Correlation between cyclooxygenase-2 and tumor angiogenesis in non-small cell lung cancer

Kim, Hyung-Seok; Youm, Hyung-Roul; Lee, Ji-Shin; Min, Kyung-Whan; Chung, Jooyoung; Park, Chang‐Soo

doi:10.1016/s0169-5002(03)00290-3

Cited by 70 publications

(44 citation statements)

References 20 publications

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“…In subsequent reports, elevated COX-2 expression has been shown with greater staining in lymph node metastases than in the primary tumor (62,63), and tumor COX-2 expression has been found to be a poor prognostic indicator (64,65,67). These findings, along with studies documenting increased COX-2 expression in precursor lesions (67)(68)(69), an association between a common polymorphism in the COX-2 gene and increased risk of lung cancer (70), and epidemiological studies indicating a decreased incidence of lung cancer in individuals who regularly use aspirin, support involvement of COX-2 and its enzymatic products in the pathogenesis of lung cancer (71). Thus, in lung cancer development and progression, elevations of COX-2 and PGE 2 are driving forces for the hallmarks of malignancy including apoptosis resistance (72), proliferation (73), immunosuppression (74), angiogenesis (75), invasion (76), and EMT (15).…”

Section: Pulmonary Epithelial Cells Can Serve As Targets For Inflammasupporting

confidence: 75%

Smoking and Lung Cancer: The Role of Inflammation

Walser

Cui²,

Yanagawa³

et al. 2008

Proceedings of the American Thoracic Society

275

158

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Worldwide over 1 million people die due to lung cancer each year. It is estimated that cigarette smoking explains almost 90% of lung cancer risk in men and 70 to 80% in women. Clinically evident lung cancers have multiple genetic and epigenetic abnormalities. These abnormalities may result in activation of oncogenes and inactivation of tumor-suppressor genes. Chronic inflammation, which is known to promote cancer, may result both from smoking and from genetic abnormalities. These mediators in turn may be responsible for increased macrophage recruitment, delayed neutrophil clearance, and increase in reactive oxygen species (ROS). Thus, the pulmonary environment presents a unique milieu in which lung carcinogenesis proceeds in complicity with the host cellular network. The pulmonary diseases that are associated with the greatest risk for lung cancer are characterized by abundant and deregulated inflammation. Pulmonary disorders such as chronic obstructive pulmonary disease (COPD)/emphysema are characterized by profound abnormalities in inflammatory and fibrotic pathways. The cytokines and growth factors aberrantly produced in COPD and the developing tumor microenvironment have been found to have deleterious properties that simultaneously pave the way for both epithelialmesenchymal transition (EMT) and destruction of specific host cellmediated immune responses. Full definition of these pathways will afford the opportunity to intervene in specific inflammatory events mediating lung tumorigenesis and resistance to therapy.

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Section: Pulmonary Epithelial Cells Can Serve As Targets For Inflammasupporting

confidence: 75%

Smoking and Lung Cancer: The Role of Inflammation

Walser

Cui²,

Yanagawa³

et al. 2008

Proceedings of the American Thoracic Society

275

158

View full text Add to dashboard Cite

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“…Expression of both CD44 and COX-2 can be induced by cytokines, growth factors, and tumor promoters (45)(46)(47)(48), and COX-2 is a source of PG formation during inflammation, embryogenesis, and tumor growth, processes in which CD44 also plays major roles. Both CD44 and COX-2 are overexpressed in a variety of malignancies and have been linked to matrix metalloproteinase expression/activity, cell migration, invasion, and tumor metastasis (49,50). Both COX-2 and CD44 (particularly variant CD44) have been implicated in the pathogenesis of colon cancer (51,52).…”

Section: Discussionmentioning

confidence: 99%

Engagement of CD44 modulates cyclooxygenase induction, VEGF generation, and cell proliferation in human vascular endothelial cells

et al. 2005

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CD44 is a receptor for hyaluronic acid and is found on the surface of hematopoetic cells and in mesenchymal tissue. It is also expressed on endothelial cells (EC). Cyclooxygenase (COX) is the rate-limiting enzyme in the production of prostaglandins in EC. Here we show that engagement of CD44 with signaling monoclonal antibodies (mAbs) or its natural ligand hyaluronic acid induces COX-2 and prostacyclin (PGI 2 ) formation in human EC. This induction was blocked by mAbs that have been shown to inhibit CD44-mediated intracellular signaling. COX-1 induction was not observed after CD44 ligation. CD44-stimulated COX-2 activation/PGI 2 production was accompanied by the production of the potent endothelial mitogen, vascular endothelial growth factor (VEGF) and was inhibited by a neutralizing VEGF antibody. Moreover, this COX-2 induction was also associated with an increase in EC proliferation that was inhibited by the blocking anti-CD44 mAbs and a COX-2-specific inhibitor. This is the first study to show that engagement of CD44 with mAbs or its natural ligand induces COX-2, generates VEGF, and thus leads to an increase in EC proliferation. Results from this study may have important and widespread implications for the development of novel therapeutic agents for modulating blood vessel growth during ischemic heart disease, during inflammation, or around solid tumors.Key words: vascular endothelial growth factor • prostacyclin • COX he cell adhesion molecule CD44 is involved in a variety of important biological events such as embryogenesis, hematopoiesis, lymphocyte homing and activation, inflammatory reactions, and tumor dissemination (1-4). CD44 represents a large protein family, which includes the standard form or CD44 with a molecular mass of 85-90 kDa, and a multiplicity of isoforms generated by alternative splicing of transcripts and subsequent variable glycosylation (reviewed in ref 5). These high molecular mass variants are rarely expressed on normal cells. CD44 is the principal cell surface receptor for extracellular matrix glycosaminoglycan hyaluronan (HA). CD44-HA-mediated cell adhesion is important in several pathophysiological processes such as inflammation and metastatic spread of cancer cells. In this context, it has been recognized that CD44 can function as a signaling receptor in a variety of cell types (6). Cell stimulation by monoclonal anti-CD44 antibody or natural CD44 ligands activate signaling pathways that culminate in cell proliferation, cytokine secretion, chemokine gene expression, and cytolytic effector functions. Normal endothelial cells (EC) express low levels of CD44, but expression is up-regulated by activation with, for example, cytokines, and by culturing of these cells (7). Expression is also increased on the vasculature of solid tumors (7,8). Expression of CD44 on EC is associated with homing and migration of leukocytes (i.e., inflammation and migration). In addition, it has been demonstrated that CD44 plays some role in new blood vessel formation (angiogenesis), although its pre...

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“…While these findings are problematic for long-term use, the possibilities of using COX-2 inhibitors for a short term in combination with ionizing radiation therapy are intriguing. Several studies have shown that COX-2 inhibitors reduce the growth of tumors in vivo and in vitro and can enhance the radiosensitivity of certain tumors (23)(24)(25)(26)(27)(28)(29). While there has been a great deal of research and speculation on the exact mechanism by which COX-2 inhibitors produce their anti-tumor effect, there has been no definitive answer to explain the phenomenon or how COX-2 inhibitors enhance the effects of radiation therapy.…”

Section: Discussionmentioning

confidence: 99%

Cyclooxygenase-2 inhibitor, nimesulide, improves radiation treatment against non-small cell lung cancer both in vitro and in vivo

Grimes

Warren²,

Fang³

et al. 2006

Oncol Rep

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Abstract. Lung cancer is the leading cause of cancer-related deaths in the United States. Despite improvements in radiation, surgery and chemotherapy the 5 year survival statistics of non-small cell lung cancer (NSCLC) have improved little over the past two decades. It has been proposed that NF-κB is a participant in the cytoprotection against several redox-mediated therapeutic agents including ionizing radiation. Cyclooxygenase-2 (COX-2) inhibition has become an attractive target for enhancing the efficacy of radiation and chemotherapy. Numerous mechanistic pathways have been proposed as the means through which COX-2 inhibition enhances the efficacy of radiation. We hypothesize that the COX-2 inhibitor, nimesulide, will improve the efficacy of radiation therapy (RT), at least in part, via the suppression of NF-κB mediated cytoprotective pathways. In this study we used the COX-2 inhibitor nimesulide to improve the efficacy of RT when measured by tumor regrowth assays in vivo and clonegenic survival in vitro. For the in vivo assay, A549 tumor cells representing NSCLC were subcutaneously injected into the right flanks of female athymic nude mice (n=10/group). Mice were given nimesulide via drinking water at a concentration of 5 μg/g body weight (b.w.) and the water was replenished daily. Tumors were treated with 30 Gy fractionated radiation and measured biweekly. For our in vitro study, clonogenic survival assays were evaluated to determine the effect of nimesulide, radiation, and the combination. The NF-κB mediated mechanism of nimesulide was measured by Western blot analysis of NF-κB target genes, MnSOD and survivin. In vivo, mice that received combined treatments of 5 μg/g b.w. nimesulide and 30 Gy radiation (3 Gy/fraction, 10 daily fractions) had significant reduction in tumor size in comparison to the 30 Gy radiation control group (p<0.05). In vitro, nimesulide alone produced a significant decrease in clonogenic survival at doses from 0-300 μM. Nimesulide demonstrated an additive effect in combination with radiation. Nimesulide alone reduced MnSOD and survivin protein levels in a dose-dependent manner. 6 Gy radiation caused an initial elevation of MnSOD protein levels which was inhibited by prior treatment of nimesulide suggesting an inhibition of radiation induced NF-κB target genes. These results support the hypothesis that COX-2 inhibitors such as nimesulide can increase the efficacy of radiation therapy. In vitro, our results suggest that the radiosensitization of A549 tumor cells by nimesulide is mediated by the suppression of NF-κB-mediated, radiation-induced cytoprotective genes.

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Correlation between cyclooxygenase-2 and tumor angiogenesis in non-small cell lung cancer

Cited by 70 publications

References 20 publications

Smoking and Lung Cancer: The Role of Inflammation

Smoking and Lung Cancer: The Role of Inflammation

Engagement of CD44 modulates cyclooxygenase induction, VEGF generation, and cell proliferation in human vascular endothelial cells

Cyclooxygenase-2 inhibitor, nimesulide, improves radiation treatment against non-small cell lung cancer both in vitro and in vivo

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