Cyclooxygenase-2-Dependent Expression of Angiogenic CXC Chemokines ENA-78/CXC Ligand (CXCL) 5 and Interleukin-8/CXCL8 in Human Non-Small Cell Lung Cancer

Abstract

Elevated tumor cyclooxygenase (COX)-2 activity plays a multifaceted role in non-small cell lung cancer (NSCLC). To elucidate the role of COX-2 in the in vitro and in vivo expression of two known NSCLC angiogenic peptides, CXC ligand (CXCL) 8 and CXCL5, we studied two COX-2 gene-modified NSCLC cell lines, A549 and H157. COX-2 overexpression enhanced the in vitro expression of both CXCL8 and CXCL5. In contrast, specific COX-2 inhibition decreased the production of both peptides as well as nuclear translocation of nuclear factor B. In a severe combined immunodeficient mouse model of human NSCLC, the enhanced tumor growth of COX-2-overexpressing tumors was inhibited by neutralizing anti-CXCL5 and anti-CXCL8 antisera. We conclude that COX-2 contributes to the progression of NSCLC tumorigenesis by enhancing the expression of angiogenic chemokines CXCL8 and CXCL5.

Inhibition of arachidonic acid metabolism and its implication on cell proliferation and tumour-angiogenesis

“…In head and neck cancer, increased expression levels of COX-2 was found to correlate with the extent of lymph node metastasis and tumour vascularisation, the latter being clearly correlated to PGE 2 biosynthesis and vascular endothelial growth factor (VEGF) expression levels [ 36 , 37 ]. Corresponding findings were reported for COX involvement in angiogenic signalling in non-small cell lung cancers [38]. Indeed, raised PGE 2 expression was shown to trigger β-catenin signalling via the Wnt pathway, thereby activating the proto-oncogenes c-myc and c-jun as well as cyclin D1 expression [39,40].…”

Unphosphorylated STAT6 contributes to constitutive cyclooxygenase-2 expression in human non-small cell lung cancer

“…COX-2 protein levels were significantly increased in STAT6Y641W cells compared to parental or vector-containing cells (Figure 2b). Because COX-2 is often the rate-limiting enzyme in the production of prostaglandin E 2 (PGE 2 ) which mediates many tumorigenic effects (Sheng et al, 1998;Stolina et al, 2000;Dohadwala et al, 2002;Pold et al, 2004), we determined the PGE 2 concentrations in the supernatants of STAT6Y641W cell lines. Compared to the vector-containing cells, PGE 2 production was increased 149 and 137% in A427 and H2122 STA-T6Y641W cells, respectively (Figure 3).…”

“…Two forms of COX have been described: a constitutively expressed enzyme, COX-1, present in most cells and tissues, and an inducible isoenzyme, COX-2, expressed in response to cytokines, growth factors and other stimuli (Herschman, 1999). COX-2 has been found to be constitutively elevated in lung cancer and may be involved in tumorigenesis by regulation of apoptosis, angiogenesis, tumor invasion and tumor immunity (Sheng et al, 1998;Stolina et al, 2000;Dohadwala et al, 2002;Pold et al, 2004).…”

The Inflammatory Tumor Microenvironment, Epithelial Mesenchymal Transition and Lung Carcinogenesis

“…Overexpression of the inflammatory mediator COX-2 in tumors is associated with angiogenesis, enhanced invasion and metastasis [85][86][87][88]. Exposure to PGE2 has been shown to upregulate the transcription factor Snail in NSCLC, as have the cytokines TGF-β and interleukin-6 in other tumor types [40,89].…”