Coexpression of COX-2 and iNOS in Angiogenesis of Superficial Esophageal Squamous Cell Carcinoma

Abstract

Using immunohistochemical staining, the present study was conducted to examine whether cyclooxygenase (COX)-2 and inducible nitric oxide synthase (iNOS) affect angiogenesis in early-stage esophageal squamous cell carcinoma (ESCC). We also analyzed the correlation between these two factors. Cyclooxygenase 2, iNOS, and angiogenesis in early-stage ESCC are unclear. Using 10 samples of normal squamous epithelium, 7 samples of low-grade intraepithelial neoplasia (LGIN), and 45 samples of superficial esophageal cancer, we observed the expression of COX-2 and iNOS. We then investigated the COX-2 and iNOS immunoreactivity scores and the correlation between COX-2 or iNOS scores and microvessel density (MVD) using CD34 or CD105. The intensity of COX-2 or iNOS expression differed significantly according to histological type (P , 0.001). The scores of COX-2 and iNOS were lowest for normal squamous epithelium, followed in ascending order by LGIN, carcinoma in situ and tumor invading the lamina propria mucosae (M1-M2 cancer); and tumor invading the muscularis mucosa (M3) or deeper cancer. The differences were significant (P , 0.001). Cancers classified M1-M2 (P , 0.01 and P , 0.05, respectively); M3; or deeper cancer (P , 0.01) had significantly higher COX-2 and iNOS scores than normal squamous epithelium. There was a significant correlation between COX-2 and iNOS scores (P , 0.001, r s ¼ 0.51). Correlations between COX-2 score and CD34-positive MVD or CD105-positive MVD were significant (r s ¼ 0.53, P , 0.001; r s ¼ 0.62, P , 0.001, respectively). Inducible nitric oxide synthase score was also significantly correlated with CD34 MVD and CD105 MVD (r s ¼ 0.45, P , 0.001; r s ¼ 0.60, P , 0.001, respectively). Chemoprevention of COX-2 or iNOS activity may blunt the development of ESCC from precancerous lesions.Key words: COX-2 -iNOS -CD34 -CD105 -Esophageal cancer -Angiogenesis T he depth of invasion of superficial esophageal carcinoma is expressed in accordance with the sub-classification criteria of the Japan Esophageal Society (Guidelines for clinical and pathologic studies on carcinoma of the esophagus). 1Angiogenesis is essential for cancer progression in order to supply nutrients and oxygen, and remove metabolic waste. Understanding the mechanism of angiogenesis, especially during the early stage of cancer progression, may uncover new targets for treatment or prevention.We have previously reported in detail the use of microvessel density (MVD) as a feature of earlystage esophageal squamous cell carcinoma (ESCC) revealed by immunostaining using CD34 and CD105.2 In that report, we mentioned that MVD based on CD34 and CD105 immunostaining increased according to the grade of atypia or depth of ESCC progression, and also that these findings were correlated with the morphological features of microvessels at the surface of superficial ESCC observed by magnifying endoscopy.As a subsequent step, we examined the angiogenic factors that induced these newly recruited capillaries at the early stage of ESCC progression. Based on a revie...

Anti-Inflammatory Activity of Populus deltoides Leaf Extract via Modulating NF-κB and p38/JNK Pathways

“…In addition to NO, prostaglandin E2 (PGE 2) released from immune cells plays a major role in a variety of inflammatory responses catalyzed by the expression of COX-2 [44]. NO produced by iNOS in the inflammatory response contributes to upregulation of COX-2 via crosstalk between NO, COX-2, and PGE2 [45]. However, PLE did not inhibit the expression COX-2 or prostaglandin E2 in the present study.…”

Cyclooxygenase-2, a Potential Therapeutic Target, Is Regulated by miR-101 in Esophageal Squamous Cell Carcinoma

“…COX-1 is constitutively expressed in most tissues, while COX-2 is the inducible isoform, which is responsible for the elevated production of PGs in response to various inflammatory stimuli, hormones, and growth factors [ 4 ]. Accumulating evidence has demonstrated that COX-2 plays an important role both in tumor development and progression [ 5 – 10 ], including ESCC [ 11 – 16 ]. Epidemiological studies have indicated that the regular use of aspirin can reduce the risk of esophageal cancer by up to 90% [ 17 – 19 ].…”

“…Epidemiological studies have indicated that the regular use of aspirin can reduce the risk of esophageal cancer by up to 90% [ 17 – 19 ]. We and others have shown that (1) COX-2 expression is a frequent phenomenon in human ESCC tissue samples and that positive expression is related to lymphatic metastasis [ 11 – 16 ]; (2) COX-2 inhibitors inhibit cell proliferation and induce apoptosis by inducing G0 / G1 cell-cycle arrest and down-regulating Bcl-2 expression [ 20 , 21 ] and the inhibition of COX-2 leads to tumor reduction in vivo [ 22 ]; and (3) a COX-2 inhibitor can inhibit migration and invasion of ESCC cells [ 23 ] These findings thus provide compelling evidence that COX-2 is an obligatory player in ESCC and that blocking COX-2 is an important therapeutic targets of ESCC.…”

Tumor-associated macrophages and angiogenesis in early stage esophageal squamous cell carcinoma

“…These angiogenic factors have been implicated in angiogenesis, vessel invasion, distant metastasis, and prognosis. We have previously calculated and reported the cyclooxygenase (COX)-2 and iNOS scores in early stage ESCC [30]. The expression of both COX-2 and iNOS by host cells was also strongly upregulated in M1 and M2 cancer and significantly correlated with MVD.…”

“…This is one limitation of the present study, and further investigation of this issue seems warranted. ESCC cells are also reported to express various angiogenic factors [7,8,12,19,[26][27][28][29][30] in the early stage of cancer progression. These angiogenic factors have been implicated in angiogenesis, vessel invasion, distant metastasis, and prognosis.…”