Bone marrow-derived EP3-expressing stromal cells enhance tumor-associated angiogenesis and tumor growth.

Recent results suggest that bone marrow (BM)-derived hematopoietic cells are major components of tumor stroma and play crucial roles in tumor growth and angiogenesis. An E-type prostaglandin is known to regulate angiogenesis. We examined the role of BM-derived cells expressing an E-type prostaglandin receptor subtype (EP3) in tumor-induced angiogenesis and tumor growth. The replacement of wild-type (WT) BM with BM cells (BMCs) from green fluorescent protein (GFP) transgenic mice revealed that the stroma developed via the recruitment of BMCs. Selective knockdown of EP3 by recruitment of genetically modified BMCs lacking EP3 receptors was performed by transplantation of BMCs from EP3 knockout (EP3(-/-)) mice. Tumor growth and tumor-associated angiogenesis were suppressed in WT mice transplanted with BMCs from EP3(-/-) mice, but not in mice transplanted with BMCs from either EP1(-/-), EP2(-/-), or EP4(-/-) mice. Immunohistochemical analysis revealed that vascular endothelial growth factor (VEGF) expression was suppressed in the stroma of mice transplanted with BMCs from EP3(-/-) mice. EP3 signaling played a significant role in the recruitment of VEGFR-1- and VEGFR-2-positive cells from the BM to the stroma. These results indicate that the EP3 signaling expressed in bone marrow-derived cells has a crucial role in tumor-associated angiogenesis and tumor growth with upregulation of the expression of the host stromal VEGF together with the recruitment of VEGFR-1/VEGFR-2-positive. The present study suggests that the blockade of EP3 signaling and the recruitment of EP3-expressing stromal cells may become a novel strategy to treat solid tumors.