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  • American Association for Cancer Research (AACR)  (3)
  • 1
    Online Resource
    Online Resource
    Abstract 5518: Bi-allelic loss of CDKN2A initiates melanoma invasion and metastasis via E2F1-BRN2 axis
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Research Vol. 78, No. 13_Supplement ( 2018-07-01), p. 5518-5518
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 13_Supplement ( 2018-07-01), p. 5518-5518
    Abstract: CDKN2A acts as a critical tumor suppressor in melanoma, as evidenced by frequent loss of function mutations and deletion. Loss of CDKN2A is believed to permit escape from senescent pre-neoplastic cell populations through relieve of a cell cycle block mediated by its two gene products. We performed a comprehensive analysis of CDKN2A gene status, mRNA and protein expression levels of p16 and p14 in a cohort of melanomas and their adjacent pre-neoplastic lesions and observed that bi-allelic CDKN2A loss coincides with the progression stage when primary melanomas become invasive. In melanoma lines, p16INK4A, one of the protein products of the CDKN2A locus, is a potent barrier to metastasis, independent of its known role inhibiting cell proliferation. We genetically engineered primary human melanocytes to harbor CDKN2A deletions and/or BRAF V600E mutation at their endogenous BRAF locus. Using this physiologic model for the early phases of neoplastic transformation, we found no evidence for BRAF-induced senescence, rather observing that p16INK4A loss activates a master regulator of melanoma invasion, BRN2, through Rb-E2F1 pathway. These results demonstrate that one of the most frequently altered genes across human cancers, CDKN2A, has an unexpected novel role in inhibiting cellular invasion through lineage specific transcription factors and acts as an essential gatekeeper of early metastatic dissemination. Citation Format: Hanlin Zeng, Aparna Jorapur, A. Hunter Shain, Ursula E. Lang, Rodrigo Torres, Yuntian Zhang, Thomas Botton, Jue Lin, Andrew S. Mcneal, Matthew Donne, Ingmar N. Bastian, Jeffrey North, Laura Pincus, Richard Yu, Beth S. Ruben, Nancy Joseph, Iwei Ye, Boris C. Bastian, Robert L. Judson. Bi-allelic loss of CDKN2A initiates melanoma invasion and metastasis via E2F1-BRN2 axis [abstract] . In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5518.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2018-5518
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 2
    Online Resource
    Online Resource
    Phosphatidylinositol 3-Kinase in the G Protein-Coupled Receptor–Induced Chemokinesis and Chemotaxis of MDA-MB-468 Breast Carcinoma Cells: A Comparison with Leukocytes
    American Association for Cancer Research (AACR) ; 2006
    In:  Molecular Cancer Research Vol. 4, No. 6 ( 2006-06-01), p. 411-421
    Details
    In: Molecular Cancer Research, American Association for Cancer Research (AACR), Vol. 4, No. 6 ( 2006-06-01), p. 411-421
    Abstract: The polarization of tumor cells and leukocytes into a front end and a rear end is a crucial prerequisite for their autonomous, directed movement. Phosphatidylinositol 3-kinase (PI3K) is assumed to play an important role in this polarization process, whereas the results obtained with different cell types and different migration assays widely vary. Thus, we conducted a comparative study on the role of the PI3K in the locomotor activity and directionality of the migration of tumor cells on the example of MDA-MB-468 breast carcinoma cells in comparison with CTLs and neutrophil granulocytes. We used our well-established, collagen-based, three-dimensional migration assay for the investigation of the chemokinesis and chemotaxis of these cells. Our results show that the role of the PI3K in the regulation of migratory activity is distinct between the investigated cell types: the migration of CTLs and MDA-MB-468 cells was impaired by the inhibition of the PI3K with wortmannin, whereas neutrophil granulocytes were only slightly affected. However, neither cell type was impaired in the ability to respond chemotactically to gradients of ligands to G protein-coupled receptors. Thus, the PI3K contributes to the regulation of migratory activity but not to the directionality of migration of MDA-MB-468 breast carcinoma cells. As a further conclusion with regard to cancer treatment, the PI3K is not a suitable target for the inhibition of metastasis formation, because the migration of leukocytes is also affected, which leads to a dysfunction of the immune defense. (Mol Cancer Res 2006;4(6):411–21)
    Type of Medium: Online Resource
    ISSN: 1541-7786 , 1557-3125
    URL: Article
    DOI: 10.1158/1541-7786.MCR-06-0030
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2006
    detail.hit.zdb_id: 2097884-4
    SSG: 12
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  • 3
    Online Resource
    Online Resource
    Effects of Adjuvant Chemoradiotherapy on the Frequency and Function of Regulatory T Cells in Patients with Head and Neck Cancer
    American Association for Cancer Research (AACR) ; 2013
    In:  Clinical Cancer Research Vol. 19, No. 23 ( 2013-12-01), p. 6585-6596
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 19, No. 23 ( 2013-12-01), p. 6585-6596
    Abstract: Purpose: Regulatory T cells (Treg) accumulate in tumor tissues and the peripheral blood of cancer patients and may persist after therapies. This cross-sectional study examines effects of adjuvant chemoradiotherapy (CRT) on Treg numbers and function in head and neck squamous cell carcinoma (HNSCC) patients. Experimental Design: The frequency and absolute numbers of CD4+, ATP-hydrolyzing CD4+CD39+ and CD8+ T cells, and expression levels of CD39, CD25, TGF-β–associated LAP and GARP on Treg were measured by flow cytometry in 40 healthy donors (NC) and 71 HNSCC patients [29 untreated with active disease (AD); 22 treated with surgery; 20 treated with CRT] . All treated subjects had no evident disease (NED) at the time of phlebotomy. In an additional cohort of 40 subjects with AD (n = 15), NED (n = 10), and NC (n = 15), in vitro sensitivity of CD4+ T-cell subsets to cisplatin and activation-induced cell death (AICD) was tested in Annexin V–binding assays. Results: CRT decreased the frequency of circulating CD4+ T cells (P & lt; 0.002) but increased that of CD4+CD39+ Treg (P ≤ 0.001) compared with untreated or surgery-only patients. Treg frequency remained elevated for & gt;3 years. CRT increased surface expression of LAP, GARP, and CD39 on Treg. In vitro Treg were resistant to AICD or cisplatin but conventional CD4+ T cells (Tconv) were not. CRT-induced Treg from AD or NC subjects upregulated prosurvival proteins whereas Tconv upregulated proapoptotic Bax. Conclusions: Highly suppressive, cisplatin-resistant Treg increase in frequency and persist after CRT and could be responsible for suppression of antitumor immune responses and recurrence in HNSCC. Clin Cancer Res; 19(23); 6585–96. ©2013 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-13-0900
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
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    detail.hit.zdb_id: 2036787-9
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