Department of Pathology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
Cyclooxygenase 2 has become an important pharmacological target in anticancer therapy due to the over expression of COX 2 in pathological conditions. Wilms’ tumor is a common kidney cancer in children which has shown an increase in COX 2 enzyme level. Here we reviewed various articles that considered the cyclooxygenase 2 changes specifically in Wilms’ tumor regarding the mechanisms of action and inhibitors of COX 2.
Introduction During every malignancy there may be various changes in normal gene expression and protein synthesis which lead to functional changes of the affected limb. Cyclooxygenase 2 (COX2) is one of the major enzymes which will be overexpressed in cancers and tumors which consequently lead to the increased in the prostaglandins synthesis. Various evidence have proposed COX2 a major therapeutic target which may be suppressed by using non-steroidal anti-inflammatory drugs (NSAIDs) or prototypic inhibitors of COX-2 such as celecoxib, rofecoxib. Wilms’ tumor is the most common cancer of kidney which primarily affects children kidney (1,2). In this article we aimed to review the literature considered the expression of COX2 in Wilms’ tumor.
COX enzyme Cyclooxygenase (COX) is the key enzyme in charge for the synthesis of prostanoids, consisting of prostaglandins, prostacyclins and thromboxanes, which are the biological mediators that eventually lead to the activation of anaphylactic, inflammatory and vasoconstriction reactions. Among the major physiological adjuster of kidney can be mentioned to the Prostaglandins which interfere in water and salt equilibrium, vascular resistance, renal hemodynamic and rennin release. COX1, COX2 and COX3 are the identified COX isoenzymes. COX 1 and COX 2 have almost 60% homology in their amino acids sequences (3). Unlike COX 1 which is present in almost all tissues, COX2 is an inducible enzyme with a low possibility of being detected in normal tissues. Although COX2 expression is detected in brain and kidney of rodents, but it is actively expresses in specific unusual circumstances and disease processes such as carcinomas and tumorogenesis due to several stimuli such as growth factors, cytokines, mitogens and tumor protomers. The conditional activation of COX2 protein turned it to one of the main target for therapeutic and chemoprotective procedures, pathological situations and a noticeable indicator of abnormal of cell growth and malignancies (4,5). Previous studies have been detected the expression of COX2 in various types of malignancies such as nervous system, gynecologic system, bone structure, breast, lung, colorectal tumors, intestinal neoplasia, gastrointestinal, pancreatic, prostate cancer, head and neck carcinoma (6-14). According to reported results, over expression of COX2 positively participates in tumorogenesis, invasion and metastasis through modulation of the mechanisms such as apoptosis, angiogenesis, inflammation and immune system function, carcinogen production and tumor cell proliferation (3).
COX expression in kidney Expression of both isoforms of COX has been detected in normal kidney using a variety of molecular techniques. A substantial expression of COX1 is observed in vascular smooth muscle and collecting ducts. The expression of COX2, not only is detected in pathological conditions of kidney but also a low level of its expression is identified in macula densa, interstitial cells, podocytes and arteriolar smooth muscle cells. Expression of COX2 enzymes is also observed in fetal kidneys which have shown influential role in renal development. An altered in the expression of kidney COX1 and COX2 mRNA during the senescence is observed which leads to the increases of the COX2 expression in protein level. Tissue prostanoids content which is related to the rate of COX expression, have shown some supporting action including maintenance of vessels stability, glumerolar filtration, renal hemodynamic in stressful conditions such as dehydration, salt diminution and hypertension (15,16).
COX2 and Wilms’ tumor Wilms’ tumor is the most prevalent kidney cancer in children. This cancer is resulted from germline mutations or deletions of Wilms’ tumor gene-1 (WT1) which is located on the short arm of chromosome 11. The blastemal, epithelial and stromal parts constitute the triphasic histology of Wilms’ tumor. Hematuria, fever, malaise and anorexia, are some primary indicators of this tumor (17). There are limited data regarding the overexpression of COX2 in Wilms’tumor and the mechanisms result in tumor progression and metastasis. Only four studies have specifically considered the expression of COX2 in Wilms’ tumor with the aim of evaluating the prognostic value of this criterion, identifying the effectual signaling pathways in tomorogenesis and detecting the efficacy of several inhibitors of COX2 expression and eventually the oncological diseases. SC-236 and its analogue celecoxib are used as the COX2 inhibitors in considering the effect of COX2 on tumor vessel density. Almost 78% reduction in tumor growth and lung metastasis after 28 days of treating tumors using mentioned inhibitor is observed, however the declared changes are not significant statically. Using terminaldeoxynucleotidyl transferase–mediated nick-end labeling (TUNEL) procedure showed that induced limitation of the tumor growth is not the consequence of the increased apoptosis however disrupted proliferation, angiogenesis and vascular density are the responsible causes of this effect (20,25). Angiogenesis of other tumor models are reported to be inhibited by arresting endothelial cell cycles, increasing the expression of endostatin, or inducing apoptosis by decreasing endothelial growth factor (26,27). In the considered studies, using COX2 inhibitor did not lead to decreased expression of the endothelial growth factor. Using COX2 inhibitor (SC-236), yielded some changes in gene expression of Wilms’ tumor which lead to increase or decrease in the expression of genes to suppress the vascular proliferation and stability. Data regarding altered genes expression after administrating COX2 inhibitor are summarized in Table 2. By considering all the studies performed on evaluating the changes in expression level of COX2 protein during Wilms’ tumor a considered malignancy, increase in COX2 expression was the indication of its role in pathogenesis of Wilms’ tumor and immonureactivity of COX2 protein was demonstrated in all stages of the tumor development thus Cox2 inhibitors could be considered as a therapeutic agent.
Acknowledgement We would like to thank Clinical Research Development Center of Ghaem Hospital for their assistant in this manuscript. This study was supported by a grant from the Vice Chancellor for Research of the Mashhad University of Medical Sciences for the research project as a medical student thesis with approval number of 900848.
Conflict of Interest The authors declare no conflict of interest.
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