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  1. Article ; Online: The MIC-1/GDF15-GFRAL Pathway in Energy Homeostasis: Implications for Obesity, Cachexia, and Other Associated Diseases.

    Tsai, Vicky W W / Husaini, Yasmin / Sainsbury, Amanda / Brown, David A / Breit, Samuel N

    Cell metabolism

    2018  Volume 28, Issue 3, Page(s) 353–368

    Abstract: MIC-1/GDF15 is a stress response cytokine and a distant member of the transforming growth factor beta (TGFb) superfamily, with no close relatives. It acts via a recently identified receptor called glial-derived neurotrophic factor (GDNF) receptor alpha- ... ...

    Abstract MIC-1/GDF15 is a stress response cytokine and a distant member of the transforming growth factor beta (TGFb) superfamily, with no close relatives. It acts via a recently identified receptor called glial-derived neurotrophic factor (GDNF) receptor alpha-like (GFRAL), which is a distant orphan member of the GDNF receptor family that signals through the tyrosine kinase receptor Ret. MIC-1/GDF15 expression and serum levels rise in response to many stimuli that initiate cell stress and as part of a wide variety of disease processes, most prominently cancer and cardiovascular disease. The best documented actions of MIC-1/GDF15 are on regulation of energy homeostasis. When MIC-1/GDF15 serum levels are substantially elevated in diseases like cancer, it subverts a physiological pathway of appetite regulation to induce an anorexia/cachexia syndrome initiated by its actions on hindbrain neurons. These effects make it a potential target for the treatment of both obesity and anorexia/cachexia syndromes, disorders lacking any highly effective, readily accessible therapies.
    MeSH term(s) Animals ; Anorexia/metabolism ; Cachexia/metabolism ; Cardiovascular Diseases/metabolism ; Diabetes Mellitus/metabolism ; Energy Metabolism/physiology ; Glial Cell Line-Derived Neurotrophic Factor Receptors/metabolism ; Growth Differentiation Factor 15/metabolism ; Homeostasis ; Humans ; Inflammation/metabolism ; Mice ; Mitochondrial Diseases/metabolism ; Neoplasms/metabolism ; Obesity/metabolism ; Rats
    Chemical Substances Glial Cell Line-Derived Neurotrophic Factor Receptors ; Growth Differentiation Factor 15
    Language English
    Publishing date 2018-09-05
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 2176834-1
    ISSN 1932-7420 ; 1550-4131
    ISSN (online) 1932-7420
    ISSN 1550-4131
    DOI 10.1016/j.cmet.2018.07.018
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Growth differentiation factor-15 slows the growth of murine prostate cancer by stimulating tumor immunity.

    Husaini, Yasmin / Tsai, Vicky Wang-Wei / Manandhar, Rakesh / Zhang, Hong Ping / Lee-Ng, Ka Ki Michelle / Lebhar, Hélène / Marquis, Christopher P / Brown, David A / Breit, Samuel N

    PloS one

    2020  Volume 15, Issue 6, Page(s) e0233846

    Abstract: Growth Differentiation Factor-15 (GDF15) is a divergent TGF-beta superfamily cytokine that is overexpressed by most cancers and is induced by anticancer therapy. Transgenic and induced animal models suggest that it protects from cancer development but ... ...

    Abstract Growth Differentiation Factor-15 (GDF15) is a divergent TGF-beta superfamily cytokine that is overexpressed by most cancers and is induced by anticancer therapy. Transgenic and induced animal models suggest that it protects from cancer development but the mechanisms are uncertain. We investigated the role of immunity in GDF15 induced reduction in prostate cancer (PCa) growth. The C57BL/6 transgenic TRAMP prostate cancer prone mice were bred with mice that were immunodeficient and/or systemically overexpressed GDF15. We developed a novel orthotopic TRAMP PCa model in which primary TRAMP tumor cells were implanted into prostates of mice to reduce the study time. These mice were administered recombinant mouse GDF15, antibody to CD8, PD1 or their respective controls. We found that GDF15 induced protection from tumor growth was reversed by lack of adaptive immunity. Flow cytometric evaluation of lymphocytes within these orthotopic tumors showed that GDF15 overexpression was associated with increased CD8 T cell numbers and an increased number and proportion of recently activated CD8+CD11c+ T cells and a reduced proportion of "exhausted" CD8+PD1+ T cells. Further, depletion of CD8 T cells in tumor bearing mice abolished the GDF15 induced protection from tumor growth. Infusion of GDF15 into mice bearing orthotopic TRAMP tumor, substantially reduced tumor growth that was further reduced by concurrent PD1 antibody administration. GDF15 overexpression or recombinant protein protects from TRAMP tumor growth by modulating CD8 T cell mediated antitumor immunity and augments the positive effects of anti-PD1 blockers.
    MeSH term(s) Adaptive Immunity/drug effects ; Animals ; Antineoplastic Agents/therapeutic use ; Female ; Growth Differentiation Factor 15/therapeutic use ; Lymphocyte Count ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Neoplasm Transplantation ; Neoplasms, Experimental ; Prostatic Neoplasms/drug therapy ; Prostatic Neoplasms/immunology
    Chemical Substances Antineoplastic Agents ; Gdf15 protein, mouse ; Growth Differentiation Factor 15
    Language English
    Publishing date 2020-06-05
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 1932-6203
    ISSN (online) 1932-6203
    DOI 10.1371/journal.pone.0233846
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: GDF15 mediates adiposity resistance through actions on GFRAL neurons in the hindbrain AP/NTS.

    Tsai, Vicky Wang-Wei / Zhang, Hong Ping / Manandhar, Rakesh / Schofield, Peter / Christ, Daniel / Lee-Ng, Ka Ki Michelle / Lebhar, Hélène / Marquis, Christopher Peter / Husaini, Yasmin / Brown, David A / Breit, Samuel N

    International journal of obesity (2005)

    2019  Volume 43, Issue 12, Page(s) 2370–2380

    Abstract: Background: Elevated circulating levels of the divergent transforming growth factor-beta (TGFb) family cytokine, growth differentiation factor 15 (GDF15), acting through its CNS receptor, glial-derived neurotrophic factor receptor alpha-like (GFRAL), ... ...

    Abstract Background: Elevated circulating levels of the divergent transforming growth factor-beta (TGFb) family cytokine, growth differentiation factor 15 (GDF15), acting through its CNS receptor, glial-derived neurotrophic factor receptor alpha-like (GFRAL), can cause anorexia and weight loss leading to anorexia/cachexia syndrome of cancer and other diseases. Preclinical studies suggest that administration of drugs based on recombinant GDF15 might be used to treat severe obesity. However, the role of the GDF15-GFRAL pathway in the physiological regulation of body weight and metabolism is unclear. The critical site of action of GFRAL in the CNS has also not been proven beyond doubt. To investigate these two aspects, we have inhibited the actions of GDF15 in mice started on high-fat diet (HFD).
    Methods: The actions of GDF15 were inhibited using two methods: (1) Groups of 8 mice under HFD had their endogenous GDF15 neutralised by monoclonal antibody treatment, (2) Groups of 15 mice received AAV-shRNA to knockdown GFRAL at its hypothesised major sites of action, the hindbrain area postrema (AP) and the nucleus of the solitary tract (NTS). Metabolic measurements were determined during both experiments.
    Conclusions: Treating mice with monoclonal antibody to GDF15 shortly after commencing HFD results in more rapid gain of body weight, adiposity and hepatic lipid deposition than the control groups. This is accompanied by reduced glucose and insulin tolerance and greater expression of pro-inflammatory cytokines in adipose tissue. Localised AP and NTS shRNA-GFRAL knockdown in mice commencing HFD similarly caused an increase in body weight and adiposity. This effect was in proportion to the effectiveness of GFRAL knockdown, indicated by quantitative analysis of hindbrain GFRAL staining. We conclude that the GDF15-GFRAL axis plays an important role in resistance to obesity in HFD-fed mice and that the major site of action of GDF15 in the CNS is GFRAL-expressing neurons in the AP and NTS.
    MeSH term(s) Adiposity/genetics ; Adiposity/physiology ; Animals ; Area Postrema/cytology ; Area Postrema/metabolism ; Area Postrema/physiology ; Body Weight/physiology ; Diet, High-Fat ; Glial Cell Line-Derived Neurotrophic Factor Receptors/genetics ; Glial Cell Line-Derived Neurotrophic Factor Receptors/metabolism ; Growth Differentiation Factor 15/genetics ; Growth Differentiation Factor 15/metabolism ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Neurons/cytology ; Neurons/metabolism ; Neurons/physiology ; Obesity/metabolism ; Rhombencephalon/cytology ; Rhombencephalon/metabolism ; Rhombencephalon/physiology ; Solitary Nucleus/cytology ; Solitary Nucleus/metabolism ; Solitary Nucleus/physiology
    Chemical Substances GDF15 protein, human ; GFRAL protein, mouse ; Gdf15 protein, mouse ; Glial Cell Line-Derived Neurotrophic Factor Receptors ; Growth Differentiation Factor 15
    Language English
    Publishing date 2019-05-31
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 752409-2
    ISSN 1476-5497 ; 0307-0565
    ISSN (online) 1476-5497
    ISSN 0307-0565
    DOI 10.1038/s41366-019-0365-5
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article: Murine CTLL-2 cells respond to mIL12: prospects for developing an alternative bioassay for measurement of murine cytokines IL12 and IL18.

    Khatri, Aparajita / Husaini, Yasmin / Russell, Pamela J

    Journal of immunological methods

    2007  Volume 326, Issue 1-2, Page(s) 41–53

    Abstract: Cell line-based bioassays are becoming increasingly popular for assessment of biological activities of cytokines primarily because these are easy to perform and are not subject to donor variation. A well characterised cell line with world wide ... ...

    Abstract Cell line-based bioassays are becoming increasingly popular for assessment of biological activities of cytokines primarily because these are easy to perform and are not subject to donor variation. A well characterised cell line with world wide availability would further minimise the inter-assay variations. C57BL/6 mice derived T cell line; CTLL-2 fits this criterion. We explored the potential of CTLL-2 cells to develop a bioassay to detection of murine (m) IL12 and mIL18. Both cytokines have shown significant activity against a number of cancers and importantly, act synergistically via mutual upregulation of each other's receptors. The preliminary flow cytometric analyses of immunostained CTLL-2 cells showed that approximately 65% expressed mIL12 and approximately 5% expressed mIL18 receptors suggesting that these may respond to mIL12. As predicted, cells incubated with different doses of mIL12 or mIL18 for 72 h were responsive to mIL12 and not to mIL18. However, when pre-treated with mIL12 for 24 h prior to incubation with mIL18, there was a significant enhancement in response. The sensitivity of the response was comparable to that obtained using the conventional splenocyte-based IFNgamma release assay. The cytokine specificity of the response was proven unequivocally when significant reduction in CTLL-2 response was observed in the presence of the relevant neutralising antibodies. Finally, we could successfully detect lowest doses of approximately 0.1 pg/microL mIL12 or 40 pg/mL of mIL18 in cell supernatants in a cytokine specific manner, which is lower than the resting levels of these cytokines in mouse sera. Again the sensitivity was comparable to that observed in the conventional IFNgamma release assay. Hence, we have demonstrated the potential of CTLL-2-based bioassay to detect biologically active mIL12 and mIL18 in biological samples accurately and reproducibly.
    MeSH term(s) Animals ; Cell Line ; Cell Proliferation ; Colorimetry ; Humans ; Immunologic Tests/methods ; Interleukin-12/analysis ; Interleukin-12/metabolism ; Interleukin-12/physiology ; Interleukin-18/analysis ; Interleukin-18/metabolism ; Lymphocyte Activation/immunology ; Mice ; Mice, Inbred C57BL ; Receptors, Interleukin-12/biosynthesis ; Receptors, Interleukin-12/genetics ; Receptors, Interleukin-18/biosynthesis ; Receptors, Interleukin-18/genetics ; T-Lymphocytes/immunology ; T-Lymphocytes/metabolism ; Tetrazolium Salts/chemistry
    Chemical Substances 2-(4-iodophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium ; Interleukin-18 ; Receptors, Interleukin-12 ; Receptors, Interleukin-18 ; Tetrazolium Salts ; Interleukin-12 (187348-17-0)
    Language English
    Publishing date 2007-09-30
    Publishing country Netherlands
    Document type Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S. ; Validation Studies
    ZDB-ID 120142-6
    ISSN 1872-7905 ; 0022-1759
    ISSN (online) 1872-7905
    ISSN 0022-1759
    DOI 10.1016/j.jim.2007.07.002
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  5. Article ; Online: Macrophage inhibitory cytokine-1 (MIC-1/GDF15) gene deletion promotes cancer growth in TRAMP prostate cancer prone mice.

    Husaini, Yasmin / Lockwood, Glen P / Nguyen, Trung V / Tsai, Vicky Wang-Wei / Mohammad, Mohammad G / Russell, Pamela J / Brown, David A / Breit, Samuel N

    PloS one

    2015  Volume 10, Issue 2, Page(s) e0115189

    Abstract: The divergent TGF-β superfamily member, macrophage inhibitory cytokine-1 (MIC-1/GDF15), is overexpressed by most cancers, including prostate cancer (PCa). Whilst its circulating levels are linked to cancer outcome, the role MIC-1/GDF15 plays in cancer ... ...

    Abstract The divergent TGF-β superfamily member, macrophage inhibitory cytokine-1 (MIC-1/GDF15), is overexpressed by most cancers, including prostate cancer (PCa). Whilst its circulating levels are linked to cancer outcome, the role MIC-1/GDF15 plays in cancer development and progression is incompletely understood. To investigate its effect on PCa development and spread, we have used TRAMP prostate cancer prone mice bearing a germline deletion of MIC-1/GDF15 (TRAMPMIC-/-). On average TRAMPMIC-/- mice died about 5 weeks earlier and had larger prostatic tumors compared with TRAMP mice that were wild type for MIC-1/GDF15 (TRAMPMIC+/+). Additionally, at the time of death or ethical end point, even when adjusted for lifespan, there were no significant differences in the number of mice with metastases between the TRAMPMIC+/+ and TRAMPMIC-/- groups. However, consistent with our previous data, more than twice as many TRAMP mice overexpressing MIC-1/GDF15 (TRAMPfmsmic-1) had metastases than TRAMPMIC+/+ mice (p<0.0001). We conclude that germ line gene deletion of MIC-1/GDF15 leads to increased local tumor growth resulting in decreased survival consistent with an overall protective role for MIC-1/GDF15 in early primary tumor development. However, in advancing disease, as we have previously noted, MIC-1/GDF15 overexpression may promote local invasion and metastatic spread.
    MeSH term(s) Animals ; Gene Deletion ; Growth Differentiation Factor 15/deficiency ; Growth Differentiation Factor 15/genetics ; Growth Differentiation Factor 15/metabolism ; Male ; Mice ; Mice, Transgenic ; Prostatic Neoplasms/genetics ; Prostatic Neoplasms/metabolism ; Prostatic Neoplasms/pathology
    Chemical Substances Growth Differentiation Factor 15
    Language English
    Publishing date 2015
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 1932-6203
    ISSN (online) 1932-6203
    DOI 10.1371/journal.pone.0115189
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  6. Article: CLIC1 regulates dendritic cell antigen processing and presentation by modulating phagosome acidification and proteolysis.

    Salao, Kanin / Jiang, Lele / Li, Hui / Tsai, Vicky W-W / Husaini, Yasmin / Curmi, Paul M G / Brown, Louise J / Brown, David A / Breit, Samuel N

    Biology open

    2016  Volume 5, Issue 5, Page(s) 620–630

    Abstract: Intracellular chloride channel protein 1 (CLIC1) participates in inflammatory processes by regulating macrophage phagosomal functions such as pH and proteolysis. Here, we sought to determine if CLIC1 can regulate adaptive immunity by actions on dendritic ...

    Abstract Intracellular chloride channel protein 1 (CLIC1) participates in inflammatory processes by regulating macrophage phagosomal functions such as pH and proteolysis. Here, we sought to determine if CLIC1 can regulate adaptive immunity by actions on dendritic cells (DCs), the key professional antigen presenting cells. To do this, we first generated bone marrow-derived DCs (BMDCs) from germline CLIC1 gene-deleted (CLIC1(-/-)) and wild-type (CLIC1(+/+)) mice, then studied them in vitro and in vivo We found phagocytosis triggered cytoplasmic CLIC1 translocation to the phagosomal membrane where it regulated phagosomal pH and proteolysis. Phagosomes from CLIC1(-/-) BMDCs displayed impaired acidification and proteolysis, which could be reproduced if CLIC1(+/+), but not CLIC1(-/-) cells, were treated with IAA94, a CLIC family ion channel blocker. CLIC1(-/-) BMDC displayed reduced in vitro antigen processing and presentation of full-length myelin oligodendrocyte glycoprotein (MOG) and reduced MOG-induced experimental autoimmune encephalomyelitis. These data suggest that CLIC1 regulates DC phagosomal pH to ensure optimal processing of antigen for presentation to antigen-specific T-cells. Further, they indicate that CLIC1 is a novel therapeutic target to help reduce the adaptive immune response in autoimmune diseases.
    Language English
    Publishing date 2016-05-15
    Publishing country England
    Document type Journal Article
    ZDB-ID 2632264-X
    ISSN 2046-6390
    ISSN 2046-6390
    DOI 10.1242/bio.018119
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  7. Article: Cytosine deaminase-uracil phosphoribosyltransferase and interleukin (IL)-12 and IL-18: a multimodal anticancer interface marked by specific modulation in serum cytokines.

    Khatri, Aparajita / Husaini, Yasmin / Ow, Kim / Chapman, Jane / Russell, Pamela J

    Clinical cancer research : an official journal of the American Association for Cancer Research

    2009  Volume 15, Issue 7, Page(s) 2323–2334

    Abstract: Purpose: To test the effects of a new combination, cytosine deaminase (CD) + uracil phosphoribosyltransferase (UPRT)-mediated gene-directed enzyme prodrug therapy (GDEPT) with interleukin (IL)-12 and IL-18, on (a) growth of murine prostate and remote ... ...

    Abstract Purpose: To test the effects of a new combination, cytosine deaminase (CD) + uracil phosphoribosyltransferase (UPRT)-mediated gene-directed enzyme prodrug therapy (GDEPT) with interleukin (IL)-12 and IL-18, on (a) growth of murine prostate and remote tumor deposits, (b) mouse survival, and (c) T helper (Th) 1/Th2 serum cytokine balance with a special focus to assess correlation with tumor burden/survival.
    Experimental design: Efficacy of intraprostatic administration of adenovirally delivered murine IL-12 and IL-18 against orthotopic RM1 tumors and lung pseudometastases was assessed in C57BL/6 mice. At necropsy, tumor growth, lung colony counts, effects on immune cell infiltration, vasculature, apoptosis, and proliferation were estimated. Next, CDUPRT-GDEPT + cytokines were tested at suboptimal doses in mice with RM1CDUPRT prostate tumors/RM1 lung deposits and analyzed as above. Effects on mouse survival were also assessed. Host immune responses to different treatments were assessed by monitoring 11 serum cytokines using Luminex technology.
    Results: Our data show that IL-12 and IL-18, when combined with CDUPRT-GDEPT, caused significant reduction in local RM1 tumors and lung colonies with enhanced long-term survival versus individual treatments. A dramatic enhancement of tumor infiltration by a wider repertoire of immune cells and disruption of vasculature implied the combination to be more immunostimulatory and antiangiogenic. Remarkably, lowering of serum IL-4 and monocyte chemoattractant protein-1 (MCP-1) was consistently associated with lower tumor burden (local and systemic), and this, rather than an increase in Th1 cytokines, better predicted treatment efficacy. In addition, mouse survival correlated with substantially higher cytokine (Th1/Th2) levels after treatment.
    Conclusion: Locoregional application of CDUPRT-GDEPT and IL-12/IL-18 was effective against local and systemic prostate cancer and improved survival. Monitoring serum levels of IL-4 and MCP-1 may accurately reflect tumor burden and, hence, host response to therapy.
    MeSH term(s) Animals ; Apoptosis ; Cell Line, Tumor ; Cell Proliferation ; Combined Modality Therapy ; Cytokines/blood ; Cytosine Deaminase/genetics ; Flucytosine/therapeutic use ; Interleukin-12/genetics ; Interleukin-18/genetics ; Lung Neoplasms/secondary ; Lymphocytes, Tumor-Infiltrating/immunology ; Male ; Mice ; Mice, Inbred C57BL ; Pentosyltransferases/genetics ; Prodrugs/therapeutic use ; Prostatic Neoplasms/immunology ; Prostatic Neoplasms/pathology ; Prostatic Neoplasms/therapy ; Survival Analysis ; Th2 Cells/immunology
    Chemical Substances Cytokines ; Interleukin-18 ; Prodrugs ; Interleukin-12 (187348-17-0) ; Flucytosine (D83282DT06) ; Pentosyltransferases (EC 2.4.2.-) ; uracil phosphoribosyltransferase (EC 2.4.2.9) ; Cytosine Deaminase (EC 3.5.4.1)
    Language English
    Publishing date 2009-04-01
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 1225457-5
    ISSN 1557-3265 ; 1078-0432
    ISSN (online) 1557-3265
    ISSN 1078-0432
    DOI 10.1158/1078-0432.CCR-08-2039
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    Zs.A 4223: Show issues Location:
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  8. Article ; Online: The anorectic actions of the TGFβ cytokine MIC-1/GDF15 require an intact brainstem area postrema and nucleus of the solitary tract.

    Tsai, Vicky Wang-Wei / Manandhar, Rakesh / Jørgensen, Sebastian Beck / Lee-Ng, Ka Ki Michelle / Zhang, Hong Ping / Marquis, Christopher Peter / Jiang, Lele / Husaini, Yasmin / Lin, Shu / Sainsbury, Amanda / Sawchenko, Paul E / Brown, David A / Breit, Samuel N

    PloS one

    2014  Volume 9, Issue 6, Page(s) e100370

    Abstract: Macrophage inhibitory cytokine-1 (MIC-1/GDF15) modulates food intake and body weight under physiological and pathological conditions by acting on the hypothalamus and brainstem. When overexpressed in disease, such as in advanced cancer, elevated serum ... ...

    Abstract Macrophage inhibitory cytokine-1 (MIC-1/GDF15) modulates food intake and body weight under physiological and pathological conditions by acting on the hypothalamus and brainstem. When overexpressed in disease, such as in advanced cancer, elevated serum MIC-1/GDF15 levels lead to an anorexia/cachexia syndrome. To gain a better understanding of its actions in the brainstem we studied MIC-1/GDF15 induced neuronal activation identified by induction of Fos protein. Intraperitoneal injection of human MIC-1/GDF15 in mice activated brainstem neurons in the area postrema (AP) and the medial (m) portion of the nucleus of the solitary tract (NTS), which did not stain with tyrosine hydroxylase (TH). To determine the importance of these brainstem nuclei in the anorexigenic effect of MIC-1/GDF15, we ablated the AP alone or the AP and the NTS. The latter combined lesion completely reversed the anorexigenic effects of MIC-1/GDF15. Altogether, this study identified neurons in the AP and/or NTS, as being critical for the regulation of food intake and body weight by MIC-1/GDF15.
    MeSH term(s) Animals ; Anorexia/chemically induced ; Appetite Depressants/administration & dosage ; Appetite Depressants/pharmacology ; Area Postrema/drug effects ; Area Postrema/physiology ; Growth Differentiation Factor 15/administration & dosage ; Growth Differentiation Factor 15/pharmacology ; Infusions, Intraventricular ; Male ; Mice ; Neurons/drug effects ; Neurons/metabolism ; Proto-Oncogene Proteins c-fos/metabolism ; Solitary Nucleus/drug effects ; Solitary Nucleus/physiology ; Tyrosine 3-Monooxygenase/metabolism ; Weight Loss/drug effects
    Chemical Substances Appetite Depressants ; Growth Differentiation Factor 15 ; Proto-Oncogene Proteins c-fos ; Tyrosine 3-Monooxygenase (EC 1.14.16.2)
    Language English
    Publishing date 2014-06-27
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ISSN 1932-6203
    ISSN (online) 1932-6203
    DOI 10.1371/journal.pone.0100370
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  9. Article ; Online: Macrophage inhibitory cytokine-1 (MIC-1/GDF15) slows cancer development but increases metastases in TRAMP prostate cancer prone mice.

    Husaini, Yasmin / Qiu, Min Ru / Lockwood, Glen P / Luo, Xu Wei / Shang, Ping / Kuffner, Tamara / Tsai, Vicky Wang-Wei / Jiang, Lele / Russell, Pamela J / Brown, David A / Breit, Samuel N

    PloS one

    2012  Volume 7, Issue 8, Page(s) e43833

    Abstract: Macrophage inhibitory cytokine-1 (MIC-1/GDF15), a divergent member of the TGF-β superfamily, is over-expressed by many common cancers including those of the prostate (PCa) and its expression is linked to cancer outcome. We have evaluated the effect of ... ...

    Abstract Macrophage inhibitory cytokine-1 (MIC-1/GDF15), a divergent member of the TGF-β superfamily, is over-expressed by many common cancers including those of the prostate (PCa) and its expression is linked to cancer outcome. We have evaluated the effect of MIC-1/GDF15 overexpression on PCa development and spread in the TRAMP transgenic model of spontaneous prostate cancer. TRAMP mice were crossed with MIC-1/GDF15 overexpressing mice (MIC-1(fms)) to produce syngeneic TRAMP(fmsmic-1) mice. Survival rate, prostate tumor size, histopathological grades and extent of distant organ metastases were compared. Metastasis of TC1-T5, an androgen independent TRAMP cell line that lacks MIC-1/GDF15 expression, was compared by injecting intravenously into MIC-1(fms) and syngeneic C57BL/6 mice. Whilst TRAMP(fmsmic-1) survived on average 7.4 weeks longer, had significantly smaller genitourinary (GU) tumors and lower PCa histopathological grades than TRAMP mice, more of these mice developed distant organ metastases. Additionally, a higher number of TC1-T5 lung tumor colonies were observed in MIC-1(fms) mice than syngeneic WT C57BL/6 mice. Our studies strongly suggest that MIC-1/GDF15 has complex actions on tumor behavior: it limits local tumor growth but may with advancing disease, promote metastases. As MIC-1/GDF15 is induced by all cancer treatments and metastasis is the major cause of cancer treatment failure and cancer deaths, these results, if applicable to humans, may have a direct impact on patient care.
    MeSH term(s) Animals ; Cell Line, Tumor ; Cell Proliferation ; Disease Susceptibility ; Female ; Growth Differentiation Factor 15/genetics ; Growth Differentiation Factor 15/metabolism ; Male ; Mice ; Mice, Transgenic ; Neoplasm Grading ; Neoplasm Metastasis ; Prostatic Neoplasms/genetics ; Prostatic Neoplasms/pathology ; Receptors, Tumor Necrosis Factor, Member 25/genetics ; Survival Analysis
    Chemical Substances Gdf15 protein, mouse ; Growth Differentiation Factor 15 ; Receptors, Tumor Necrosis Factor, Member 25 ; Tnfrsf25 protein, mouse
    Language English
    Publishing date 2012-08-27
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 1932-6203
    ISSN (online) 1932-6203
    DOI 10.1371/journal.pone.0043833
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article ; Online: Anorexia/cachexia of chronic diseases: a role for the TGF-β family cytokine MIC-1/GDF15.

    Tsai, Vicky W W / Husaini, Yasmin / Manandhar, Rakesh / Lee-Ng, K K Michelle / Zhang, Hong Ping / Harriott, Kate / Jiang, Lele / Lin, Shu / Sainsbury, Amanda / Brown, David A / Breit, Samuel N

    Journal of cachexia, sarcopenia and muscle

    2012  Volume 3, Issue 4, Page(s) 239–243

    Abstract: Anorexia/cachexia is a common and currently mostly untreatable complication of advanced cancer. It is also a feature of a number of chronic diseases and can also occur as part of the normal ageing process. Over recent years, two different, but sometimes ... ...

    Abstract Anorexia/cachexia is a common and currently mostly untreatable complication of advanced cancer. It is also a feature of a number of chronic diseases and can also occur as part of the normal ageing process. Over recent years, two different, but sometimes overlapping, processes have been identified to mediate anorexia/cachexia: those that act primarily on muscle reducing its mass and function, and processes that decrease nutrition leading to loss of both fat and muscle. In the case of at least some cancers, the latter process is sometimes driven by marked overexpression of macrophage inhibitory cytokine-1/growth differentiation factor 15 (MIC-1/GDF15). MIC-1/GDF15 is a transforming growth factor beta (TGF-β) family cytokine that is found in the serum of all normal individuals at an average concentration of about 0.6 ng/ml. Its increased expression in both cancers and other diseases can result in 10-100-fold or more elevation of its serum levels. In experimental animals, serum MIC-1/GDF15 levels at the lower end of this range induce anorexia by direct actions of the circulating cytokine on feeding centres in the brain. Mice with tumours overexpressing MIC-1/GDF15 display decreased food intake, loss of lean and fat mass and cachexia. That this process also mediates anorexia/cachexia in humans is suggested by the fact that there is a direct correlation between the degree of serum MIC-1/GDF15 elevation and the amount of cancer-related weight loss, the first such relationship demonstrated. Further, in experimental animals, weight loss can be reversed by neutralisation of tumour-produced MIC-1/GDF15 with a specific monoclonal antibody, suggesting the possibility of effective therapy of patients with the devastating complication of anorexia/cachexia.
    Language English
    Publishing date 2012-08-31
    Publishing country Germany
    Document type Journal Article
    ZDB-ID 2586864-0
    ISSN 2190-6009 ; 2190-5991
    ISSN (online) 2190-6009
    ISSN 2190-5991
    DOI 10.1007/s13539-012-0082-6
    Database MEDical Literature Analysis and Retrieval System OnLINE

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