PDGF-BB modulates hematopoiesis and tumor angiogenesis by inducing erythropoietin production in stromal cells

 Yuan Xue et al. 2012. Nat. Med. 18(1):100-110

Speaker: Wei-Hung Lin(林韋宏)                                  Time: 14:00~15:00, Apr. 18, 2012

Commentator: Bei-Chang Yang, Ph.D. (楊倍昌)         Place: Room 601

Abstract

During malignant progression, angiogenesis is one of the most important events for tumor growth, invasion and metastasis. Platelet-derived growth factor (PDGF)-BB, a dimer of PDGF-B, may contribute to angiogenesis by either direct modulation of endothelial proliferation¹ or indirect recruitment of perivascular cells². This study tested whether PDGF-BB has other effects on angiogenesis. The authors injected PDGF-BB-expressing tumor cells to mice subcutaneously and found that PDGF-BB enhanced tumor growth and intratumoral angiogenesis. Unexpectedly, the PDGF-BBproduced from tumors also resulted in hepatosplenomegaly and extramedullary hematopoiesis in liver and spleen. Immunofluorescence staining showed that PDGFR-β, the receptor of PDGF-BB, is majorly expressed on various stromal cells in tumors, liver and spleen. Surprisingly, the authors found that PDGF-BB-PDGFR-β signaling in the stromal cells induced expression of erythropoietin (EPO), a hormone stimulating erythropoiesis. Neutralization of EPO restrained PDGF-BB-promoted intratumoral angiogenesis and extramedullary hematopoiesis, thus reducing tumor growth andhepatosplenomegaly. These findings suggest that PDGF-BB-induced EPO may promote tumor growth through two mechanisms: paracrine induction of intratumoral angiogenesis and endocrine stimulation of red blood cell production that may increase oxygen perfusion. Overall, this study revealsa novel mechanism of PDGF-BB-induced, EPO-mediated tumorigenesis, which may explain the poor clinical outcome when cancer patients suffering from anemia are treated with EPO, and may also explain why some cancer patients suffer from hepatosplenomegaly.

References

1.      Battegay E.J., Rupp J., Iruela-Arispe L., Sage E.H. & Pech M. PDGF-BB modulates endothelial proliferation and angiogenesis in vitro via PDGFb-receptors. J Cell Biol 125, 917-28 (1994).

2.      Abramsson A., Lindblom P. & Betsholtz C. Endothelial and nonendothelial sources of PDGF-B regulate pericyte recruitment and influence vascular pattern formation in tumors. J Clin Invest 112, 1142-1151 (2003).