Cyclooxygenase (COX), a key enzyme in the prostanoid biosynthetic pathway, has received considerable attention due to its role in human cancers. Observational and randomized controlled studies in many different population cohorts and settings have demonstrated protective effects of nonsteroidal anti-inflammatory drugs (NSAIDs; the inhibitors of COX activity) for colorectal cancers (CRCs). COX-2, the inducible isoform of cyclooxygenase, is overexpressed in early and advanced CRC tissues, which portends a poor prognosis. Experimental studies have thus identified important mechanisms and pathways by which COX-2 plays an important role in carcinogenesis. Selective COX-2 inhibitors have been approved for use as adjunctive therapy for patients with familial polyposis. The role of COX-2 inhibitors is currently being evaluated for use in wider populations.

Chronic inflammation is a well-known risk factor for cancer. Proinflammatory mediators such as prostaglandin E2 (PGE2) promote colorectal tumor growth by stimulating angiogenesis, cell invasion, and cell growth, and inhibiting apoptosis. Molecules that regulate tumor-associated angiogenesis provide promising therapeutic targets for treatment of colorectal cancer (CRC) as indicated by the recent development of the novel anti-angiogenic agent bevacizumab (Avastin). However, use of this drug only prolongs survival by several months, highlighting the importance of finding more effective treatment regimens. We report here that PGE2 induces expression of CXCL1 (growth-regulated oncogene α), a pro-angiogenic chemokine, in human CRC cells. More importantly, CXCL1 released from carcinoma cells induces microvascular endothelial cell migration and tube formation in vitro. Furthermore, PGE2 promotes tumor growth in vivo by induction of CXCL1 expression, which results in increased tumor microvessel formation. These results have potential clinical significance because we found that CXCL1 expression correlates with PGE2 levels in human CRCs. Collectively, our findings show for the first time that CXCL1 is regulated by PGE2 and indicate that CXCL1 inhibitors should be evaluated further as potential anti-angiogenic agents for treatment of CRC.

Genetic defects in the phagocyte nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase enzyme system result in chronic granulomatous disease (CGD). In addition to recurrent, life-threatening infections, patients with CGD frequently present with sterile inflammatory complications, suggesting that NADPH-oxidase deficiency predisposes to these responses in the absence of persistent microbial infection. The mechanisms involved in the aberrant, inflammatory process are unknown. In this study, we have shown that neutrophils isolated from CGD patients, which are more resistant to spontaneous apoptosis in vitro, also produce significantly less of the anti-inflammatory mediator cyclopentenone prostaglandin D(2) (PGD(2)). In addition, during phagocytosis of opsonized and nonopsonized apoptotic targets, CGD macrophages are severely compromised in their ability to produce PGD(2) and transforming growth factor-beta (TGF-beta). We suggest that delayed apoptosis of inflammatory cells, such as neutrophils and deficient production of the anti-inflammatory mediators PGD(2) and TGF-beta during macrophage clearance of apoptotic debris and invading pathogens, contributes to persistence of inflammation in CGD.

Preclinical studies suggest that cyclooxygenase (COX)-2 may be involved in the molecular pathogenesis of some types of lung cancer. Most of the available studies point to its involvement in non-small cell lung cancer. Survival of patients with non-small cell lung cancer expressing high levels of COX-2 is markedly reduced. Treatment of humans with the selective COX-2 inhibitor celecoxib augments the antitumor effects of chemotherapy in patients with non-small cell lung cancer. COX-2 has been shown to regulate some aspects of tumor-associated angiogenesis. Most of the results we have published point to effects on the regulation of vascular endothelial growth factor. However, prostaglandins derived from COX-2 affect other signaling pathways as well, such as the epidermal growth factor and its receptor. Others have recently shown that non-small cell lung cancer exhibits a COX-2 downstream enzyme expression pattern that is altered in lung tumor cells and tumor-supplying vessels. Therefore, COX-2 and prostaglandins may have a major impact on lung tumor progression and tumor-associated inflammation. Clinical trials currently underway are exploring the potential of targeting COX-2 in lung cancer.