Bowel preparation for colonoscopy using standard vs reduced doses of sodium phosphate: A single-blind randomized controlled study.

AIM: To evaluate the efficacy of a colonoscopy preparation that utilizes a reduced dose of sodium phosphate (NaP) and an adjunct. METHODS: Sixty-two patients requiring screening colonoscopies were studied. Each patient was randomly allocated to receive either 50 NaP tablets (50 g) or 30 NaP tablets (30 g) with 10 mL of 0.75% sodium picosulfate for bowel preparation. NaP was administered at a rate of five tablets (5 g) or three tablets (3 g) every 15 min with 200 mL of water, beginning five to six hours before colonoscopy. The sodium picosulfate was administered with 200 mL of water on the night before the procedure. Both groups were compared in term of the efficacies of colonic cleansing, the time required for completion of the bowel preparation, and acceptability of the preparation. RESULTS: Sixty patients (n = 30 for each group) were analyzed. The cleansing efficacy tended to be higher in the 30 g NaP plus sodium picosulfate group as assessed by the mean total Ottawa scale score (50 g NaP 6.70 ± 1. 42 vs 30 g NaP plus sodium picosulfate 6.17 ± 1.18 P = 0.072). The mean time for bowel preparation tended to be shorter in the 30 g NaP plus sodium picosulfate group (50 g NaP 189.9 ± 64.0 min vs 30 g NaP plus sodium picosulfate 161.8 ± 57.6 min, P = 0.065). There were no significant differences between the two groups in the acceptability of the preparations (50 g NaP 83.3% vs 30 g NaP plus sodium picosulfate 86.7%, P = 0.500). There were no adverse events related to bowel preparation in either of the groups. CONCLUSION: The colonoscopy preparation that utilized 30 g NaP with sodium picosulfate was comparable to that utilizing 50 g NaP. This novel bowel preparation might be useful before colonoscopy.

Successful outcome after laparoscopic surgery for sporadic colonic desmoid tumor with ß-catenin mutation: a case report.

INTRODUCTION: Desmoid tumors (also called aggressive fibromatosis) are histologically benign, but have a strong tendency to recur locally after resection. They are rare neoplastic tumors that may occur sporadically or in association with familial adenomatous polyposis caused by a germline mutation in the adenomatous polyposis coli gene. The etiology of desmoid tumors is unknown, but their association with a history of abdominal surgery, trauma, and estrogen therapy is well known. CASE PRESENTATION: A 36-year-old Asian woman was referred complaining of an abdominal tumor. She had no history of familial adenomatous polyposis, abdominal surgery, trauma or pregnancy. A laparoscopy-assisted right hemicolectomy with a minilaparotomy was conducted for resection of her right-side colon and the anterior wall of her duodenum. The histopathological diagnosis was a desmoid tumor that grew from the transverse mesocolon. Mutational analysis indicated a mutation of the ß-catenin gene (CTNNB1), consisting of a substitution of threonine for alanine at codon 41. The patient has been followed postoperatively for more than 3 years without any sign of recurrence. CONCLUSION: We report a case of sporadic colonic desmoid tumor which was resected by laparoscopic surgery. A successful outcome was achieved because there has been no local recurrence for more than 3 years. The tumor grew from the transverse mesocolon, and harbored a mutation of the CTNNB1 gene. Mutational analysis of CTNNB1 gene may play an important role as a prognostic marker of desmoid tumors.

Inhibitory role of Gas6 in intestinal tumorigenesis.

Growth arrest-specific gene (Gas) 6 is a γ-carboxyglutamic acid domain-containing protein, which shares 43% amino acid identity with protein S. Gas6 has been shown to enhance cancer cell proliferation in vitro. On the other hand, recent studies have demonstrated that Gas6 inhibits toll-like receptor-mediated immune reactions. Immune reactions are known to affect intestinal tumorigenesis. In this study, we investigated how Gas6 contributes to tumorigenesis in the intestine. Administration of recombinant Gas6 weakly, but significantly, enhanced proliferation of intestinal cancer cells (SW480 and HT29), whereas it suppressed the inflammatory responses of Lipopolysaccharide (LPS)-stimulated monocytes (THP-1). Compared with Gas6(+/+) mice, Gas6(-/-) mice exhibited enhanced azoxymethane/dextran sulfate sodium (DSS)-induced tumorigenesis and had a shorter survival. Gas6(-/-) mice also exhibited more severe DSS-induced colitis. DSS-treated Gas6(-/-) mice showed attenuated Socs1/3 messenger RNA expression and enhanced nuclear factor-kappaB activation in the colonic stroma, suggesting that the target of Gas6 is stromal cells. Bone marrow transplantation experiments indicated that both epithelial cells and bone marrow-derived cells are Gas6 sources. Furthermore, the number of intestinal tumors in Apc(Min) Gas6(-/-) mice was higher than that in Apc(Min) Gas6(+/+) mice, resulting in shorter survival. In a group of 62 patients with advanced colorectal cancer, Gas6 immunoreactivity in cancer tissues was positively correlated with prognosis. Thus, we revealed a unique in vivo inhibitory role of Gas6 during the progression of intestinal tumors associated with suppression of stromal immune reactions. These results suggest a novel therapeutic approach for colorectal cancer patients by regulation of stromal immune responses.

The role of CXCR3 and CXCR4 in colorectal cancer metastasis.

Chemokines and their receptors play key roles in leukocyte trafficking and are also implicated in cancer metastasis. We previously demonstrated that forced expression of CXCR3 promotes colon cancer metastasis preferentially to the draining lymph nodes (LNs), with poor prognosis. Using clinical colorectal cancer (CRC) samples, here, we show that expressions of CXCR3 and CXCR4 are significantly higher in metastatic foci within LNs and liver compared to primary tumors, whereas ligands for CXCR3 and CXCR4 are not. We also have demonstrated that some human CRC cell lines constitutively express both CXCR3 and CXCR4, and that activation of CXCR3 strengthens the CXCR4-mediated cell migration in vitro in a synergistic manner. By constructing SW620 cell lines with reduced expression of CXCR3 and/or CXCR4 using microRNA, we investigated in vivo metastatic activities in a mouse rectal transplantation model. Six weeks after inoculation, CXCR3-, CXCR4-, and CXCR3/CXCR4 double-knockdowns significantly reduced metastasis to LNs, liver and lungs, compared to the control (p < 0.05). Importantly, its suppressive effect on LN metastasis was significantly stronger in CXCR3- and CXCR3/CXCR4 double-knockdowns. In addition, CXCR3- and CXCR3/CXCR4 double-knockdowns significantly decreased the dissemination of cancer cells to liver and lungs, even after 2 weeks. These results indicate that targeting CXCR3 and CXCR4 can be a promising therapy against CRC metastasis.

Dclk1 distinguishes between tumor and normal stem cells in the intestine.

There is great interest in tumor stem cells (TSCs) as potential therapeutic targets; however, cancer therapies targeting TSCs are limited. A drawback is that TSC markers are often shared by normal stem cells (NSCs); thus, therapies that target these markers may cause severe injury to normal tissues. To identify a potential TSC-specific marker, we focused on doublecortin-like kinase 1 (Dclk1). Dclk1 was reported as a candidate NSC marker in the gut, but recent reports have implicated it as a marker of differentiated cells (for example, Tuft cells). Using lineage-tracing experiments, we show here that Dclk1 does not mark NSCs in the intestine but instead marks TSCs that continuously produce tumor progeny in the polyps of Apc(Min/+) mice. Specific ablation of Dclk1-positive TSCs resulted in a marked regression of polyps without apparent damage to the normal intestine. Our data suggest the potential for developing a therapy for colorectal cancer based on targeting Dclk1-positive TSCs.

Clinical performance of 2 dedicated PET scanners for breast imaging: initial evaluation.

UNLABELLED: The purpose of this study was to investigate the diagnostic performance of 2 newly developed dedicated breast PET scanners in patients with known or suspected breast cancer. METHODS: Two types of scanner were evaluated, an O-shaped scanner and a C-shaped scanner. The O scanner was designed for imaging patients who were prone, and the C scanner was designed for those patients positioned leaning forward. Sixty-nine women with known or suspected breast carcinoma (80 lesions: 72 invasive carcinomas, 4 noninvasive carcinomas [ductal carcinoma in situ, or DCIS], 1 case of adenomatous ductal hyperplasia, and 3 benign lesions) were enrolled in this study. All patients underwent a conventional whole-body PET/CT scan, followed by breast scanning using both dedicated devices. The diagnostic performance of each scanner was assessed. RESULTS: The maximal diameter of invasive tumors ranged from 4 to 112 mm, with an average of 26 mm. With the O scanner, 62 of 76 malignant lesions (including 3 DCIS) were detected, 5 lesions were not detected, and the remaining 9 lesions were outside the field of view. With the C scanner, 63 of 76 malignant lesions (including 2 DCIS) were detected, 7 lesions were not detected, and the remaining 6 lesions were outside the field of view. The lesion-based sensitivities of the O and C scanners were 82% (62/76) and 83% (63/76), respectively; sensitivities excluding lesions outside the field of view were 93% (62/67) and 90% (63/70), respectively. The sensitivity of conventional PET/CT was 92% (70/76). All lesions outside the field of view were close to the chest wall. The breast-based specificities of the O, C, and conventional scanners were 98% (48/49), 98% (56/57), and 100% (70/70), respectively. CONCLUSION: Our preliminary study indicates that both dedicated breast PET scanners are clinically feasible and yield reasonably high sensitivity. More detailed information was obtained with these scanners than with the conventional scanner.

Nardilysin and ADAM proteases promote gastric cancer cell growth by activating intrinsic cytokine signalling via enhanced ectodomain shedding of TNF-α.

Nardilysin (NRDc), a metalloendopeptidase of the M16 family, promotes ectodomain shedding of the precursor forms of various growth factors and cytokines by enhancing the protease activities of ADAM proteins. Here, we show the growth-promoting role of NRDc in gastric cancer cells. Analyses of clinical samples demonstrated that NRDc protein expression was frequently elevated both in the serum and cancer epithelium of gastric cancer patients. After NRDc knockdown, tumour cell growth was suppressed both in vitro and in xenograft experiments. In gastric cancer cells, NRDc promotes shedding of pro-tumour necrosis factor-alpha (pro-TNF-α), which stimulates expression of NF-κB-regulated multiple cytokines such as interleukin (IL)-6. In turn, IL-6 activates STAT3, leading to transcriptional upregulation of downstream growth-related genes. Gene silencing of ADAM17 or ADAM10, representative ADAM proteases, phenocopied the changes in cytokine expression and cell growth induced by NRDc knockdown. Our results demonstrate that gastric cancer cell growth is maintained by autonomous TNF-α-NF-κB and IL-6-STAT3 signalling, and that NRDc and ADAM proteases turn on these signalling cascades by stimulating ectodomain shedding of TNF-α.

Relationship between 18F-fluorodeoxyglucose accumulation and KRAS/BRAF mutations in colorectal cancer.

PURPOSE: Positron emission tomography (PET) with (18)F-fluorodeoxyglucose (FDG) has been widely used in the management of colorectal cancer (CRC). However, the relationship between FDG accumulation and KRAS/BRAF mutations has not yet been investigated. The purpose of this study was to investigate whether KRAS/BRAF mutations affect FDG accumulation in CRC. EXPERIMENTAL DESIGN: Retrospective analysis was conducted in 51 patients with CRC who underwent FDG-PET/computed tomographic (CT) scans for staging before primary tumor resection. The maximum standardized uptake value (SUV(max)) for the primary tumor and the tumor-to-liver ratio (TLR) were calculated from FDG accumulation and compared between KRAS/BRAF mutated and wild-type groups. Expression levels of glucose transporter-1 (GLUT1) and hexokinase type-II (HXK-II) were assessed by immunohistochemical analysis. RESULTS: Both SUV(max) and TLR were significantly higher in the KRAS/BRAF-mutated group compared with the wild-type group (P = 0.006 and 0.001, respectively). Multivariate analysis indicated that SUV(max) and TLR remained significantly associated with KRAS/BRAF mutations (P = 0.016 and 0.01, respectively). KRAS/BRAF status could be predicted with an accuracy of 75% when a SUV(max) cutoff value of 13 or 14 was used. GLUT1 expression in cancer cells was positively correlated with FDG accumulation and KRAS/BRAF status whereas HXK-II expression was not. CONCLUSION: FDG accumulation was higher in CRC with KRAS/BRAF mutations. FDG-PET/CT scans may be useful for predicting the KRAS/BRAF status of patients with CRC and thus aid in determination of therapeutic strategies for patients with CRC.

COX-2 inhibition alters the phenotype of tumor-associated macrophages from M2 to M1 in ApcMin/+ mouse polyps.

Macrophages are a major component of tumor stroma. Tumor-associated macrophages (TAMs) show anti- (M1) or protumor (M2) functions depending on the cytokine milieu of the tumor microenvironment. Cyclooxygenase-2 (COX-2) is constitutively expressed in a variety of tumors including colorectal cancer. TAMs are known to be a major source of COX-2 in human and mice intestinal tumors. COX-2 inhibitor reduces the number and size of intestinal adenomas in familial adenomatous polyposis patients and Apc(Min/+) mice. Although COX-2 inhibitor is thought to regulate cancer-related inflammation, its effect on TAM phenotype remains unknown. Here, we examined the effects of COX-2 inhibition on TAM phenotype and cytokine expression both in vivo and in vitro. Firstly, the selective COX-2 inhibitor celecoxib changed the TAM phenotype from M2 to M1, in proportion to the reduction in number of Apc(Min/+) mouse polyps. Concomitantly, the expression of M1-related cytokine interfron (IFN)-γ was significantly upregulated by celecoxib, although the M2-related cytokines interleukin (IL)-4, IL-13 and IL-10 were not significantly altered. Secondly, IFN-γ treatment attenuated M2 phenotype of mouse peritoneal macrophages and oriented them to M1 even in the presence of M2-polarizing cytokines such as IL-4, IL-13 and IL-10. Thus, our results suggest that COX-2 inhibition alters TAM phenotype in an IFN-γ-dependent manner and subsequently may reduce intestinal tumor progression.

Transcriptional factor Prox1 plays an essential role in the antiproliferative action of interferon-γ in esophageal cancer cells.

BACKGROUND: We previously reported interferon-γ (IFN-γ)-induced apoptosis in 10 (32%) of 31 esophageal squamous cell carcinoma (ESCC) cell lines. However, the molecular basis of antiproliferative action by IFN-γ remains elusive. Here we demonstrate that IFN-γ induces transcriptional factor Prox1, and we explore the link between Prox1 and the IFN-γ system in ESCC cells. METHODS: By using ESCC cell lines, we investigated the relationship between p53 mutations and the responsibility to IFN-γ, and studied the role of Prox1 in the antiproliferative effect of IFN-γ by knockdown and overexpression methods. RESULTS: p53 mutations were found in seven of nine ESCC cell lines responsible for IFN-γ. The frequency was not different from that of p53 mutations in total ESCC cell lines (21 of 28 cell lines). Treatment of ESCC cells with IFN-ß but not IFN-γ resulted in increase of p53 messenger RNA (mRNA) expression, whereas IFN-γ but not IFN-ß induced cell growth inhibition of ESCCs harboring p53 mutations. IFN-γ induced Prox1 expression in ESCC cells but not in those transfected with dominant-negative STAT1. Cell growth inhibition by IFN-γ was significantly suppressed in ESCC cells transfected with Prox1 short interfering RNA (siRNA). In addition, overexpression of Prox1 induced antiproliferative effect in ESCC cells. We also demonstrate that Prox1 is expressed in primary esophageal cancer tissues (five of nine samples treated with neoadjuvant chemotherapy before surgery). CONCLUSIONS: Prox1 mediates the antiproliferative effect by IFN-γ in ESCC cells. Prox1 may be a candidate target for novel therapeutic strategies of ESCCs.

Pharmacokinetics of prophylactic micafungin in very-low-birth-weight infants.

We evaluated the use of micafungin as a prophylaxis in very-low-birth-weight infants. Micafungin was first administered to 25 very-low-birth-weight infants 12 to 24 hours after birth at a dose of 1 mg/kg/d. the apparent volume of distribution, the apparent elimination rate constant, the elimination half-life, and the total body clearance (mean +/- SD) were 0.76 +/- 0.28 L/kg, 0.12 +/- 0.041 1/h, 6.7 +/- 2.2 h, and 0.089 +/- 0.047 L/kg/h, respectively.

A unique B2 B cell subset in the intestine.

Over 80% of the body's activated B cells are located in mucosal sites, including the intestine. The intestine contains IgM(+) B cells, but these cells have not been characterized phenotypically or in terms of their developmental origins. We describe a previously unidentified and unique subset of immunoglobulin M(+) B cells that present with an AA4.1(-)CD21(-)CD23(-) major histocompatibility complex class II(bright) surface phenotype and are characterized by a low frequency of somatic hypermutation and the potential ability to produce interleukin-12p70. This B cell subset resides within the normal mucosa of the large intestine and expands in response to inflammation. Some of these intestinal B cells originate from the AA4.1(+) immature B2 cell pool in the steady state and are also recruited from the recirculating naive B cell pool in the context of intestinal inflammation. They develop in an antigen-independent and BAFF-dependent manner in the absence of T cell help. Expansion of these cells can be induced in the absence of the spleen and gut-associated lymphoid tissues. These results describe the existence of an alternative pathway of B cell maturation in the periphery that gives rise to a tissue-specific B cell subset.

Chitinase 3-like-1 enhances bacterial adhesion to colonic epithelial cells through the interaction with bacterial chitin-binding protein.

Dysregulated host/microbial interactions play a pivotal role in the pathogenesis of inflammatory bowel disease. We previously reported that chitinase 3-like-1 (CHI3L1) enhances bacterial adhesion and invasion on/into colonic epithelial cells (CECs). In this study, we designed to identify the exact mechanism of how CHI3L1 enhances the bacterial adhesion on CECs in vitro. As compared with wild type (WT) of Serratia marcescens, chitin binding protein (CBP) 21 knockout strain of S. marcescens significantly decreased the adhesion to SW480 cells that express CHI3L1 endogenously. A CBP21 fusion protein was produced with CBP21-expressing vector, which was transformed into BL21 strain of Escherichia coli. CBP21 overexpression significantly increased the adhesion, but not invasion, of nonpathogenic E. coli. The adhesion of S. marcescens and CBP21-overexpressing E. coli was inhibited by coculture with chitin, but not with other carbohydrates. After overexpressing CHI3L1 on SW480 cells, the adhesion rate of CBP21-overexpressing E. coli was further increased by approximately twofold. Genetically engineered E. coli with a single mutation of either Thy-54 or Glu-55 position of CBP21 exhibited a decreased binding ability, and the binding was 74% diminished by the combined mutations of three amino acids (Thy-54, Glu-55 and Glu-60) as compared with WT. Inhibition of CHI3L1 by anti-CHI3L1 antibody or CHI3L1-specific short interfering RNA reduced the adhesion of CBP21-overexpressing E. coli to CECs. In conclusion, CHI3L1 is involved in the enhancement of CBP-expressing bacterial adhesion to CECs. CBP21 and its homologs may be required for the CHI3L1-mediated enhancement of bacterial adhesion to CECs through the conserved amino-acid residues.

TNF receptor type I-dependent activation of innate responses to reduce intestinal damage-associated mortality.

BACKGROUND & AIMS: Ligation of tumor necrosis factor (TNF) receptors (TNFRs) with TNF plays a critical role in the pathogenesis of human inflammatory bowel disease (IBD). However, it remains unclear which cell types activated through TNFR-associated signaling cascades are involved in the pathogenesis of colitis. METHODS: Recombination activating gene-1 (RAG) knockout (KO) (no T or B cells)-based TNFR double and triple KO mice were generated. Bone marrow (BM) chimera mice in which BM-derived myeloid cells, but not colonic epithelial cells (CECs), express TNFRs were also generated. Colitis was induced by administration of dextran sodium sulfate (DSS) in distilled water. Murine lines and chimeras were assessed for disease severity, histopathology, apoptotic cell rate, epithelial proliferation, and bacterial invasion rate. RESULTS: Following DSS administration, mice lacking both RAG and TNFR1 exhibited a high mortality (>80%) rate with an impaired CEC regeneration compared with RAG KO and RAG x TNFR2 double KO (DKO) mice. Transplantation of RAG KO-derived BM cells restored CEC regeneration and rescued the majority of recipient RAG x TNFR1 DKO mice from DSS-induced mortality. After BM transplantation, RAG x TNFR1 DKO mice exhibited an increased rate of apoptosis in the colonic lamina propria macrophages in association with the activation of caspases. In addition, BM reconstitution directly or indirectly enhanced the proliferation of CECs by activating mitogen-activated protein kinase and phosphoinositide-3 kinase/Akt pathways. CONCLUSIONS: TNFR1-signaling cascade in colonic myeloid lineage cells contributes to the suppression of acute damage-associated mortality presumably by controlling CEC homeostasis.

Insights from advances in research of chemically induced experimental models of human inflammatory bowel disease.

Inflammatory bowel disease (IBD), the most important being Crohn's disease and ulcerative colitis, results from chronic dysregulation of the mucosal immune system in the gastrointestinal tract. Although the pathogenesis of IBD remains unclear, it is widely accepted that genetic, environmental, and immunological factors are involved. Recent studies suggest that intestinal epithelial defenses are important to prevent inflammation by protecting against microbial pathogens and oxidative stresses. To investigate the etiology of IBD, animal models of experimental colitis have been developed and are frequently used to evaluate new anti-inflammatory treatments for IBD. Several models of experimental colitis that demonstrate various pathophysiological aspects of the human disease have been described. In this manuscript, we review the characteristic features of IBD through a discussion of the various chemically induced experimental models of colitis (e.g. dextran sodium sulfate-, 2,4,6-trinitrobenzene sulfonic acid-, oxazolone-, acetic acid-, and indomethacin-induced models). We also summarize some regulatory and pathogenic factors demonstrated by these models that can, hopefully, be exploited to develop future therapeutic strategies against IBD.

Role of mammalian chitinases in inflammatory conditions.

It has been hypothesized that dysregulated host/microbial interactions play a pivotal role in the pathogenesis of inflammatory bowel disease. However, the exact mechanisms underlying the induction and perpetuation of the intestinal disorder are unclear. Recently, we unexpectedly discovered significantly upregulated gene expression of chitinase 3-like-1 in inflamed colon of the dextran sulfate sodium-induced colitis model by employing the DNA-microarray analysis. Chitinase 3-like-1 has a chitin binding ability, but lacks the enzymatic activity of lysing microbial cell wall. Chitinase 3-like-1 protein is mainly expressed in colonic epithelial cells and macrophages in the inflamed colon of dextran sulfate sodium-induced colitis. Chitinase 3-like-1, which can be upregulated after pro-inflammatory cytokine stimulation, possesses an ability to enhance the adhesion and internalization of intracellular bacteria into colonic epithelial cells. Most importantly, in vivo neutralization of chitinase 3-like-1 significantly suppressed the development of dextran sulfate sodium-induced colitis by dramatically decreasing the bacterial adhesion and invasion into colonic epithelial cells. Furthermore, anti-chitinase 3-like-1 antibody-treated mice exhibited a significantly lower load of Salmonella typhimurium in peripheral organs as compared to control rabbit IgG-treated mice. Recently, it has been reported that acidic mammalian chitinase is expressed in the setting of T helper-2-associated inflammation and subsequently induces airway hyperresponsiveness in allergic asthma patients. In addition, pan-chitinase inhibitor significantly ameliorates T helper-2-mediated inflammation and airway hypersensitivity. These studies provide to be a novel insight into the physiological role of mammalian chitinases in host/microbial interactions, and inhibition of chitinase activity would be considered a novel therapeutic strategy of allergic and inflammatory disorders.

Growth arrest-specific gene 6 and Axl signaling enhances gastric cancer cell survival via Akt pathway.

Activation of tyrosine kinases is an important factor during cancer development. Axl, one of the receptor tyrosine kinases, binds to the specific ligand growth arrest-specific gene 6 (Gas6), which encodes a vitamin K-dependent gamma-carboxyglutamyl protein. Although many receptor tyrosine kinases and their ligands are involved in gastric carcinogenesis, whether Gas6-Axl signaling is involved in gastric carcinogenesis has not been elucidated. The aim of this study was to investigate the expression of Gas6 and Axl in gastric cancer and also their roles during gastric carcinogenesis. mRNA and protein of Gas6 and Axl were highly expressed in a substantial proportion of human gastric cancer tissue and cell lines, and Gas6 expression was significantly associated with lymph node metastasis. With recombinant Gas6 and a decoy-receptor of Axl in vitro, we demonstrated that Gas6-Axl signaling pathway enhanced cellular survival and invasion and suppressed apoptosis via Akt pathway. Our results suggests that Gas6-Axl signaling plays a role during gastric carcinogenesis, and that targeting Gas6-Axl signaling could be a novel therapeutic for gastric cancer.

Signal transducers and activators of transcription 3 activation is involved in nuclear accumulation of beta-catenin in colorectal cancer.

Nuclear accumulation of beta-catenin is a key event for the development of colorectal cancer. Little is known, however, about the mechanisms underlying translocation of beta-catenin from the cytoplasm or the membrane to the nucleus. The present study examined whether signal transducers and activators of transcription 3 (STAT3) activation is involved in the nuclear accumulation of beta-catenin in colorectal cancer cells. Of the 90 primary colorectal cancer tissues, 40 (44.4%) were positive for nuclear staining of p-STAT3 and 63 (70.0%) were positive for nuclear staining of beta-catenin. The nuclear staining of both p-STAT3 and beta-catenin were observed predominantly in the periphery of the cancer tissues. Importantly, of the 40 tumors with p-STAT3 nuclear staining, 37 (92.5%) were also positive for nuclear beta-catenin staining and there was a significant correlation between p-STAT3 and beta-catenin nuclear staining (P < 0.01). Coexpression of nuclear p-STAT3 and beta-catenin was associated with lower patient survival (P < 0.01). In an in vitro study using a human colon cancer cell line, SW480, inhibition of STAT3 by dominant negative STAT3 or the Janus kinase inhibitor, AG490, induced translocation of beta-catenin from the nucleus to the cytoplasm or membrane. Luciferase assays revealed that STAT3 inhibition resulted in significant suppression of beta-catenin/T-cell factor transcription in association with significant inhibition of cell proliferation (P < 0.05). These findings suggest that in colorectal cancer, STAT3 activation is involved in the nuclear accumulation of beta-catenin, resulting in poor patient survival.

Involvement of cyclooxygenase-2 in gastric mucosal hypertrophy in gastrin transgenic mice.

Gastrin promotes gastric mucosal growth, and hypergastrinemia induces gastric mucosal hypertrophy. Recently, it has been reported that gastrin induces cyclooxygenase-2 (COX-2) in human gastric and colorectal cancer cell lines. However, whether COX-2 is involved in gastrin-induced gastric mucosal growth in vivo is unknown. We investigated the role of COX-2 in gastrin-induced gastric mucosal hypertrophy using gastrin transgenic mice. Hypergastrinemic mice [mice with mutated gastrin under the control of the beta-actin promoter (ACT-GAS mice)] received the COX-2 inhibitor celecoxib (0, 200, or 500 mg/kg of diet) from 5 wk of age and were killed at 16 or 24 wk. Some ACT-GAS mice received celecoxib from 16 wk and were killed at 24 wk. Eighty-week-old ACT-GAS mice without celecoxib treatment were also examined. The thickness of the gastric mucosa, cell populations, COX-2 expression, and PGE(2) levels were evaluated. All ACT-GAS mice showed gastric mucosal hypertrophy, and four of six 80-wk-old ACT-GAS mice developed gastric cancer. COX-2 was expressed in interstitial cells of the hypertrophic gastric mucosa and gastric cancers. Moreover, PGE(2) levels in the gastric mucosa of ACT-GAS mice were significantly higher than those of normal mice. With treatment with celecoxib, PGE(2) levels, the gastric mucosal thickness, and the number of total gastric cells per gastric gland of ACT-GAS mice were significantly decreased. The decrease in gastric mucosal thickness was caused by a reduction of foveolar hyperplasia. The thickness of glandules and the number of Ki67-positive cells were not significantly changed. In conclusion, COX-2 contributes to gastrin-induced mucosal hypertrophy of the stomach.

STAT3 is constitutively activated and supports cell survival in association with survivin expression in gastric cancer cells.

Signal transduction and activator of transcription 3(STAT3) signaling is constitutively activated in various tumors, and is involved in cell survival and proliferation during oncogenesis. There are few reports, however, on the role of STAT3 signaling in gastric cancer. The aim of the present study was to clarify the role of STAT3 signaling in apoptosis and cellular proliferation in gastric cancer. Here we reported that STAT3 was constitutively activated in various human gastric cancer cells and its inhibition by ectopic dominant-negative STAT3 or Janus kinase inhibitor, tyrphostin AG490, induced apoptosis. Furthermore, STAT3 inhibition markedly decreased survivin expression, and forced expression of survivin rescued AGS cells from apoptosis induced by STAT3 inhibition. Although some reports demonstrated that the PI3K/Akt pathway regulates survivin expression, inhibition of the PI3K/Akt pathway did not affect survivin expression in AGS and MKN1 cells. Finally, activated form of STAT3, Tyr-705 phospho-stat3, was found in the nucleus of cancer cells in 11 of 40 (27.5%) human gastric cancer specimens. These findings suggest that constitutively activated STAT3 signaling supports gastric cancer cell survival in association with survivin expression.2004