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@PHDTHESIS{Erdem:764823,
      author       = {Erdem, Merve},
      othercontributors = {Cramer, Thorsten and van Dongen, Joost Thomas and
                          Marquardt, Till},
      title        = {{C}onditional gene targeting of {H}if1a reveals an
                      unexpected protective role of myeloid cells in liver cancer
                      cachexia},
      school       = {RWTH Aachen University},
      type         = {Dissertation},
      address      = {Aachen},
      reportid     = {RWTH-2019-07041},
      pages        = {1 Online-Ressource (XI, 129 Seiten) : Illustrationen,
                      Diagramme},
      year         = {2019},
      note         = {Veröffentlicht auf dem Publikationsserver der RWTH Aachen
                      University; Dissertation, RWTH Aachen University, 2019},
      abstract     = {Cachexia is a wasting syndrome affecting $30-80\%$ of
                      cancer patients and represents a central obstacle in medical
                      oncology as it is associated with poor therapy response and
                      reduced overall survival. Cachexia is a hallmark in the
                      context of solid tumors and especially prevalent in
                      gastrointestinal cancers. While murine models for cancer
                      cachexia in the context of pancreas and colon cancer are
                      well established, no common mouse model exists for liver
                      cancer (hepatocellular carcinoma (HCC))-associated cachexia.
                      Here, the ASV-B mouse, a transgenic murine HCC model, is
                      introduced as a means to study cancer cachexia. During HCC
                      development, ASV-B mice showed robust cachexia as evidenced
                      by the loss of fat and lean mass. In addition, these mice
                      showed elevated inflammatory markers in blood, increased fat
                      mobilization and browning of adipose tissue, all hallmarks
                      of cancer cachexia. Next, the molecular mechanisms
                      underlying HCC cachexia were characterized. The
                      transcription factor hypoxia inducible factor 1-alpha
                      (HIF-1α) is centrally involved in the control of
                      pro-tumorigenic as well as pro-inflammatory pathways. Given
                      the well-established importance of inflammation in cachexia,
                      the functional significance of HIF-1α was investigated in
                      ASV-B mice lacking Hif1a gene expression specifically in
                      tumor or myeloid cells by the Cre-loxP system. Cachexia
                      development was not affected by deleting Hif1a in tumor
                      cells. Rather unexpected, myeloid cell-specific Hif1a loss
                      aggravated cachexia as evidenced by enhanced body fat loss,
                      despite reduced expression of pro-inflammatory cytokines in
                      the serum of HCC-bearing mice. Furthermore, myeloid
                      cell-specific Hif1a deficiency was associated with decreased
                      macrophage infiltration and macrophage proliferation in
                      adipose tissue compared to wild-type mice, suggesting a role
                      for local macrophages in the regulation of cancer-induced
                      fat loss. Taken together, myeloid cell-mediated inflammation
                      displays a rather unexpected beneficial function against
                      cancer-induced tissue wasting in a murine HCC model, adding
                      a further layer of complexity to the pathogenesis of
                      cachexia. Computed tomography-based analyses of HCC patients
                      revealed that $34\%$ of subjects displayed reduced visceral
                      fat mass as part of the cancer cachexia phenotype, nicely
                      complementing the murine phenotype identified in this
                      study.},
      cin          = {163720 / 160000 / 533501-2},
      ddc          = {570},
      cid          = {$I:(DE-82)163720_20140620$ / $I:(DE-82)160000_20140620$ /
                      $I:(DE-82)533501-2_20150520$},
      typ          = {PUB:(DE-HGF)11},
      doi          = {10.18154/RWTH-2019-07041},
      url          = {https://publications.rwth-aachen.de/record/764823},
}