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Bone marrow (BM)-derived hematopoietic cells, which are major components of tumor stroma, determine the tumor microenvironment and regulate tumor phenotypes. Cyclooxygenase (COX)؊2 and endogenous prostaglandins are important determinants for tumor growth and tumor-associated angiogenesis; however, their contributions to stromal formation and angiogenesis remain unclear. In this study, we observed that Lewis lung carcinoma cells implanted in wild-type mice formed a tumor mass with extensive stromal formation that was markedly suppressed by COX-2 inhibition, which reduced the recruitment of BM cells. Notably, COX-2 inhibition attenuated CXCL12/CXCR4 expression as well as expression of several other chemokines. Indeed, in a Matrigel model, prostaglandin (PG) E 2 enhanced stromal formation and CXCL12/CXCR4 expression. In addition, a COX-2 inhibitor suppressed stromal formation and reduced expression of CXCL12/CXCR4 and a fibroblast marker (S100A4) in a micropore chamber model. Moreover, stromal formation after tumor implantation was suppressed in EP3 ؊/؊ mice and EP4 ؊/؊ mice, in which stromal expression of CXCL12/ CXCR4 and S100A4 was reduced. The EP3 or EP4 knockout suppressed S100A4 Recent advances in tumor biology have identified the stroma as an important regulator of carcinogenesis and a potentially valuable therapeutic target. Although interactions between the epithelium and stroma have long been considered to be important in tumor progression, the efficacy of targeting stromal components as a therapeutic strategy has not been established, because the specific regulators of such interactions remain unclear. In addition to endothelial cells, macrophages and fibroblasts 1 are the major stromal components of the tumor microenvironment, and they play key roles in the enhancement of angiogenesis. It has recently been established that bone marrow (BM)-derived hematopoietic cells are the major components of the stroma of tumors, and that they determine the tumor microenvironment [2][3][4][5][6][7][8] ; however, the specific factors that enhance the functions of BM-derived precursor cells, and the mechanism of recruitment of these cells during tumor angiogenesis, are not fully understood. Tumor-associated angiogenesis in the tumor stroma is a prerequisite for invasive growth of a tumor larger than 2 to 3 mm in diameter, and then metas-

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Vascular endothelial growth factor (VEGF) and its receptors promote liver regeneration. The objective of the present study was to examine the role of VEGF receptor 1 (VEGFR1) signaling in hepatic tissue repair after acetaminophen (N-acetyl-para-aminophenol) (APAP)-induced liver injury. To do this, we treated VEGFR1 tyrosine kinase knockout (VEGFR1 TK(-/-)) and wild-type (WT) mice with APAP (300 mg/kg, ip). In WT mice, serum levels of alanine aminotransferase (ALT) and the necrotic area peaked between 8 and 24 h and then declined. In VEGFR1 TK(-/-) mice, ALT levels remained high at 48 h and extensive hepatic necrosis and hemorrhage were observed, as well as high mortality. Downregulation of hepatic messenger RNA expression of VEGFR1 and VEGFR2 was also noted in VEGFR1 TK(-/-) mice. VEGFR1 TK(-/-) mice displayed lower expression of proliferating cell nuclear antigen and of growth factors including hepatocyte growth factor, CD31, and basic fibroblast growth factor than WT. The hepatic microvasculature in VEGFR1 TK(-/-) was compromised as evidenced by impaired sinusoidal perfusion, suppressed endocytosis in liver sinusoidal endothelial cells (LSECs), and the formation of large gaps in LSECs. In WT mice, immunofluorescence revealed that recruited VEGFR1(+) cells in the necrotic area were positive for CD11b. VEGFR1 TK(-/-) exhibited fewer VEGFR1(+) and VEGFR2(+) cells. These results suggest that VEGFR1 signaling facilitates liver recovery from APAP hepatotoxicity by preventing excessive hemorrhage and reconstituting the sinusoids through recruitment of VEGFR1-expressing macrophages to the injured area and also through affecting expression of genes including hepatotrophic and pro-angiogenic growth factors.

Objective— One of the hallmarks of inflammation is lymphangiogesis that drains the interstitial fluids. During chronic inflammation, angiogenesis is induced by a variety of inflammatory mediators, such as prostaglandins (PGs). However, it remains unknown whether they enhance lymphangiogenesis. We examined the roles of cyclooxygenase-2 (COX-2) and PGE 2 receptor signaling in enhancement of lymphangiogenesis during proliferative inflammation. Methods and Results— Lymphangiogenesis estimated by podoplanin/vascular endothelial growth factor (VEGF) receptor-3/LYVE-1 expression was upregulated during proliferative inflammation seen around and into subcutaneous Matrigel plugs containing fibroblast growth factor-2 (125 ng/site). A COX-2 inhibitor (celecoxib) significantly reduced lymphangiogenesis in a dose-dependent manner, whereas topical PGE 2 enhanced lymphangiogenesis. Topical injection of fluorescein isothiocyanate–dextran into the Matrigel revealed that lymphatic flow from the Matrigels was COX-2 dependent. Lymphangiogenesis was suppressed in the granulation tissues of mice lacking either EP3 or EP4, suggesting that these molecules are receptors in response to endogenous PGE 2 . An EP3-selective agonist (ONO-AE-248) increased the expression of VEGF-C and VEGF-D in cultured macrophages, whereas an EP4-selective agonist (ONO-AE1-329) increased VEGF-C expression in cultured macrophages and increased VEGF-D expression in cultured fibroblasts. Conclusion— Our findings suggest that COX-2 and EP3/EP4 signaling contributes to lymphangiogenesis in proliferative inflammation, possibly via induction of VEGF-C and VEGF-D, and may become a therapeutic target for controlling lymphangiogenesis.

-related peptide facilitates revascularization during hindlimb ischemia in mice.

Angiogenesis is critical in maintenance of endometrial tissues. Here, we examined the role of VEGF receptor 1 (VEGFR1) signaling in angiogenesis and tissue growth in an endometriosis model. Endometrial fragments were implanted into the peritoneal wall of mice, and endometrial tissue growth and microvessel density (MVD) were determined. Endometrial fragments from wild-type (WT) mice grew slowly with increased angiogenesis determined by CD31 + MVD, peaking on Day 14. When tissues from WT mice were transplanted into VEGFR1 tyrosine kinase-knockout mice, implant growth and angiogenesis were suppressed on Day 14 compared with growth of WT implants in a WT host. The blood vessels in the implants were not derived from the host peritoneum. Immunostaining for VEGFR1 suggested that high numbers of VEGFR1 + cells such as macrophages were infiltrated into the endometrial tissues. When macrophages were deleted with Clophosome N, both endometrial tissue growth and angiogenesis were significantly suppressed. Bone marrow chimera experiments revealed that growth and angiogenesis in endometrial implants were promoted by host bone marrow-derived VEGFR1 + /CD11b + macrophages that accumulated in the implants, and secreted basic fibroblast growth factor (bFGF). A FGF receptor kinase inhibitor, PD173047 significantly reduced size of endometrial tissues and angiogenesis. VEGFR1 signaling in host-derived cells is crucial for growth and angiogenesis in endometrial tissue. Thus, VEGFR1 blockade is a potential treatment for endometriosis.