K
ENJIO
GAWA, K
AZUHIKOY
OSHIMATSUCyclooxygenase II
– A Role in Gastric Cancer Treatment
Rola cyklooksygenazy w leczeniu raka żołądka
Department of Surgery, Tokyo Women’s Medical University Medical Center East, Japan
Adv Clin Exp Med 2007, 16, 3, 347–352 ISSN 1230−025X
EDITORIAL
Since epidemiological studies reported that long−term users of non−steroidal anti−inflammato− ry drugs (NSAIDs) would develop colon and gas− tric cancer less frequently [1, 2], a large amount of studies on a relationship between a target enzyme of NSAIDs, cyclooxygenase (COX) or prostaglan− din (PG, especially PGE2) and cancer development
has been reported. Especially for COX−2 whose expression is induced in inflammation and tumor, the expressional status in various types of carcino− ma was established [3], and it attracts a lot of attention as a target molecule for chemoprevention and treatment of cancer. This review describes a role of COX−2 in gastric cancer and the potential clinical use of a COX−2 inhibitor.
Enhanced PGE
2Production
and Its Role in Tumor Tissue
Production of some PGs particularly PGE2in−
creases in gastrointestinal cancer, especially colon
cancer. Particularly, PGE2 production enhances
[4]. PGE2is converted from a membrane phospho−
lipid to arachidonate under cytosolic phospholi− pase A2 (cPLA2) effect, as are other PGs. Sub−
sequently, it is converted to PGH2by COX−1 or
COX−2, and further converted to PGE2by prosta−
glandin E synthase (PGES). Among the kinds of PGES that are already discovered, analyses of microsomal PGES−1 (mPGES−1) which is indu− cible type and cytosolic PGES (cPGES) which constitutively express are reported. Interestingly, cPGES and COX−1, mPGES−1 and COX−2 are functionally coupled [5, 6]. In tumor tissue, PGH2
produced excessively by COX−2 could be effi− ciently converted to PGE2by mPGES−1 (Fig. 1),
and overexpression of COX−2 and mPGES−1 in various cancers has been reported (Tables 1, 2) [7–18].
Regarding carcinogenesis, although the effect by genetic change has been analyzed, the effect of PGE2produced in tumor tissue (tumor and stroma)
is still unknown on tumor cell proliferation. In
© Copyright by Silesian Piasts University of Medicine in Wrocław
Abstract
Recent studies have demonstrated that increased amount of prostaglandin E2(PGE2) produced by overexpression
of cyclooxygenase−2 (COX−2)/microsomal PGE synthase−1 (mPGES−1) is involved in tumor proliferation. Furthermore, relationships with epidermal growth factor (EGF)/mitogen activated protein (MAP) kinase signal pathway related to cell proliferation and Akt/protein kinase B (PKB) related to resistance of apoptosis are being clarified. Association of COX−2 with gastric cancer has not been established as clearly as in colon cancer. However, increased expression of COX−2 in gastric cancer was confirmed, and in cell culture or animal models, influence of COX−2 on tumor proliferation was indicated. Thus, the usefulness of COX−2 inhibitor in treatment has been demonstrated. However, in precancerous lesions of gastric cancer, COX−2 expression is controversial and the use− fulness of COX−2 inhibitor has not been demonstrated. Further studies about COX−2 and gastric cancer including clinical trials are needed, and also more studies should be performed about other PGE2related enzymes as well as
COX−2 (Adv Clin Exp Med 2007, 16, 3, 347–352).
a study using COX−2 knockout mice, COX−2 expression was involved in microvessel density in tumor tissue, and this resulted in decreased tumor proliferation [19]. It was also shown that COX−2 and mPGES−1−derived PGE2were associated with
angiogensis via EP2 [20, 21].
On the other hand, relationship between PGE2
and epidermal growth factor (EGF)−mitogen acti− vated protein (MAP) kinase signal pathway relat− ed to tumor proliferation has been recently report− ed. PGE2promotes release of transforming growth
factor−α (TGF−α), a ligand of EGF receptor (EGFR), and activates extracellular regulated MAP kinase2 (ERK2). After oral administration of PGE2to rats, phosphorylation of EGFR and ERK2
in mucosal epithelium was observed [22].
Cultured models confirmed that high and con− comitant expression of COX−2 and mPGES−1 increased cell proliferation activity and led to mor− phologic change, and showed tumorigenecity in
Fig. 1. Cascade of PGE2metabolism in premaliganat
and malignant tissue. PGH2produced excessively by
COX−2 could be efficiently converted to PGE2by
mPGES−1. Enhanced PGE2is maintained due to
decreased ability of PGE2metabolism by down−regu−
lated 15−PGDH
COX−2
mPGES−1
PGE2
cPLA2
membranous phospholipids
PGH2
arachidonate
15−keto−PG
15−PGDH COX−1
cPGES
Table 1. COX−2 expression in premalignant and malignant tissue
Organ Premalignancy Malignancy
Head and neck leukoplakia squamous cell carcinoma
Esophagus Barrett’s esophagus adenocarcinoma
squamous cell dysplasia squamous cell carcinoma
Stomach metaplasia adenocarcinoma
Colon adenoma adenocarcinoma
Liver chronic hepatitis hepatocellular carcinoma
Biliary System bile duct hyperplasia cholangiocarcinoma
adenocarcinoma of gall bladder Pancreas pancreatic intraepithelial neoplasia adenocarcinoma
Breast ductal carcinoma−in−situ adenocarcinoma
Lung atypical adenomatous hyperplasia adenocarcinoma
squamous cell carcinoma
Bladder dysplasia transitional cell carcinoma
squamous cell carcinoma Gynecologic cervical intraepithelial neoplasia squamous cell carcinoma
adenocarcinoma of cervix endometrial carcinoma
Penis penile intraepithelial neoplasia squamous cell carcinoma
Skin actinic keratoses squamous cell carcinoma
Table 2. mPGES−1 expression in premalignant and malignant tissue
Organ Premalignancy Malignancy
Head and neck leukoplakia squamous cell carcinoma
Esophagus (rat) Barrett’s esophagus squamous cell dysplasia
Stomach intestinal type adenocarcinoma
Colon adenoma adenocarcinoma
Biliary System cholangiocarcinoma
adenocarcinoma of gall bladder
Breast ductal carcinoma−in−situ adenocarcinoma
Lung tobacco smoke exposed adenocarcinoma
epithelial fibroblast squamous cell carcinoma
Bladder (rat) papilloma transitional cell carcinoma
Gynecologic adenocarcinoma of cervix
nude mice [23]. In transgenic mice in which these genes expressed in gastric mucosa, PGE2produc−
tion was enhanced and abnormal differentiation was observed. At 48 weeks old, hyperplastic tumor without dysplasia was also observed [24]. PGE2 produced excessively by COX−2 and
mPGES−1 is very important for in vivocell prolif− eration but insufficient for malignant change. A study using similar models showed that Wnt sig− nal, that played an important role in development of colon cancer, had importance also in develop− ment of gastric cancer (25).
COX−2 Expression
in Gastric Cancer
Recent epidemiological investigation reported that there were few mortalities from gastric cancer in aspirin users [26]. And also described that occurrence of gastric cancer decreased in long− term users of NSAIDs [27].
In gastric cancer as in various other cancers, COX−2 overexpressed [28]. The expression of COX−2 was mainly observed in tumor cells, but expression was also observed in stromal cells and macrophages. The COX−2 expression in gastric precancerous lesion was shown in intestinal meta− plasia and dysplasia [29, 30]. A comparison study between before and after Helicobacter pylori (H. pylori) eradication reported that COX−2 express− ion level decreased in epithelium and stroma after eradication, but that there was no change in intesti− nal metaplasia [31]. In the progression process of gastric mucosa to dysplasia and cancer, increased expression of COX−2 was observed [32]. In gastric adenoma, up−regulated COX−2 protein was detect− ed in stromal cells [33]. This indicates that COX− 2−derived PGE2 is associated with cell prolifera−
tion as in COX−2/mPGES−1 transgenic mice men− tioned above. Thus, further studies are needed to elucidate how COX−2 may be associated with genetic change in carcinogenesis in stomach that has not been clarified as well as in colon cancer. Recent reports confirmed p53 accumulation in all adenoma patients examined and indicated that 50% of the patients showed overexpression of COX−2. The same results were also found in gas− tric cancer; they demonstrated that the process of cancer development is different between gastric and colon cancer [34].
Regarding the clinicopathological findings and COX−2 expression in gastric cancer, various reports are provided. No relationship between COX−2 expression and age or gender was report− ed. The lower expression of COX−2 in cardiac gas− tric cancer was reported [35], and this supports the
data indicating that epidemiologically aspirin−use could not prevent cancer related death in patients with cardiac cancer. However, there are no other reports on difference in COX−2 expression by location thereafter. As for histological type and COX−2 expression, some reports showed a higher COX−2 expression in intestinal type [36–38], but no difference in another report [39]. Similarly, there is no consensus on the relationship between COX−2 expression and tumor depth, venous or lymphatic invasion, metastasis or stage [40–42]. Since most studies on association with prognosis were based on univariate analysis [43], further investigation using a large amount of clinical data such as meta−analysis are needed to clarify whether it can be an independent prognostic factor.
Potential of COX−2
Inhibitor in Gastric
Cancer Treatment
Using culture model, a COX−2 inhibitor, nimesulide inhibited proliferation of MKN−45 cells, and telomerase activity through blocking Akt/protein kinase B (PKB) pathway [44]. In SGC7901 cells, genetic or pharmacological inhibi− tion of COX−2 reduceded PGE2production. This
resulted that migration and tube formation of HUVEC and in vivoangiogenesis were also inhib− ited [45]. It was indicated that inhibited COX−2 prevented neovascularization related to gastric cancer. In xenograft model using MKN−45 and nude mice, another COX−2 inhibitor, NS398, inhibited tumor growth. NS398 administration decreased PGE2and PGF1αlevels in the tumor tis−
sue. In tumor cells, decreased bromodeoxyuridine (BrdU) index and increased apoptotic index were observed [46]. In other study using OCUM−2M, scirrhous type gastric cancer cell, and NF−21, gas− tric fibroblast, JTE−522, a COX−2 inhibitor, inhib− ited NF−21 proliferation but did not inhibit OCUM−2M proliferation. However, in xenograft model, the COX−2 inhibitor did not show a growth inhibition against OCUM−2M alone inoculated tumor but in contrast decreased the size of tumor inoculated with both of OCUM−2M and NF−21. In the tumor tissue, inhibited Ki67 and increased apoptosis were observed, and keratinocyte growth factor (KGF) production from NF−21 was decreased. In scirrhous type gastric cancer, it was demonstrated that COX−2 inhibitor controlled rel− evance to stromal cell proliferation [47]. In chem− ical carcinogenesis rat model, the COX−2 inhibitor, cerecoxib also reduced the incidence of gastric cancer and tumor volume [48].
ical effects of COX−2 inhibitor from the view of gastric cancer prevention. Although H. pylori carri− ers showed a high level of PGE2in gastric mucosa,
their PGE2 level, gastritis score and proliferation
indices were not improved after 2−week administra− tion of 25 mg, b.i.d. rofecoxib, a COX−2 inhibitor [49]. From another observation of rofecoxib admin− istration for 2 years, there was no difference in regression of intestinal metaplasia considered to be a precancerous lesion of gastric cancer, and COX−2 inhibitor could not return intestinal metaplasia of gastric mucosa to normal [50]. From these results, gastric cancer prevention should now be focused on H. pylori eradication. However, serum interleukin−8 (IL−8), tumor necrosis factor−α(TNF−α), progastrin and gastrin level were decreased in observation before and after administration of 25 mg, b.i.d. rofe− coxib for 2 weeks in gastric cancer patients. In addi− tion, the expression level of BAX and caspase−3 increased, and the expression level of Bcl−2 and sur− vivin decreased [51]. From these data, the above animal experiments and in vitroresults, it is expect− ed that a COX−2 inhibitor could be useful for gas− tric cancer treatment, and a large clinical trial must be needed.
Conclusion
and Further Directions
Considering the relationship of COX−2 in development of gastric cancer, the effect of COX− 2 inhibitor in gastric cancer treatment could be hopeful. However, there are not only results show− ing prospective effect but also various concerns. Also in results of large scale clinical trial of COX− 2 inhibitor administration for patients with colon polyps including familial adenomatous polyp, increase in cardiovascular events, adverse effects of COX−2 inhibitor, were reported [52–54], and careful attention will be needed to ensure the safe− ty of long−term use. It is expected that further investigation will be performed into what relation− ship exists between gastric cancer and regulation of mPGES−1 that draws attention in colon cancer [7], or 15−prostaglandin dehydrogenase (15− PGDH), a catabolic enzyme of PGE2(Fig. 1) [55,
56]. Besides, we hope the studies in the future that the control of these enzymes can prevent or treat gastric cancer.
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Address for correspondence:
Kenji Ogawa
Department of Surgery
Tokyo Women’s Medical University Medical Center East 2−1−10 Nishiogu, Arakawaku, Tokyo
116−8567, Japan Tel.: +81−3−3810−1111
E−mail: [email protected]
Conflict of interest: None declared