COX-2 and Prostaglandin EP3/EP4 Signaling Regulate the Tumor Stromal Proangiogenic Microenvironment via CXCL12-CXCR4 Chemokine Systems

Abstract

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-

Role of COX-2 in lymphangiogenesis and restoration of lymphatic flow in secondary lymphedema

“…Mice in the treated group were fed a diet containing celecoxib (150 mg per 100 g diet, approximately equal to 100 mg/kg/day/mouse) beginning on the day of surgery (week 0). 15 Some mice received a diet containing celecoxib (45 mg per 100 g diet, approximately equal to 30 mg/kg/day/mouse). A control group of age-matched, vehicle-treated mice were maintained on a diet without celecoxib.…”

“…Images were captured with a confocal scanning laser microscope (LSM710; Carl Zeiss, Jena, Germany) and computer-assisted morphometric analyses of lymphatic vessels were performed using ZEN 2008 software as described previously. 15 In some samples, we used a mixture of rat anti-mouse F4/ 80 monoclonal IgG antibody (Santa Cruz Biotechnology, Santa Cruz, CA, USA) and anti-mouse COX-2 monoclonal IgG antibody (Abcam) with use of Alexa Fluor 488 Goat Anti-rabbit IgG and Texas Reds Donkey Anti-goat IgG. Macrophage accumulation was also tested by rat anti-mouse F4/80 monoclonal IgG antibody (Santa Cruz Biotechnology) with use of an Alexa Fluor 568 Goat Anti-rat IgG.…”

“…15 Total RNA was extracted from mouse tissues using TRIzols (Invitrogen, San Diego, CA, USA) and single-stranded cDNA was generated from 1 mg of total RNA via reverse transcription with ReverTra Ace-a-TM (TOYOBO, Osaka, Japan). Real-time PCR primers were designed using Primer3 software (http://primer3.sourceforge.net/) based on GenBank data and are listed in Table 1.…”

COX-2-dependent PGE2 acts as a growth factor in mycosis fungoides (MF)

“…10 Recent findings suggest a role for COX-2/PGE 2 signaling in the regulation of the tumor microenvironment. 11 The inhibition of prostaglandin synthesis by a long-term use of non-steroidal antiinflammatory drugs has been shown to have a chemopreventive effect on several cancer types. 12 In this study, we provide the first evidence that PGE 2 is a COX-2-mediated growth factor in CTCL.…”

Chemokine CXCR-4 and cyclooxygenase-2 in the pathogenesis of pterygium

“…It was reported in a recent study that activities of COX-2/ PGE2-EP3/EP4 signaling modulate tumor biology and it was shown that the CXCL-12/CXCR-4 axis could play a crucial role in tumor stromal formation and angiogenesis under the control of prostaglandins. It was postulated that PGE2-EP3/ EP4 signaling in tumor stroma may promote tumor stromal formation and tumor growth mainly through the host CXCL-12/CXCR-4 axis by recruiting stromal fibroblasts (33). On the other hand, Obermajer et al (34) demonstrated that COX-2 inhibition also blocked CXCL-12/CXCR-4 production in the ovarian cancer environment and its ability to attract MDSCs.…”