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.