Although stromal cell-derived factor (SDF)-1a and its receptor CXCR4 are experimentally suggested to be involved in tumorigenicity, the clinicopathological significance of their expression in human disease is not fully understood. We examined SDF-1a and CXCR4 expression in colorectal cancers (CRCs) and their related lymph nodes (LNs), and investigated its relationship to clinicopathological features. Specimens of 60 primary CRCs and 27 related LNs were examined immunohistochemically for not only positivity but also immunostaining patterns for SDF-1a and CXCR4. The relationships between clinicopathological features and SDF-1a or CXCR4 expression were then analysed. Stromal cell-derived factor-1a and CXCR4 expression were significantly associated with LN metastasis, tumour stage, and survival of CRC patients. Twenty-nine of 47 CXCR4-positive CRCs (61.7%) showed clear CXCR4 immunoreactivity in the nucleus and a weak signal in the cytoplasm (nuclear type), whereas others showed no nuclear immunoreactivity but a diffuse signal in the cytoplasm and at the plasma membrane (cytomembrane type). Colorectal cancer patients with nuclear CXCR4 expression showed significantly more frequent LN metastasis than did those with cytomembrane expression. Colorectal cancer patients with nuclear CXCR4 expression in the primary lesion frequently had cytomembrane CXCR4-positive tumours in their LNs. In conclusion, expression of SDF-1a and nuclear CXCR4 predicts LN metastasis in CRCs.

Colorectal cancer (CRC) results from the progressive accumulation of genetic and epigenetic alterations that lead to the transformation of normal colonic mucosa to adenocarcinoma. Approximately 75% of CRCs are sporadic and occur in people without genetic predisposition or family history of CRC. During the past two decades, sporadic CRCs were classified into three major groups according to frequently altered/mutated genes. These genes have been identified by linkage analyses of cancer-prone families and by individual mutation analyses of candidate genes selected on the basis of functional data. In the first half of this review, we describe the genetic pathways of sporadic CRCs and their clinicopathologic features. Recently, large-scale genome analyses have detected many infrequently mutated genes as well as a small number of frequently mutated genes. These infrequently mutated genes are likely described in a limited number of pathways. Gene-oriented models of CRC progression are being replaced by pathway-oriented models. In the second half of this review, we summarize the present knowledge of this research field and discuss its prospects.

This study demonstrates that colonic HO-1 may be a prognostic marker of colorectal-cancer outcome.

Regenerating gene family members 1 (REG Ia) and 4 (REG IV) are overexpressed in a subset of gastric cancers. However, comparative characterization of the expression of these family proteins has remained unclear. Therefore, we aimed to elucidate not only the association between REG protein expression and mucin phenotype but also their significance as a prognostic marker for patients with gastric cancer. The expression of REG Ia, REG IV, CDX2, MUC2, and MUC5AC in gastric cancer tissues was examined by immunohistochemistry. The relationship between REG protein expression and clinicopathological parameters or mucin phenotype was then analyzed. REG Ia and REG IV expression was positive in 33 (52%) and 31 (49%) of 63 gastric cancers examined, respectively. REG Ia expression was significantly related to venous invasion and tumor stage, whereas REG IV expression showed no relationship to clinicopathological features. With regard to mucin phenotype, REG IV expression was significantly correlated with MUC2 and CDX2 expression, suggesting an association with the intestinal mucin phenotype of gastric cancer. On the other hand, REG Ia expression had no correlation with MUC2, CDX2, or MUC5AC in gastric cancer tissues. Expression of REG Ia but not REG IV was an independent predictor of poor outcome in patients with gastric cancer. In addition, patients with gastric cancer negative for both REG Ia and REG IV expression had a significantly better outcome than patients positive for either REG Ia or REG IV. Profiling of REG protein expression is useful to for prognostication of patients with gastric cancer. Modern Pathology ( The regenerating gene (Reg) was originally isolated from regenerating rat pancreatic islets, 1 and its gene product was shown to have a trophic effect on not only islet but also gastric epithelial cells. 2,3 Recently, many Reg-related genes have been isolated and shown to constitute a multigene family. 4 Among human REG family proteins, REG Ia and REG IV are reportedly overexpressed in a subset of gastric cancer. 5-9 Moreover, several microarray analyses have recently isolated REG Ia and REG IV as novel genes that are overexpressed in gastric cancer tissues, 10,11 suggesting that both genes have important functions in gastric carcinogenesis. Indeed, we have previously clarified that REG Ia acts as a trophic and/or anti-apoptotic factor in the development of gastric cancer, 12 and others have reported that REG IV protein confers cell resistance to chemotherapeutic agents, 9 suggesting that these proteins are both associated with tumor progression. It is noteworthy that in non-neoplastic tissues REG Ia and REG IV are commonly expressed not only in endocrine cells but also in metaplastic cells that frequently accompany gastric cancer lesions, 5,8,12,13 implying a possible link between REG protein expression and mucin phenotype of gastric lesions. In addition, there is increasing speculation as to whether REG Ia and REG IV protein expression may

Stem cells are undifferentiated cells capable of proliferation, self‐renewal, and production of a large number of differentiated progeny. Stem cells exist even in malignancies. They are called cancer stem cells, which may represent the origin of these tumors and may be one of the reasons of chemoresistance. The phosphatidylinositol‐3‐kinase (PI3K)/Akt pathway is important for the maintenance of pluripotency in stem cells. Flow cytometry assay for identifying stem cells defines a side population of cells that displays low fluorescent dye and is highly enriched for stem cells. The dye efflux is attributed to expression of ATP‐binding cassette transporters such as P‐glycoprotein and breast cancer resistance protein (BCRP)/ABCG2, which also transport a variety of anticancer drugs. The PI3K/Akt pathway can modulate functions of ABC transporters through various mechanisms. Reportedly, inhibition of the PI3K/Akt pathway caused BCRP translocation in hematopoietic stem cells and glioma stem‐like cells. On the other hand, a PI3K inhibitor, LY294002, reversed multidrug resistance in cancer cells that overexpress BCRP not by affecting BCRP translocation but putatively as a competitive inhibitor. Other PI3K inhibitors, wortmannin and PI‐103, did not reverse BCRP‐mediated drug resistance. Since LY294002 is a derivative of quercetin that is a naturally occurring flavonoid, its chemical structure is similar to those of a group of flavonoids but those of wortmannin and PI‐103 are quite different. It is known that many flavonoids are inhibitors of BCRP and PI3K. LY294002 has also been reported to exert inhibitory effects on multidrug resistance‐associated protein 1 (MRP1) function via dual mechanisms, competitive block of substrate transport and modulation of expression. Furthermore, LY294002 has been found to antagonize transport activity of P‐glycoprotein without influencing its expression. Taken together, LY294002 can inhibit all BCRP, P‐glycoprotein, and MRP1, which are three major ABC transporters that are highly expressed in stem cells and cause multidrug resistance. Due to its versatile effects, LY294002 could be a lead compound for developing more effective and tolerable reagents for cancer treatment.

Regenerating gene (Reg) family proteins, which are classified into four types, commonly act as trophic and/or antiapoptotic factors in gastrointestinal (GI) diseases. However, it remains unclear how these proteins coordinate their similar roles under such pathophysiological conditions. Here, we investigated the interrelationships of Reg family gene expression with mucosal cell proliferation and apoptosis in nonsteroidal anti-inflammatory drug (NSAID)-induced GI injury. GI injury was induced by subcutaneous injection of indomethacin into Reg I knockout (KO) and wild-type (WT) mice, and its severity was scored histopathologically. Temporal changes in the expression of Reg family genes, mucosal proliferation, and apoptosis were evaluated throughout the GI tract by real-time RT-PCR, Ki-67 immunoreactivity, and TUNEL assay, respectively. Reg I, Reg III family, and Reg IV were predominantly expressed in the upper, middle, and lower GI mucosa, respectively. Expression of Reg I and Reg III family genes was upregulated in specific portions of the GI tract after indomethacin treatment. Ki-67-positive epithelial cells were significantly decreased in the gastric and small-intestinal mucosa of Reg I KO mice under normal conditions. After treatment with indomethacin, the number of TUNEL-positive cells was significantly greater throughout the GI mucosa in Reg I KO mice than in WT mice. Expression of Reg I was independent of that of other Reg family genes in, not only normal GI tissues, but also indomethacin-induced GI lesions. Members of the Reg gene family show distinct profiles of expression in the GI tract, and Reg I independently plays a role in protecting the GI mucosa against NSAID-induced injury.Reg; nonsteroidal anti-inflammatory drug; proliferation; apoptosis; gastrointestinal mucosa NONSTEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDs) are commonly prescribed worldwide for patients with arthritis or cardiac and cerebrovascular diseases (16). Upper gastrointestinal (GI) damage is a major adverse effect of NSAID use (16), and, moreover, recent evidence suggests that NSAIDs are responsible for mucosal injury, not only in the upper, but also the lower GI tract (10, 16). Prostaglandin synthesis is considered to play a pivotal role in the mechanism of NSAID-induced GI damage (21); however, its pathophysiology still remains to be elucidated.The regenerating gene (Reg) was originally isolated from rat regenerating pancreatic islet cells, and its human homolog was named REG I␣ (23). Recently, many Reg-related genes have been isolated and shown to constitute a multigene family (types I-IV) (8). We have previously reported that REG I␣ and REG IV are involved in the pathophysiology of GI inflammation (5, 17) and that, moreover, they act as trophic and/or antiapoptotic factors under inflammatory conditions (17, 18). Other investigators have reported that Reg III family genes are overexpressed in inflamed GI mucosa (11,13) and that their products, including REG I␣ and REG IV proteins, may exert trophic and/or antiapoptotic effects on panc...

SummaryThe efficacy of tolvaptan for treating heart failure has already been shown. Adequate data relating to the effect of tolvaptan on the correlation of water balance in renal disease are not available. A retrospective study was conducted on the efficacy and adverse reactions of tolvaptan for treating nephrotic syndrome.The subjects were 26 patients with chronic kidney failure due to diabetic nephropathy with heart failure who were administered tolvaptan and seen between December 2011 and October 2013. The endpoints were urinary output, physical findings, and blood analyses. The expression of aquaporin-2 in the collecting duct, which is related to the action of tolvaptan, was investigated by immunohistochemistry using the kidney tissue obtained for the diagnosis.Responses were seen in 19 of the patients. In the histopathological investigation there was severe glomerulosclerosis in patients with diabetic nephropathy, but the responders were noticeable in that they only had mild tubulointerstitial damage. Non-responders exhibited profound tubulointerstitial damage. The expression of aquaporin-2 was determined in 8 patients, of which 7 were responders who tested positive for aquaporin-2. The remaining case was a non-responder who showed no expression of aquaporin-2.Tolvaptan is considered effective for some cases of nephrotic syndrome. There are no clear parameters for predicting an effect, but the present study showed that aquaporin-2 was expressed in the epithelial cells of the collecting ducts of tolvaptan responders. (Int Heart J 2014; 55: 533-538)

Abstract. Cellular responses toward cytotoxic drugs are influenced by crosstalk between oncogenic signals and resistance mechanisms. Inhibition of the PI3K/Akt pathway is effective in sensitizing cancer cells of various organs, although the mechanisms largely remain to be elucidated. Breast cancer resistance protein (BCRP)/ABCG2, a drug efflux pump, confers resistance to multiple anticancer agents such as SN-38 and topotecan. Previous studies reported that inhibition of the PI3K/Akt pathway, by gene knockout or PI3K inhibitors, modulated BCRP-mediated drug transport via BCRP translocation in hematopoietic stem cells, renal polarized cells and glioma stem-like cells of mammals. In this study, we assessed the effects of PI3K inhibitors, LY294002 and wortmannin, on BCRP-mediated anticancer drug resistance of human cancer MCF-7 and A431 cells. LY294002, but not wortmannin, reversed the BCRP-mediated SN-38 and topotecan resistance. LY294002 treatment did not affect total or cell surface BCRP levels as determined by western blotting and flow cytometry but blocked BCRP-mediated topotecan efflux in a dose-dependent manner. Immunohistochemical analyses also demonstrated unchanged cellular BCRP distribution. BCRP overexpression in MCF-7 and A431 cells did not confer LY294002 resistance, suggesting that LY294002 is not a transported substrate of BCRP. LY294002 is a derivative of quercetin, a member of flavonoids. Taken together, these results suggest that LY294002 inhibits BCRP-mediated drug transport not by BCRP translocation through the PI3K/ Akt signal but putatively as a competitive inhibitor in a major subset of cancer cells. Due to its dual effects, LY294002 could be a lead compound for developing more effective and tolerable reagents for cancer treatment.