Cyclooxygenase‐2 inhibition causes antiangiogenic effects on tumor endothelial and vascular progenitor cells

Abstract

Tumor angiogenesis is necessary for solid tumor progression and metastasis. Cyclooxygenase (COX)-2 is known to play an important role in cancer growth and invasion, and it activates the signaling pathways controlling cell proliferation, migration, apoptosis, and angiogenesis. COX-2 is reported to be expressed in many cancer cells. Several studies have reported successful treatment of cancer cells with COX-2 inhibitors (COX-2is). However, the effect of COX-2 inhibition on the tumor endothelium remains to be elucidated. Our study shows that COX-2 is expressed in the vasculature of surgically resected human tumors. To investigate the effects of COX-2 inhibition on the tumor endothelium in vitro, we isolated tumor endothelial cells (TECs) from human melanoma and oral carcinoma xenografts in mice, in which we confirmed that tumor growth was suppressed by inhibiting angiogenesis with the COX-2is NS398. COX-2 mRNA was upregulated in TECs compared to normal endothelial cells (NECs). Cell migration and proliferation were suppressed by NS398 in TECs but not in NECs. The effects of NS398 in vivo were consistent with the in vitro results. The number of CD133 1 /vascular endothelial growth factor receptor-2 1 cells in circulation was significantly suppressed by COX-2 inhibition. In addition, the number of progenitor marker-positive cells decreased in the tumor blood vessels after COX-2i treatment, which suggests that the homing of progenitor cells into the tumor was also blocked. We conclude that NS398 specifically targets both TECs and vascular progenitor cells without affecting NECs.

Integrated Proteomics Identified Novel Activation of Dynein IC2-GR-COX-1 Signaling in Neurofibromatosis Type I (NF1) Disease Model Cells

“…Upregulation of COX-2 expression has been reported in cancer cells including malignant neural cancer and malignant peripheral nerve sheath tumor, and in response to inflammation and cell proliferation, it up-regulates prostaglandin synthases (34 -36). Thus, many studies on COX-2 as a target of drug development have been conducted (37,38). However, limited information concerning the function of COX-1, such as for the mucosal protection of the stomach and blood flow maintenance, has been available (39).…”

Size-controlled, dual-ligand modified liposomes that target the tumor vasculature show promise for use in drug-resistant cancer therapy

“…TECs were isolated, as described previously [17][18][19][20][21][22]. In a typical procedure, the TECs were isolated from OS-RC-2 tumors and dermal tissue in tumor-bearing mice using a magnetic cell sorting system (MACS; Milteny Biotec, Tokyo, Japan).…”

“…TECs from OS-RC-2 tumor tissue were successfully collected, as described previously [17][18][19][20][21][22]. As shown in Fig.…”

The effect of diclofenac on proliferation and production of growth factors by endothelial cells (HMEC-1) under hypoxia and inflammatory conditions

“…However, there is no explicit information about the effects of non-steroidal anti-inflammatory drugs (NSAIDs) on the secretion of angiogenic growth factors (VEGF, bFGF) by normal endothelial cells. Many studies have reported antiangiogenic effects of cyclooxygenase COX-2 inhibitors on cancer cells (6). Among traditional NSAIDs, diclofenac is the strongest inhibitor of COX-2.…”