Major finding: Tumor-derived PDGF-BB induces stromal EPO to drive tumor growth and angiogenesis.
Mechanism: EPO stimulates tumor angiogenesis and extramedullary hematopoiesis.
Impact: Elevated EPO levels may confer resistance to antiangiogenic therapies.
Cytokines can stimulate neovascularization by recruiting stromal cells to newly formed blood vessels. Tumor cells can co-opt this process through deregulated cytokine signaling to stromal cells, the recruitment of which supports the tumor vasculature and promotes an angiogenic phenotype. Xue and colleagues analyzed the role of one such cytokine, platelet-derived growth factor-BB (PDGF-BB, a dimer of PDGF-B), to promote angiogenesis, growth, and stromal expansion by overexpressing PDGF-BB in xenografted cancer cells. PDGF-BB–expressing tumors grew at a significantly faster rate and exhibited a significantly higher degree of stromal infiltration and microvessel density. Surprisingly, increased blood cell precursor proliferation was specifically observed in the spleens and livers of mice with PDGF-BB–expressing tumors, which also exhibited increased concentrations of erythropoietin (EPO), a hormone normally produced primarily in the kidney that stimulates erythropoiesis. The authors used an EPO reporter gene construct and specific PDGF receptor (PDGFR) inhibitors to demonstrate that PDGF-BB activates EPO transcription in stromal target cells in a PDGFR-β–dependent manner, which was substantiated in vivo by immunohistochemical and fluorescence-activated cell sorting analysis of tumor, spleen, and liver tissue. Importantly, regulation of stromal EPO by PDGF-BB was required for tumor proliferation and angiogenesis, as antibody blockade of either EPO or PDGFR-β similarly inhibited PDGF-BB–induced tumor growth, tumor microvessel formation, and splenic and hepatic blood cell hyperproliferation. Collectively, these results establish a role for PDGF-BB–induced EPO in both paracrine stimulation of tumor angiogenesis and endocrine stimulation of extramedullary hematopoiesis and suggest that combined inhibition of PDGF and EPO may be an effective antiangiogenic therapy.
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