COX-2/VEGF-Dependent Facilitation of Tumor-Associated Angiogenesis and Tumor Growth in vivo

Abstract

SUMMARY:Nonsteroidal anti-inflammatory drugs are known to suppress the occurrence and progression of malignancies such as colorectal cancers. However, the precise mechanism of these actions remains unknown. We have evaluated the role of an inducible cyclo-oxygenase (COX-2) in tumor-associated angiogenesis and tumor growth, and identified the downstream molecules involved using a ddy mouse model of sponge angiogenesis, which mimics tumor angiogenesis and is COX-2 and vascular endothelial growth factor (VEGF) dependent. In this model, VEGF expression was down-regulated by selective COX-2 inhibition with NS-398. To find out the involvement of COX-2/VEGF pathway in tumor-associated angiogenesis, we estimated angiogenesis occurring around implanted Millipore chambers containing sarcoma-180 (S-180) cells or Lewis lung carcinoma cells. Daily oral administration of NS-398 or of aspirin, a nonselective COX inhibitor, suppressed angiogenesis seen around the Millipore chambers. S-180 cells implanted in ddy mice formed substantial tumors with extensive angiogenesis markedly suppressed by aspirin and COX-2 inhibitors NS-398 and JTE522, but not by mofezolac, an inhibitor of constitutive COX-1. Tumor-associated angiogenesis was also significantly suppressed by a neutralizing antibody against VEGF. S-180 tumor growth in the subcutaneous tissues was also suppressed by aspirin, COX-2 selective inhibitors, and the VEGF antibody, but not by the COX-1 inhibitor. These results demonstrate that the inhibition of the COX-2/VEGF-dependent pathway was effective in tumor-associated angiogenesis, tumor growth, and tumor metastasis. (Lab Invest 2003, 83:1385-1394.

Roles of Prostaglandin E 2 –EP3/EP4 Receptor Signaling in the Enhancement of Lymphangiogenesis During Fibroblast Growth Factor-2–Induced Granulation Formation

“…In the sponge model, granulation tissues with the property of chronic inflammation were formed around the sponge implants with enough reproducibility, and we can easily determine the active molecules at the site of the chronic inflammation, because rapid sampling and easy extractions of active molecules and mRNA can be performed in the sponge model. The results with this sponge model have been published in some journals, 5,6,26,27,29,[31][32][33][34][35][36][37][38][39][40] and many researchers have a strong interest in this model. In the beginning of this study, we had tried to test this sponge model to clarify the involvement of PGs in lymphangiogenesis during the chronic inflammation, but the detection of newly developed lymphatics was quite difficult in the sponge model.…”

“…[23][24][25][26] Thus, future therapeutic strategies may involve controlling PG formation and receptor signaling. [27][28][29] However, the roles of PGs in lymphangiogenesis remain not fully clarified. 30 In the present study, we used Matrigel plugs to evaluate lymphangiogenesis during development of proliferative granulation tissues around the gels, although this Matrigel model was used for the evaluation of angiogenesis and cell migration assays.…”

Prostanoid induces premetastatic niche in regional lymph nodes

“…COX-2 expression is associated with poor patient prognosis and survival (33,34). We previously reported that, in addition to tumor COX-2 expression, COX-2 present in stromal tissues had a significant effect on tumor-associated angiogenesis (35). Further studies showed that COX-2 induced lung metastasis via EP3 signaling (14).…”

Growth compensatory role of sulindac sulfide-induced thrombospondin-1 linked with ERK1/2 and RhoA GTPase signaling pathways

“…NSAIDs inhibit enzymatic activity of cyclooxygenases (COX) whose products prostaglandins are known to inhibit apoptosis, stimulate tumor growth, and enhance angiogenesis, tumor cell invasion and metastasis in many cancer models (Connolly et al, 2002;Yoshida et al, 2003). NSAIDs, by inhibiting COX activity, enhance apoptosis and exert anti-metastatic and anti-angiogenesis effects, thereby inhibiting tumor growth.…”