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  • American Association for Cancer Research (AACR)  (4)
  • 1
    Online Resource
    Online Resource
    Abstract A11: Targeting vascular endothelial growth factor in myeloid cells enhances natural killer cell responses to chemotherapy and ameliorates cachexia
    American Association for Cancer Research (AACR) ; 2016
    In:  Cancer Research Vol. 76, No. 15_Supplement ( 2016-08-01), p. A11-A11
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 15_Supplement ( 2016-08-01), p. A11-A11
    Abstract: Chemotherapy remains a mainstay of cancer treatment but its use is often limited by the development of adverse reactions. Severe involuntary loss of body weight (cachexia) is a frequent cause of death in cancer patients and is exacerbated by chemotherapy. We show that, in contrast to antibody-mediated neutralization of Vascular Endothelial Growth Factor (VEGF)-A, genetic inactivation of VEGF-A in tumor-associated myeloid cells prevents chemotherapy-induced cachexia by inhibiting skeletal muscle loss and the lipolysis of white adipose tissue. It also improves clearance of senescent tumor cells by natural killer cells and inhibits tumor regrowth after chemotherapy. The effects depend on the adipokine and chemoattractant chemerin, which is released by the tumur endothelium in response to chemotherapy. The findings define chemerin as a critical mediator of the immune response elicited by chemotherapy as well as an important inhibitor of cancer cachexia. Efficient targeting of VEGF signaling within the tumor microenvironment should impede weight loss that is frequently associated with chemotherapy, thereby dramatically improving the therapeutic outcome. Citation Format: Magali Castells, Ralph Klose, Dagmar Gotthardt, Eva-Maria Putz, Ewelina Krzywinska, Chahrazade Kantari-Mimoun, Naima Chikdene, Anna-Katharina Meinecke, Katrin Schroedter, Iris Helfrich, Joachim Fandrey, Veronika Sexl, Christian Stockmann. Targeting vascular endothelial growth factor in myeloid cells enhances natural killer cell responses to chemotherapy and ameliorates cachexia. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr A11.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.TME16-A11
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
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  • 2
    Online Resource
    Online Resource
    Abstract A10: The hypoxic response in natural killer cells: Linking cytoxicity and tumor immune surveillance to angiogenesis
    American Association for Cancer Research (AACR) ; 2016
    In:  Cancer Research Vol. 76, No. 15_Supplement ( 2016-08-01), p. A10-A10
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 15_Supplement ( 2016-08-01), p. A10-A10
    Abstract: Hypoxia-inducible transcription factors (HIFs) are central mediators of cellular adaptation to low oxygen and play a pivotal role in inflammatory responses. Natural Killer (NK) cells, unifying characteristics of innate and adaptive immunity, are cytotoxic innate lymphoid cells with a unique ability to instantly recognize and kill “aberrant” cancer cells while sparing “normal” cells. Owing to these tumoricidal features, NK cells are able to restrict primary tumor growth and limit metastatic spread. By genetic targeting HIFs in NK cells HIFs, we define a crucial role of HIF-1 in NK cell function and cancer immune surveillance. We show that NK cells preferentially infiltrate into hypoxic zones of solid primary tumors and that HIF-1-deficiency in NK cells slows impairs primary tumor growth as well as distant metastasis. This is due to reduced susceptibility of HIF-1-deficient NK cells to tumor cell-derived inhibitory stimuli, resulting in improved recognition and killing of tumor cells. Furthermore, we define the hypoxic response in NK cells as a critical mediator of tumor angiogenesis. Paradoxically, HIF-1-deficiency in NK cells results in decreased expression of various angiostatic factors within the tumor microenvironment, resulting in unproductive tumor angiogenesis, characterized by immature, non-functional vessel and severe tumor hypoxia. This suggests that the hypoxic response in NK cells slows down overall tumor angiogenesis in order to allow for vessel formation in a more coordinated fashion. In summary, we define HIF-1 as a critical mediator of NK cell effector function and cancer immune surveillance. Secondly, we show that HIF-1 in NK cells acts as a negative regulator of tumor angiogenesis that ensures the fine-tuning of the angiogenic response. These results indicate that exploiting the hypoxic response in NK cells may represent a novel therapeutic avenue. Citation Format: Ewelina Krzywinska, Chahrazade Kantari-Mimoun, Magali Castells, Dagmar Gotthardt, Yann Kerdiles, Ralph Klose, Joachim Fandrey, Veronika Sexl, Christian Stockmann. The hypoxic response in natural killer cells: Linking cytoxicity and tumor immune surveillance to angiogenesis. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr A10.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.TME16-A10
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
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  • 3
    Online Resource
    Online Resource
    Clinical Predictors and Algorithm for the Genetic Diagnosis of Pheochromocytoma Patients
    American Association for Cancer Research (AACR) ; 2009
    In:  Clinical Cancer Research Vol. 15, No. 20 ( 2009-10-15), p. 6378-6385
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 15, No. 20 ( 2009-10-15), p. 6378-6385
    Abstract: Purpose: Six pheochromocytoma susceptibility genes causing distinct syndromes have been identified; approximately one of three of all pheochromocytoma patients carry a predisposing germline mutation. When four major genes (VHL, RET, SDHB, SDHD) are analyzed in a clinical laboratory, costs are ∼$3,400 per patient. The aim of the study is to systematically obtain a robust algorithm to identify who should be genetically tested, and to determine the order in which genes should be tested. Experimental Design: DNA from 989 apparently nonsyndromic patients were scanned for germline mutations in the genes VHL, RET, SDHB, SDHC, and SDHD. Clinical parameters were analyzed as potential predictors for finding mutations by multiple logistic regression, validated by bootstrapping. Cost reduction was calculated between prioritized gene testing compared with that for all genes. Results: Of 989 apparently nonsyndromic pheochromocytoma cases, 187 (19%) harbored germline mutations. Predictors for presence of mutation are age & lt;45 years, multiple pheochromocytoma, extra-adrenal location, and previous head and neck paraganglioma. If we used the presence of any one predictor as indicative of proceeding with gene testing, then 342 (34.6%) patients would be excluded, and only 8 carriers (4.3%) would be missed. We were also able to statistically model the priority of genes to be tested given certain clinical features. E.g., for patients with prior head and neck paraganglioma, the priority would be SDHD & gt;SDHB & gt;RET & gt;VHL. Using the clinical predictor algorithm to prioritize gene testing and order, a 44.7% cost reduction in diagnostic process can be achieved. Conclusions: Clinical parameters can predict for mutation carriers and help prioritize gene testing to reduce costs in nonsyndromic pheochromocytoma presentations. (Clin Cancer Res 2009;15(20):6378–85)
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-09-1237
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2009
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
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  • 4
    Online Resource
    Online Resource
    Anti–Tumor Necrosis Factor Therapy Inhibits Pancreatic Tumor Growth and Metastasis
    American Association for Cancer Research (AACR) ; 2008
    In:  Cancer Research Vol. 68, No. 5 ( 2008-03-01), p. 1443-1450
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 68, No. 5 ( 2008-03-01), p. 1443-1450
    Abstract: Chronic inflammation has been implicated in the pathogenesis of many severe autoimmune disorders, as well as in diabetes, pulmonary diseases, and cancer. Inflammation accompanies most solid cancers including pancreatic ductal adenocarcinoma (PDAC), one of the most fatal cancers with surgery being the only curative therapeutic approach currently available. In the present work, we investigated the role of the major proinflammatory cytokine tumor necrosis factor α (TNFα) in the malignancy of PDAC cells in vitro and in vivo. In vitro, TNFα strongly increased invasiveness of Colo357, BxPc3, and PancTuI cells and showed only moderate antiproliferative effect. TNFα treatment of mice bearing orthotopically growing PDAC tumors led to dramatically enhanced tumor growth and metastasis. Notably, we found that PDAC cells themselves secrete TNFα. Although inhibition of TNFα with infliximab or etanercept only marginally affected proliferation and invasiveness of PDAC cells in vitro, both reagents exerted strong antitumoral effects in vivo. In severe combined immunodeficient mice with orthotopically growing Colo357, BxPc3, or PancTuI tumors, human-specific anti-TNF antibody infliximab reduced tumor growth and metastasis by about 30% and 50%, respectively. Importantly, in a PDAC resection model performed with PancTuI cells, we found an even stronger therapeutic effect for both anti-TNF compounds. Infliximab and etanercept reduced the number of liver metastases by 69% and 42%, respectively, as well as volumes of recurrent tumors by 73% and 51%. Thus, tumor cell–derived TNFα plays a profound role in malignancy of PDAC, and inhibition of TNFα represents a promising therapeutic option particularly in adjuvant therapy after subtotal pancreatectomy. [Cancer Res 2008;68(5):1443–50]
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-07-5704
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2008
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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