SwePub
Sök i SwePub databas

  Utökad sökning

Träfflista för sökning "L773:1538 7445 ;lar1:(gu)"

Sökning: L773:1538 7445 > Göteborgs universitet

  • Resultat 1-10 av 15
Sortera/gruppera träfflistan
   
NumreringReferensOmslagsbildHitta
1.
  • Besse, Lenka, et al. (författare)
  • Treatment with HIV-protease inhibitor nelfinavir identifies membrane lipid composition and fluidity as a therapeutic target in advanced multiple myeloma
  • 2021
  • Ingår i: Cancer Research. - 0008-5472 .- 1538-7445. ; 81, s. 4581-4593
  • Tidskriftsartikel (refereegranskat)abstract
    • The HIV-protease inhibitor nelfinavir has shown broad anticancer activity in various preclinical and clinical contexts.In patients with advanced, proteasome inhibitor (PI)-refractory multiple myeloma, nelfinavir-based therapy resulted in 65% partial response or better, suggesting that this may be a highly active chemotherapeutic option in this setting.The broad anticancer mechanism of action of nelfinavir implies that it interferes with fundamental aspects of cancer cell biology.We combined proteome-wide affinity-purification of nelfinavir-interacting proteins with genome-wide CRISPR/Cas9-based screening to identify protein partners that interact with nelfinavir in an activity-dependent manner alongside candidate genetic contributors affecting nelfinavir cytotoxicity.Nelfinavir had multiple activity-specific binding partners embedded in lipid bilayers of mitochondria and the endoplasmic reticulum.Nelfinavir affected the fluidity and composition of lipid-rich membranes, disrupted mitochondrial respiration, blocked vesicular transport, and affected the function of membrane-embedded drug efflux transporter ABCB1, triggering the integrated stress response.Sensitivity to nelfinavir was dependent on ADIPOR2, which maintains membrane fluidity by promoting fatty acid desaturation and incorporation into phospholipids.Supplementation with fatty acids prevented the nelfinavir-induced effect on mitochondrial metabolism, drug-efflux transporters, and stress-response activation.Conversely, depletion of fatty acids/cholesterol pools by the FDAapproved drug ezetimibe showed a synergistic anticancer activity with nelfinavir in vitro.These results identify the modification of lipid-rich membranes by nelfinavir as a novel mechanism of action to achieve broad anticancer activity, which may be suitable for the treatment of PI-refractory multiple myeloma.
  •  
2.
  • Brodin, G, et al. (författare)
  • Increased smad expression and activation are associated with apoptosis in normal and malignant prostate after castration.
  • 1999
  • Ingår i: Cancer research. - : American Association for Cancer Research. - 0008-5472 .- 1538-7445. ; 59:11, s. 2731-8
  • Tidskriftsartikel (refereegranskat)abstract
    • Transforming growth factor (TGF)-beta1 is induced in the prostate after castration and has been implicated in apoptosis of epithelial cells during involution. TGF-beta1-mediated receptor activation induces phosphorylation of Smad2 and Smad3, which form complexes with Smad4, that translocate to the nucleus to regulate transcription of target genes. Smad6 and Smad7 antagonize the action of signal-transducing Smads. We have examined the immunohistochemical expression of different Smad molecules in the epithelium of rat ventral prostate before and after castration, in androgen-sensitive Dunning R3327 PAP prostatic tumor cells from untreated and castrated rats, and after treatment with estrogen. In the ventral prostate, a significant increase of phosphorylated Smad2 (P-Smad2) was observed after castration. In prostatic tumor cells we observed an increased expression of Smad2 and P-Smad2 after treatment. The levels of Smad3 and, in particular, Smad4 were enhanced in the normal ventral prostate, as well as in the tumors after castration. Interestingly, Smad6 and Smad7 expression was also up-regulated in cells with increased Smad2 activation. The staining for Smad2, P-Smad2, Smad3, Smad4, and Smad7 was nuclear in some cells and was present in areas with a large number of apoptotic cells identified by various morphological criteria, formation of apoptotic bodies and, in adjacent sections, by terminal deoxynucleotidyl transferase-mediated nick end labeling assay. Our results suggest that the signal transduction pathway for TGF-beta, leading to apoptosis, is activated in the normal prostate after castration and in the tumor model after castration, without or with estrogen treatment.
  •  
3.
  • Busch, Susann, et al. (författare)
  • Loss of TGF beta Receptor Type 2 Expression Impairs Estrogen Response and Confers Tamoxifen Resistance
  • 2015
  • Ingår i: Cancer Research. - : American Association for Cancer Research (AACR). - 0008-5472 .- 1538-7445. ; 75:7, s. 1457-1469
  • 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.
  •  
4.
  • Donia, M., et al. (författare)
  • Acquired Immune Resistance Follows Complete Tumor Regression without Loss of Target Antigens or IFN gamma Signaling
  • 2017
  • Ingår i: Cancer Research. - : American Association for Cancer Research (AACR). - 0008-5472 .- 1538-7445. ; 77:17, s. 4562-4566
  • Tidskriftsartikel (refereegranskat)abstract
    • Cancer immunotherapy can result in durable tumor regressions in some patients. However, patients who initially respond often experience tumor progression. Here, we report mechanistic evidence of tumoral immune escape in an exemplary clinical case: a patient with metastatic melanoma who developed disease recurrence following an initial, unequivocal radiologic complete regression after T-cell-based immunotherapy. Functional cytotoxic T-cell responses, including responses to one mutant neoantigen, were amplified effectively with therapy and generated durable immunologic memory. However, these immune responses, including apparently effective surveillance of the tumor mutanome, did not prevent recurrence. Alterations of the MHC class I antigen-processing and presentation machinery (APM) in resistant cancer cells, but not antigen loss or impaired IFN gamma signaling, led to impaired recognition by tumor-specific CD8(+) T cells. Our results suggest that future immunotherapy combinations should take into account targeting cancer cells with intact and impaired MHC class I-related APM. Loss of target antigens or impaired IFN gamma signaling does not appear to be mandatory for tumor relapse after a complete radiologic regression. Personalized studies to uncover mechanisms leading to disease recurrence within each individual patient are warranted.
  •  
5.
  • Furuhashi, Masao, et al. (författare)
  • Platelet-derived growth factor production by B16 melanoma cells leads to increased pericyte abundance in tumors and an associated increase in tumor growth rate
  • 2004
  • Ingår i: Cancer Research. - : American Association for Cancer Research (AACR). - 0008-5472 .- 1538-7445. ; 64:8, s. 2725-2733
  • Tidskriftsartikel (refereegranskat)abstract
    • Platelet-derived growth factor (PDGF) receptor signaling participates in different processes in solid tumors, including autocrine stimulation of tumor cell growth, recruitment of tumor stroma fibroblasts, and stimulation of tumor angiogenesis. In the present study, the B16 mouse melanoma tumor model was used to investigate the functional consequences of paracrine PDGF stimulation of host-derived cells. Production of PDGF-BB or PDGF-DD by tumor cells was associated with an increased tumor growth rate. Characterization of tumors revealed an increase in pericyte abundance in tumors derived from B16 cells producing PDGF-BB or PDGF-DD. The increased tumor growth rate associated with PDGF-DD production was not seen in mice expressing an attenuated PDGF beta-receptor and was thus dependent on host PDGF beta-receptor signaling. The increased pericyte abundance was not associated with an increased tumor vessel density. However, tumor cell apoptosis, but not proliferation, was reduced in tumors displaying PDGF-induced increased pericyte coverage. Our findings thus demonstrate that paracrine PDGF production stimulates pericyte recruitment to tumor vessels and suggest that pericyte abundance influences tumor cell apoptosis and tumor growth.
  •  
6.
  • Gerlee, Philip, 1980 (författare)
  • The Model Muddle: In Search of Tumor Growth Laws
  • 2013
  • Ingår i: Cancer Research. - : American Association for Cancer Research (AACR). - 0008-5472 .- 1538-7445. ; 73:8, s. 2407-2411
  • Tidskriftsartikel (refereegranskat)abstract
    • In this article, we will trace the historical development of tumor growth laws, which in a quantitative fashion describe the increase in tumor mass/volume over time. These models are usually formulated in terms of differential equations that relate the growth rate of the tumor to its current state and range from the simple one-parameter exponential growth model to more advanced models that contain a large number of parameters. Understanding the assumptions and consequences of such models is important, as they often underpin more complex models of tumor growth. The conclusion of this brief survey is that although much improvement has occurred over the last century, more effort and new models are required if we are to understand the intricacies of tumor growth.
  •  
7.
  • Harrison, Hannah, et al. (författare)
  • Contrasting hypoxic effects on breast cancer stem cell hierarchy is dependent on ERα status.
  • 2013
  • Ingår i: Cancer research. - 1538-7445. ; 73:4, s. 1420-33
  • Tidskriftsartikel (refereegranskat)abstract
    • Tumor hypoxia is often linked to decreased survival in breast cancer patients and current therapeutic strategies aim to target the hypoxic response. One way in which this is done is by blocking hypoxia induced angiogenesis. Anti-angiogenic therapies show some therapeutic potential with increased disease free survival but these initial promising results are short lived and followed by tumor progression. We hypothesized that this may be due to altered cancer stem cell (CSC) activity resulting from increased tumor hypoxia. We studied the effects of hypoxia on CSC activity, using in vitro mammosphere and holoclone assays as well as in vivo limiting dilution experiments, in 13 patient-derived samples and 4 cell lines. There was a HIF1-alpha-dependent CSC increase in ER-alpha-positive cancers following hypoxic exposure which was blocked by inhibition of estrogen and Notch signaling. A contrasting decrease in CSC was seen in ER-alpha-negative cancers. We next developed a xenograft model of cell lines and patient-derived samples to assess the hypoxic-CSC response. Varying sizes of xenografts were collected and analyzed for HIF1-alpha expression and CSC. The same ER-alpha-dependent contrasting hypoxic-CSC response was seen validating the initial observation. These data suggest that ER-alpha-positive and negative breast cancer sub-types respond differently to hypoxia and, as a consequence, anti-angiogenic therapies will not be suitable for both subgroups.
  •  
8.
  • Martinsson, Tommy, 1956, et al. (författare)
  • Appearance of the novel activating F1174S ALK mutation in neuroblastoma correlates with aggressive tumor progression and unresponsiveness to therapy.
  • 2011
  • Ingår i: Cancer research. - : American Association for Cancer Research. - 1538-7445 .- 0008-5472. ; 71:1, s. 98-105
  • Tidskriftsartikel (refereegranskat)abstract
    • Mutations in the kinase domain of the ALK kinase have emerged recently as important players in the genetics of the childhood tumor neuroblastoma. Here, we report the appearance of a novel ALK mutation in neuroblastoma, correlating with aggressive tumor behavior. Analyses of genomic DNA from biopsy samples initially showed ALK sequence to be wild type. However, during disease progression, mutation of amino acid F1174 to a serine within the ALK kinase domain was observed, which correlated with aggressive neuroblastoma progression in the patient. We show that mutation of F1174 to serine generates a potent gain-of-function mutant, as observed in 2 independent systems. First, PC12 cell lines expressing ALK(F1174S) display ligand-independent activation of ALK and further downstream signaling activation. Second, analysis of ALK(F1174S) in Drosophila models confirms that the mutation mediates a strong, rough eye phenotype upon expression in the developing eye. Thus, we report a novel ALK(F1174S) mutation that displays ligand-independent activity in vivo, correlating with rapid and treatment-resistant tumor growth. The study also shows that initial screening in the first tumor biopsy of a patient may not be sufficient and that further molecular analysis, in particular in tumor progression and/or tumor relapse, is warranted for better understanding of the treatment of neuroblastoma patients.
  •  
9.
  •  
10.
  • Mitra, Sanhita, et al. (författare)
  • Subcellular distribution of p53 by the p53-responsive lncRNA NBAT1 determines chemotherapeutic response in neuroblastoma.
  • 2021
  • Ingår i: Cancer research. - 1538-7445. ; 81:6, s. 1457-1471
  • Tidskriftsartikel (refereegranskat)abstract
    • Neuroblastoma has a low mutation rate for the p53 gene. Alternative ways of p53 inactivation have been proposed in neuroblastoma, such as abnormal cytoplasmic accumulation of wild-type p53. However, mechanisms leading to p53 inactivation via cytoplasmic accumulation are not well investigated. Here we show that the neuroblastoma risk-associated locus 6p22.3-derived tumor suppressor NBAT1 is a p53-responsive lncRNA that regulates p53 subcellular levels. Low expression of NBAT1 provided resistance to genotoxic drugs by promoting p53 accumulation in cytoplasm and loss from mitochondrial and nuclear compartments. Depletion of NBAT1 altered CRM1 function and contributed to the loss of p53-dependent nuclear gene expression during genotoxic drug treatment. CRM1 inhibition rescued p53-dependent nuclear functions and sensitized NBAT1-depleted cells to genotoxic drugs. Combined inhibition of CRM1 and MDM2 was even more effective in sensitizing aggressive neuroblastoma cells with p53 cytoplasmic accumulation. Thus, our mechanistic studies uncover an NBAT1-dependent CRM1/MDM2-based potential combination therapy for high-risk neuroblastoma patients.
  •  
Skapa referenser, mejla, bekava och länka
  • Resultat 1-10 av 15
Typ av publikation
tidskriftsartikel (15)
Typ av innehåll
refereegranskat (15)
Författare/redaktör
Landberg, Göran (2)
Kogner, Per (2)
Carlsson, Peter, 195 ... (2)
Micke, Patrick (2)
Carén, Helena, 1979 (1)
Fernö, Mårten (1)
visa fler...
Bendahl, Pär Ola (1)
Schmidt, H. (1)
Ludwig, Heinz (1)
Hansson, Magnus (1)
Jönsson, Per (1)
Sacerdote, Carlotta (1)
Heuchel, Rainer (1)
Martinsson, Tommy, 1 ... (1)
Abrahamsson, Jonas, ... (1)
Abramsson, Alexandra ... (1)
Helou, Khalil, 1966 (1)
Kogevinas, Manolis (1)
Gago Dominguez, Manu ... (1)
Steineck, Gunnar, 19 ... (1)
Borén, Jan, 1963 (1)
Heldin, Carl-Henrik (1)
Jonsson, G (1)
Bishop, D Timothy (1)
Joshi, Amit D. (1)
Stern, Mariana C. (1)
Vineis, Paolo (1)
Jirström, Karin (1)
Taylor, Jack A. (1)
Garcia-Closas, Monts ... (1)
Olofsson Bagge, Roge ... (1)
Teneberg, Susann, 19 ... (1)
Fletcher, Tony (1)
Li, Hong (1)
Matullo, Giuseppe (1)
Kanduri, Chandrasekh ... (1)
Martner, Anna, 1979 (1)
Funa, Keiko, 1949 (1)
Ståhlman, Marcus, 19 ... (1)
Bhadury, Joydeep (1)
Johansson, Leif (1)
Chanock, Stephen (1)
Demir, Dagsu, 1992 (1)
Sjöblom, Tobias (1)
Jachimowicz, Daniel (1)
Kosalai, Subazini Th ... (1)
Subhash, Santhilal, ... (1)
Mondal, Tanmoy, 1981 (1)
Östman, Arne (1)
Allione, Alessandra (1)
visa färre...
Lärosäte
Karolinska Institutet (3)
Uppsala universitet (2)
Lunds universitet (2)
Chalmers tekniska högskola (1)
Språk
Engelska (15)
Forskningsämne (UKÄ/SCB)
Medicin och hälsovetenskap (15)
Naturvetenskap (1)

År

Kungliga biblioteket hanterar dina personuppgifter i enlighet med EU:s dataskyddsförordning (2018), GDPR. Läs mer om hur det funkar här.
Så här hanterar KB dina uppgifter vid användning av denna tjänst.

 
pil uppåt Stäng

Kopiera och spara länken för att återkomma till aktuell vy