Erythropoietin biology in cancer: A role in apoptosis and angiogenesis.

摘要

Nearly 70% of cancer patients become anemic at some point during their disease. One treatment strategy involves systemic administration of recombinant erythropoietin, which increases hematocrit and hemoglobin levels and improves quality of life. However, two recent clinical trials have questioned the use of erythropoietin in this setting, demonstrating negative treatment outcomes in cancer patients receiving erythropoietin therapy.;In this study, we attempt to determine the effects, if any, of systemic erythropoietin on tumor progression, apoptosis, and response to chemotherapy, as well as establish erythropoietin as a modulator of early tumor growth and angiogenesis and a potential target for antiangiogenic therapy. We demonstrate in preclinical animal models that systemic recombinant erythropoietin does not affect tumor growth in a variety of tumor types. Further, systemic administration of erythropoietin does not affect the tumor angiogenic response in an orthotopic model of breast cancer. In vitro, we demonstrate that erythropoietin can act as a cytoprotectant; Epo signaling through the PI3K/Akt pathway inhibits both serum starvationinduced and taxol-induced apoptosis. However, when combined with two different dosing schedules of taxol in vivo, systemic erythropoietin had no effect on tumor cell apoptosis, proliferation, and tumor growth delay. To further investigate the role of autocrine/paracrine Epo signaling in tumors, we used two strategies to increase Epo signaling (local administration of rEpo and a stably-transfected tumor cell line expressing a mutant EpoR (R129C) that is constitutively active) and two strategies to block Epo signaling (local administration of sEpoR and (alpha-Epo mAb) and a stably-transfected tumor cell line expressing a mutant Epo (R103A) that is an Epo antagonist). Activation of EpoR significantly promoted early tumor angiogenesis and tumor growth above controls, while blockade of Epo signaling inhibited tumor angiogenesis and almost completely abolished tumor growth in window chamber and xenograft models.;These data demonstrate that while systemic Epo therapy remains a safe treatment option for malignancy-related anemia, an autocrine/paracrine Epo loop may exist in certain tumor types and can contribute to tumor angiogenesis and growth. Specific targeting of this system may represent an additional antiangiogenic strategy.