Iron- and erythropoietin-resistant anemia in a spontaneous breast cancer mouse model
Nuria Fabregas Bregolat,
Maja Ruetten,
Milene Costa da Silva,
Mostafa A. Aboouf,
Hyrije Ademi,
Nadine von Büren,
Julia Armbruster,
Martina Stirn,
Sandro Altamura,
Oriana Marques,
Josep M. Monné Rodriguez,
Victor J. Samillan,
Rashim Pal Singh,
Ben Wielockx,
Martina U. Muckenthaler,
Max Gassmann,
Markus Thiersch
Affiliations
Nuria Fabregas Bregolat
Institute of Veterinary Physiology, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland; Center for Clinical Studies, Vetsuisse Faculty, University of Zurich, Zurich
Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, Heidelberg
Mostafa A. Aboouf
Institute of Veterinary Physiology, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland; Center for Clinical Studies, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland; Departement of Biochemistry, Faculty of Pharmacy, Ain Shams University, Cairo
Hyrije Ademi
Institute of Veterinary Physiology, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland; Center for Clinical Studies, Vetsuisse Faculty, University of Zurich, Zurich
Nadine von Büren
Institute of Veterinary Physiology, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland; Center for Clinical Studies, Vetsuisse Faculty, University of Zurich, Zurich
Julia Armbruster
Institute of Veterinary Physiology, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland; Center for Clinical Studies, Vetsuisse Faculty, University of Zurich, Zurich
Martina Stirn
Clinical Laboratory, Department of Clinical Diagnostics and Services, Vetsuisse Faculty, University of Zurich, Zurich
Sandro Altamura
Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, Heidelberg, Germany; Molecular Medicine Partnership Unit, Heidelberg
Oriana Marques
Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, Heidelberg, Germany; Molecular Medicine Partnership Unit, Heidelberg
Josep M. Monné Rodriguez
Laboratory for Animal Model Pathology, Institute of Veterinary Pathology, Vetsuisse Faculty, University of Zurich, Zurich
Victor J. Samillan
Universidad Le Cordon Bleu, School of Human Nutrition, Lima
Rashim Pal Singh
Institute of Clinical Chemistry and Laboratory Medicine, Carl Gustav Carus, TU Dresden
Ben Wielockx
Institute of Clinical Chemistry and Laboratory Medicine, Carl Gustav Carus, TU Dresden
Martina U. Muckenthaler
Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, Heidelberg, Germany; 7Molecular Medicine Partnership Unit, Heidelberg, Germany; Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), University of Heidelberg, Germany; German Centre for Cardiovascular Research, Partner Site
Max Gassmann
Institute of Veterinary Physiology, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland; Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich
Markus Thiersch
Institute of Veterinary Physiology, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland; Center for Clinical Studies, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland; Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich
Anemia of cancer (AoC) with its multifactorial etiology and complex pathology is a poor prognostic indicator for cancer patients. One of the main causes of AoC is cancer-associated inflammation that activates mechanisms, commonly observed in anemia of inflammation, whereby functional iron deficiency and iron-restricted erythropoiesis are induced by increased hepcidin levels in response to raised levels of interleukin-6. So far only a few AoC mouse models have been described, and most of them did not fully recapitulate the interplay of anemia, increased hepcidin levels and functional iron deficiency in human patients. To test if the selection and the complexity of AoC mouse models dictates the pathology or if AoC in mice per se develops independently of iron deficiency, we characterized AoC in Trp53floxWapCre mice that spontaneously develop breast cancer. These mice developed AoC associated with high levels of interleukin-6 and iron deficiency. However, hepcidin levels were not increased and hypoferremia coincided with anemia rather than causing it. Instead, an early shift in the commitment of common myeloid progenitors from the erythroid to the myeloid lineage resulted in increased myelopoiesis and in the excessive production of neutrophils that accumulate in necrotic tumor regions. This process could not be prevented by either iron or erythropoietin treatment. Trp53floxWapCre mice are the first mouse model in which erythropoietin-resistant anemia is described and may serve as a disease model to test therapeutic approaches for a subpopulation of human cancer patients with normal or corrected iron levels who do not respond to erythropoietin.
