teratoma tissues was indicated by the melanoma exclusively being found in areas compatible with condensed mesenchyme, similar to neural crest development. Here, also enhanced neovascularization was seen within the human mesenchymal tissues facing the BL melanoma growth. Furthermore, in the hEST model an additional melanoma cell phenotype occurred, located at the border of, or infiltrating into, the surrounding human loose mesenchymal fibrous stroma. This BL population had a desmoplastic spindle-like appearance, with markers indicative of dedifferentiation and migration. The appearance of this apparently more aggressive phenotype, as well as the induction of human angiogenesis, shows specific interactions with the human embryonic microenvironment in the hEST model. In conclusion, these data provide exciting options for using the hEST model in molecular in vivo studies on differentiation, invasiveness, and malignancy of human melanoma, while analyzing species-specific reactions in vivo.
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| 67. |
- Cedervall, Jessica, et al.
(författare)
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Tumor-Induced NETosis as a Risk Factor for Metastasis and Organ Failure
- 2016
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Ingår i: Cancer Research. - 0008-5472 .- 1538-7445. ; 76:15, s. 4311-4315
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Forskningsöversikt (refereegranskat)abstract
- A large proportion of cancer-related deaths are caused by thrombosis and general organ failure. One example is acute renal failure, a major cause of morbidity and mortality in cancer patients. Surprisingly, however, little is known about the situation in organs that are not targets for metastasis or affected by the primary tumor. Recently, neutrophil extracellular traps (NET) were implicated in tumor-induced effects on distant organs unaffected by the actual tumor cells. Formation of NETs (NETosis) was identified a decade ago as amechanismby which the innate immune system protects us from infections, especially in situations with sepsis. NETs are formed when neutrophils externalize their nuclear DNA together with antimicrobial granule proteins and form a web-like structure that can trap and kill microbes. It is now becoming increasingly clear that NETs also form under noninfectious inflammatory conditions like cancer, thrombosis, autoimmunity, and diabetes and significantly contribute to disease development. The existence of NET-dissolving drugs like heparin and DNase I, already in clinical use, and recent development of specific inhibitors of proteinarginine deiminase 4 (PAD4), an enzyme required for NET formation, should enable clinical targeting of NETosis. Preventing NETosis in cancer could provide a strategy to counteract tumor-induced thrombosis and organ failure as well as to suppress metastasis.
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| 68. |
- Cha, Shih-Ting, et al.
(författare)
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MicroRNA-519c suppresses hypoxia-inducible factor-1alpha expression and tumor angiogenesis.
- 2010
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Ingår i: Cancer Research. - : American Association for Cancer Research. - 0008-5472 .- 1538-7445. ; 70:7, s. 2675-2685
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Tidskriftsartikel (refereegranskat)abstract
- Hypoxia-inducible factor-1alpha (HIF-1alpha) is widely considered to be one of the key regulators of tumor angiogenesis. The upstream regulation is complex and involves several growth factors, cytokines, and hypoxia. Herein, we have identified miR-519c as a hypoxia-independent regulator of HIF-1alpha, acting through direct binding to the HIF-1alpha 3' untranslated region and leading to reduced tumor angiogenesis. Overexpression of miR-519c resulted in a significant decrease of HIF-1alpha protein levels and reduced the tube formation of human umbilical vein endothelial cells; similarly, antagomir inhibition of miR-519c increased the level of HIF-1alpha protein and enhanced angiogenic activity, suggesting an important role of miR-519c in HIF-1alpha-mediated angiogenesis. Consistent with the overexpression of miR-519c in cancer patients with better prognosis, mice injected with miR-519c-overexpressing cells exhibited dramatically reduced HIF-1alpha levels, followed by suppressed tumor angiogenesis, growth, and metastasis. In addition, we found that hepatocyte growth factor (HGF), a known HIF-1alpha inducer, reduced the miR-519c levels through an Akt-dependent pathway. This regulation was posttranscriptional and may be mediated by suppression of miR-519c maturation. Taken together, our findings provide the first evidence that miR-519c is a pivotal regulator of tumor angiogenesis and that microenvironmental HGF contributes to regulating miR-519c biogenesis in cancer cells.
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| 69. |
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| 70. |
- Chan, Norman, et al.
(författare)
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Contextual synthetic lethality of cancer cell kill based on the tumor microenvironment.
- 2010
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Ingår i: Cancer Research. - 0008-5472 .- 1538-7445. ; 70:20, s. 8045-54
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Tidskriftsartikel (refereegranskat)abstract
- Acute and chronic hypoxia exists within the three-dimensional microenvironment of solid tumors and drives therapy resistance, genetic instability, and metastasis. Replicating cells exposed to either severe acute hypoxia (16 hours with 0.02% O(2)) followed by reoxygenation or moderate chronic hypoxia (72 hours with 0.2% O(2)) treatments have decreased homologous recombination (HR) protein expression and function. As HR defects are synthetically lethal with poly(ADP-ribose) polymerase 1 (PARP1) inhibition, we evaluated the sensitivity of repair-defective hypoxic cells to PARP inhibition. Although PARP inhibition itself did not affect HR expression or function, we observed increased clonogenic killing in HR-deficient hypoxic cells following chemical inhibition of PARP1. This effect was partially reversible by RAD51 overexpression. PARP1(-/-) murine embryonic fibroblasts (MEF) showed a proliferative disadvantage under hypoxic gassing when compared with PARP1(+/+) MEFs. PARP-inhibited hypoxic cells accumulated γH2AX and 53BP1 foci as a consequence of altered DNA replication firing during S phase-specific cell killing. In support of this proposed mode of action, PARP inhibitor-treated xenografts displayed increased γH2AX and cleaved caspase-3 expression in RAD51-deficient hypoxic subregions in vivo, which was associated with decreased ex vivo clonogenic survival following experimental radiotherapy. This is the first report of selective cell killing of HR-defective hypoxic cells in vivo as a consequence of microenvironment-mediated "contextual synthetic lethality." As all solid tumors contain aggressive hypoxic cells, this may broaden the clinical utility of PARP and DNA repair inhibition, either alone or in combination with radiotherapy and chemotherapy, even in tumor cells lacking synthetically lethal, genetic mutations.
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