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  • American Association for Cancer Research (AACR)  (6)
  • 1
    Online Resource
    Online Resource
    Mouse Models of Pediatric Supratentorial High-grade Glioma Reveal How Cell-of-Origin Influences Tumor Development and Phenotype
    American Association for Cancer Research (AACR) ; 2017
    In:  Cancer Research Vol. 77, No. 3 ( 2017-02-01), p. 802-812
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 3 ( 2017-02-01), p. 802-812
    Abstract: High-grade glioma (HGG) is a group of primary malignant brain tumors with dismal prognosis. Whereas adult HGG has been studied extensively, childhood HGG, a relatively rare disease, is less well-characterized. Here, we present two novel platelet-derived growth factor (PDGF)-driven mouse models of pediatric supratentorial HGG. Tumors developed from two different cells of origin reminiscent of neural stem cells (NSC) or oligodendrocyte precursor cells (OPC). Cross-species transcriptomics showed that both models are closely related to human pediatric HGG as compared with adult HGG. Furthermore, an NSC-like cell-of-origin enhanced tumor incidence, malignancy, and the ability of mouse glioma cells (GC) to be cultured under stem cell conditions as compared with an OPC-like cell. Functional analyses of cultured GC from these tumors showed that cells of NSC-like origin were more tumorigenic, had a higher rate of self-renewal and proliferation, and were more sensitive to a panel of cancer drugs compared with GC of a more differentiated origin. These two mouse models relevant to human pediatric supratentorial HGG propose an important role of the cell-of-origin for clinicopathologic features of this disease. Cancer Res; 77(3); 802–12. ©2016 AACR.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-16-2482
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
    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
    Somatic Ephrin Receptor Mutations Are Associated with Metastasis in Primary Colorectal Cancer
    American Association for Cancer Research (AACR) ; 2017
    In:  Cancer Research Vol. 77, No. 7 ( 2017-04-01), p. 1730-1740
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 7 ( 2017-04-01), p. 1730-1740
    Abstract: The contribution of somatic mutations to metastasis of colorectal cancers is currently unknown. To find mutations involved in the colorectal cancer metastatic process, we performed deep mutational analysis of 676 genes in 107 stages II to IV primary colorectal cancer, of which half had metastasized. The mutation prevalence in the ephrin (EPH) family of tyrosine kinase receptors was 10-fold higher in primary tumors of metastatic colorectal than in nonmetastatic cases and preferentially occurred in stage III and IV tumors. Mutational analyses in situ confirmed expression of mutant EPH receptors. To enable functional studies of EPHB1 mutations, we demonstrated that DLD-1 colorectal cancer cells expressing EPHB1 form aggregates upon coculture with ephrin B1 expressing cells. When mutations in the fibronectin type III and kinase domains of EPHB1 were compared with wild-type EPHB1 in DLD-1 colorectal cancer cells, they decreased ephrin B1–induced compartmentalization. These observations provide a mechanistic link between EPHB receptor mutations and metastasis in colorectal cancer. Cancer Res; 77(7); 1730–40. ©2017 AACR.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-16-1921
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 3
    Online Resource
    Online Resource
    Prospective Study of Human Papillomavirus (HPV) Types, HPV Persistence, and Risk of Squamous Cell Carcinoma of the Cervix
    American Association for Cancer Research (AACR) ; 2010
    In:  Cancer Epidemiology, Biomarkers & Prevention Vol. 19, No. 10 ( 2010-10-01), p. 2469-2478
    Details
    In: Cancer Epidemiology, Biomarkers & Prevention, American Association for Cancer Research (AACR), Vol. 19, No. 10 ( 2010-10-01), p. 2469-2478
    Abstract: Background: The link between squamous cell cervical carcinoma and human papillomavirus (HPV) 16/18 is well established, but the magnitude of the risk association is uncertain and the importance of other high-risk HPV (HRHPV) types is unclear. Methods: In two prospective nested case-control series among women participating in cytologic screening in Sweden, we collected 2,772 cervical smears from 515 women with cancer in situ (CIS), 315 with invasive squamous cell carcinoma (SCC), and individually matched controls. All smears were tested for HPV with PCR assays, and the median follow-up until diagnosis was 5 to 7 years. Conditional logistic regression was used to estimate relative risks (RR) and 95% confidence intervals (95% CI). Results: The presence of HPV16/18 in the first smear was associated with 8.5-fold (95% CI, 5.3-13.7) and 18.6-fold (95% CI, 9.0-38.9) increased risks of CIS and SCC, respectively, compared with women negative for HPV. Infection with other HRHPV types in the first smear was also associated with significantly increased risks for both CIS and SCC. Persistence of HPV16 infection conferred a RR of 18.5 (95% CI, 6.5-52.9) for CIS and 19.5 (95% CI, 4.7-81.7) for SCC. The HPV16/18 attributable risk proportion was estimated at 30% to 50% for CIS, and 41% to 47% for SCC. Other HRHPV types also conferred significant proportions. Conclusions: Our large population-based study provides quantification of risks for different HPV types and prospective evidence that non-16/18 HRHPV types increase the risk for future cervical cancer. Impact: This study gives further insights into cervical cancer risk stratification with implications for HPV-based prevention strategies. Cancer Epidemiol Biomarkers Prev; 19(10); 2469–78. ©2010 AACR.
    Type of Medium: Online Resource
    ISSN: 1055-9965 , 1538-7755
    URL: Article
    DOI: 10.1158/1055-9965.EPI-10-0424
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2010
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    detail.hit.zdb_id: 1153420-5
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  • 4
    Online Resource
    Online Resource
    Abstract 2473: Combined BET-bromodomain and CDK2 inhibition in MYC-driven medulloblastoma
    American Association for Cancer Research (AACR) ; 2016
    In:  Cancer Research Vol. 76, No. 14_Supplement ( 2016-07-15), p. 2473-2473
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 14_Supplement ( 2016-07-15), p. 2473-2473
    Abstract: Misexpression of MYC genes (MYC and MYCN) occurs commonly in medulloblastoma (MB), the most frequent malignant childhood brain tumor. We previously showed that tumors are addicted to MYCN and that MYCN stabilization is required for MB development in mice (Swartling et al, Genes & Dev, 2010; Cancer Cell, 2012). Targeted MYCN suppression completely depleted MYCN-driven MB cells in vivo. Immediate transcriptional changes from such MYCN blockade were found by RNA-Seq and showed similarities to changes that occurred after CDK2 suppression or when inhibiting BET bromodomains. CDK2 and BET inhibitors both inhibited MYC protein expression and effectively induced cell cycle arrest or apoptosis. Compared with either agent alone a sustained combination treatment over 7-10 days displayed synergy and effectively abolished tumor cell proliferation in vitro. The combined treatment further reduced tumor growth in orthotopical MB transplants and significantly prolonged survival as compared to single agent therapy. Our data suggest that dual inhibition of CDK2 and BET Bromodomains could be a novel treatment approach in suppressing medulloblastoma by targeting MYC proteins. Citation Format: Sara Bolin, Anna Borgenvik, Camilla Persson, Gabriela Rosén, Anders Sundström, Jun Qi, James E. Bradner, William A. Weiss, Yoon-Jae Cho, Holger Weishaupt, Fredrik J. Swartling. Combined BET-bromodomain and CDK2 inhibition in MYC-driven medulloblastoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2473.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2016-2473
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
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    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 5
    Online Resource
    Online Resource
    Dormant SOX9-Positive Cells Facilitate MYC-Driven Recurrence of Medulloblastoma
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Research Vol. 82, No. 24 ( 2022-12-16), p. 4586-4603
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 24 ( 2022-12-16), p. 4586-4603
    Abstract: Relapse is the leading cause of death in patients with medulloblastoma, the most common malignant pediatric brain tumor. A better understanding of the mechanisms underlying recurrence could lead to more effective therapies for targeting tumor relapses. Here, we observed that SOX9, a transcription factor and stem cell/glial fate marker, is limited to rare, quiescent cells in high-risk medulloblastoma with MYC amplification. In paired primary-recurrent patient samples, SOX9-positive cells accumulated in medulloblastoma relapses. SOX9 expression anti-correlated with MYC expression in murine and human medulloblastoma cells. However, SOX9-positive cells were plastic and could give rise to a MYC high state. To follow relapse at the single-cell level, an inducible dual Tet model of medulloblastoma was developed, in which MYC expression was redirected in vivo from treatment-sensitive bulk cells to dormant SOX9-positive cells using doxycycline treatment. SOX9 was essential for relapse initiation and depended on suppression of MYC activity to promote therapy resistance, epithelial–mesenchymal transition, and immune escape. p53 and DNA repair pathways were downregulated in recurrent tumors, whereas MGMT was upregulated. Recurrent tumor cells were found to be sensitive to treatment with an MGMT inhibitor and doxorubicin. These findings suggest that recurrence-specific targeting coupled with DNA repair inhibition comprises a potential therapeutic strategy in patients affected by medulloblastoma relapse. Significance: SOX9 facilitates therapy escape and recurrence in medulloblastoma via temporal inhibition of MYC/MYCN genes, revealing a strategy to specifically target SOX9-positive cells to prevent tumor relapse.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-22-2108
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 6
    Online Resource
    Online Resource
    SOX9 Defines Distinct Populations of Cells in SHH Medulloblastoma but Is Not Required for Math1-Driven Tumor Formation
    American Association for Cancer Research (AACR) ; 2021
    In:  Molecular Cancer Research Vol. 19, No. 11 ( 2021-11-01), p. 1831-1839
    Details
    In: Molecular Cancer Research, American Association for Cancer Research (AACR), Vol. 19, No. 11 ( 2021-11-01), p. 1831-1839
    Abstract: Medulloblastoma is the most common malignant pediatric brain tumor and there is an urgent need for molecularly targeted and subgroup-specific therapies. The stem cell factor SOX9, has been proposed as a potential therapeutic target for the treatment of Sonic Hedgehog medulloblastoma (SHH-MB) subgroup tumors, given its role as a downstream target of Hedgehog signaling and in functionally promoting SHH-MB metastasis and treatment resistance. However, the functional requirement for SOX9 in the genesis of medulloblastoma remains to be determined. Here we report a previously undocumented level of SOX9 expression exclusively in proliferating granule cell precursors (GCP) of the postnatal mouse cerebellum, which function as the medulloblastoma-initiating cells of SHH-MBs. Wild-type GCPs express comparatively lower levels of SOX9 than neural stem cells and mature astroglia and SOX9low GCP-like tumor cells constitute the bulk of both infant (Math1Cre:Ptch1lox/lox) and adult (Ptch1LacZ/+) SHH-MB mouse models. Human medulloblastoma single-cell RNA data analyses reveal three distinct SOX9 populations present in SHH-MB and noticeably absent in other medulloblastoma subgroups: SOX9+MATH1+ (GCP), SOX9+GFAP+ (astrocytes) and SOX9+MATH1+GFAP+ (potential tumor-derived astrocytes). To functionally address whether SOX9 is required as a downstream effector of Hedgehog signaling in medulloblastoma tumor cells, we ablated Sox9 using a Math1Cre model system. Surprisingly, targeted ablation of Sox9 in GCPs (Math1Cre:Sox9lox/lox) revealed no overt phenotype and loss of Sox9 in SHH-MB (Math1Cre:Ptch1lox/lox;Sox9lox/lox) does not affect tumor formation. Implications: Despite preclinical data indicating SOX9 plays a key role in SHH-MB biology, our data argue against SOX9 as a viable therapeutic target.
    Type of Medium: Online Resource
    ISSN: 1541-7786 , 1557-3125
    URL: Article
    DOI: 10.1158/1541-7786.MCR-21-0117
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
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    SSG: 12
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