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Few large epidemiological studies have evaluated the association between dietary advanced glycation end products (AGEs) and cancer risk. We evaluated the relationship between dietary AGE intake and the incidence of total cancer and site‐specific cancers in a population‐based prospective study in Japan. Participants were 14,173 men and 16,549 women who were 35 years of age or older in 1992. Dietary intake was assessed via a validated food frequency questionnaire. Intake of the AGE Nε‐carboxymethyl‐lysine (CML) was estimated using databases of CML content in foods determined using ultraperformance liquid chromatography–tandem mass spectrometry. Cancer incidence was confirmed through regional population‐based cancer registries. During a mean follow‐up period of 13.3 years, 1954 men and 1477 women developed cancer. We did not observe a significant association between CML intake and the risk of total cancer in men or women. In men, compared with the lowest quartile of CML intake, the hazard ratios of liver cancer for the second, third, and highest quartiles were 1.69 (95% CI: 0.92–3.10), 1.48 (95% CI: 0.77–2.84), and 2.10 (95% CI: 1.10–3.98; trend p = 0.04). Conversely, a decreased relative risk of male stomach cancer was observed for the second and highest quartiles of CML intake versus the lowest quartile, with hazard ratios of 0.73 and 0.67, respectively (trend p = 0.08). Our finding on the potential harmfulness of consuming AGEs on liver cancer risk is intriguing and warrants further study. A high intake of advanced glycation end products Nε‐carboxymethyl‐lysine was associated with an increased risk of liver cancer in Japanese men. Our finding suggests the potential harmfulness of consuming advanced glycation end products on liver cancer risk.

There is some biological plausibility that exogenous melatonin plays a role in preventing liver carcinogenesis. There has been little research on the association between melatonin intake in a normal diet and health outcomes. We evaluated the association between dietary melatonin intake and the incidence of liver cancer in a population‐based prospective study in Japan. This study included 30,824 residents of Takayama city who were 35 years of age or older in 1992 and had participated in the Takayama study, Japan. Dietary intake was assessed using a validated food frequency questionnaire at the baseline. Melatonin content in foods was measured by liquid chromatography–tandem mass spectrometry. Cancer incidence was confirmed through regional population‐based cancer registries in Gifu. Liver cancer was defined as code C22 according to the International Classification of Diseases and Related Health Problems, 10th Revision. Hazard ratios for liver cancer were estimated for the tertile groups of melatonin intake using a Cox proportional hazards model. During the mean follow‐up period of 13.6 years, 189 individuals developed liver cancer. Compared with subjects in the lowest tertile of melatonin intake, those in the middle and highest tertiles had decreased risks of liver cancer, with a significant linear trend after multivariate adjustments (hazard ratios: 0.64 and 0.65, respectively, trend p  = 0.023). There was no significant interaction by sex (interaction p  = 0.54). This initial finding, which needs to be confirmed by further studies, suggests that consuming melatonin‐containing foods might play a role in the prevention of liver cancer.

The escape of preneoplastic cells from the immune system, which is caused by immune tolerance, occurs during the development of several types of tumors. Indoleamine 2,3‐dioxygenase (IDO) plays a critical role in the induction of immune tolerance. In the present study we investigated the effects of 1‐methyltryptophan (1‐MT), an IDO inhibitor, and (−1;)‐epigallocatechin gallate (EGCG), the major catechin in green tea, on the development of azoxymethane (AOM)‐induced colonic preneoplastic lesions by focusing on the inhibition of IDO. To induce colonic premalignant lesions, male F344 rats were injected with AOM (20 mg/kg body weight, s.c.) once a week for 2 weeks. They also received 0.2% 1‐MT or 0.1% EGCG in their drinking water for 4 weeks, starting 1 week before the first dose of AOM. Both 1‐MT and EGCG significantly decreased the total number of aberrant crypt foci and β‐catenin‐accumulated crypts, which overexpressed IDO protein. Treatment with EGCG decreased IDO mRNA expression in both the colonic epithelium and stroma of rats induced by AOM. The AOM‐induced increase in cyclooxygenase‐2 mRNA expression in the colonic stroma was significantly decreased by EGCG. Furthermore, AOM‐induced increases in IDO activity in the serum and stroma were significantly inhibited by 1‐MT and EGCG. Inhibition of IDO activity by 1‐MT and EGCG was also observed in cell‐free assays. These findings suggest that upregulation of IDO activity is observed in the early stages of colon carcinogenesis and that the use of IDO inhibitors, such as 1‐MT and EGCG, which suppress the occurrence of colonic preneoplastic lesions, could be a novel strategy for the chemoprevention of colon cancer. (Cancer Sci 2012; 103: 951–958)

We determined the effects of several non‐steroidal anti‐inflammatory drugs (NSAIDs), aspirin (acetylsalicylic acid, ASA), indomethacin and a cyclooxygenase‐2 (COX‐2)‐selective inhibitor (NS398), on cellular proliferation and regulation of COX‐2 protein expression in endometrial cancer cells in vitro, and investigated their modes of action. All three NSAIDs markedly inhibited the proliferation of Ishikawa, HEC‐1A and AN3CA endometrial cancer cell lines in a time‐ and concentration‐dependent manner. ASA and indomethacin triggered apoptosis in cells of all three lines through release of cytosolic cytochrome c, activation of caspase‐9 and ‐3, and cleavage of poly(ADP‐ribose) polymerase (PARP), but NS398 induced minimal apoptosis only in Ishikawa cells. ASA altered the cell cycle distribution, with G2/M phase accumulation of cells, and induced overexpression of Ki‐67 protein. Both ASA and indomethacin reduced the protein levels of Bcl‐2 and Bcl‐xl, but upregulated those of Bax and Bcl‐xs. COX‐2 protein expression and PGE2 production were upregulated by ASA and indomethacin in all three cell lines. However, NS398 did not alter COX‐2 protein expression or PGE2 production in these cells. These results indicate that NSAIDs inhibit proliferation of endometrial cancer cells independently of the reduction of COX‐2 protein expression. A cytochrome c‐dependent apoptotic pathway and/or cell cycle arrest may contribute to the inhibitory effects of these NSAIDs.

Indoleamine 2,3‐dioxygenase (IDO), an enzyme that degrades the essential amino acid l‐tryptophan along the kynurenine pathway, exerts immunomodulatory effects in a number of diseases. IDO expression is increased in tumor tissue and in draining lymph nodes; this increase is thought to play a role in tumor evasion by suppressing the immune response. A competitive inhibitor of IDO is currently being tested in clinical trials for the treatment of relapsed or refractory solid tumors, but the efficacy of IDO inhibition in colorectal tumors remains to be fully elucidated. In this study, we investigated the effect of IDO deficiency on colon tumorigenesis in mice by genetic deletion and pharmacological inhibition. Ido1‐deficient(−/−) mice were crossed with ApcMin/+ mice or were administered azoxymethane with or without dextran sodium sulfate. Ido1 deficiency did not lead to significant differences in the size and number of colon tumors. Similarly, the pharmacological inhibition of IDO using 1‐methyltryptophan (1‐mT) also resulted in no significant differences in tumor size and number in ApcMin/+ mice. However, Ido1 deficiency altered the immune response in the tumor microenvironment, showing a significant increase in mRNA expression of pro‐inflammatory cytokines and a significant decrease in the number of Foxp3‐positive regulatory T cells in the colon tumors of Ido1(−/−) mice. Importantly, 1‐mT treatment also significantly altered cytokine expression in the colon tumor tissues. These results suggest that IDO inhibition alone cannot sufficiently suppress colon cancer development in mice despite its immunomodulatory activity in the tumor microenvironment. We demonstrated that genetic deletion and pharmacological inhibition of immunosuppressive enzyme indoleamine 2,3‐dioxygenase (IDO) does not significantly affect colon tumor development in mice. On the other hand, Ido1 deficiency altered the immune response in the tumor microenvironment, showing a significant increase in mRNA expression of pro‐inflammatory cytokines and a significant decrease in the number of Foxp3‐positive regulatory T cells in the mouse colon tumors. Importantly, IDO inhibitors also significantly altered cytokine expression in the colon tumor tissues.

Hepatic immune regulation is associated with the progression from simple steatosis to non-alcoholic steatohepatitis, a severe condition of inflamed fatty liver. Indoleamine 2,3-dioxygenase (IDO), an intracellular enzyme that mediates the catabolism of L-tryptophan to L-kynurenine, plays an important role in hepatic immune regulation. In the present study, we examined the effects of IDO gene silencing on high-fat diet (HFD)-induced liver inflammation and fibrosis in mice. After being fed a HFD for 26 weeks, the IDO-knockout (KO) mice showed a marked infiltration of inflammatory cells, especially macrophages and T lymphocytes, in the liver. The expression levels of F4/80, IFNγ, IL-1β, and IL-6 mRNA in the liver and the expression levels of F4/80 and TNF-α mRNA in the white adipose tissue were significantly increased in IDO-KO mice, although hepatic steatosis, the accumulation of intrahepatic triglycerides, and the amount of oxidative stress were lower than those in IDO-wild-type mice. IDO-KO mice also developed marked pericellular fibrosis in the liver, accumulated hepatic hydroxyproline, and exhibited increased expression levels of hepatic TGF-β1 mRNA. These findings suggest that IDO-KO renders the mice more susceptible to HFD-induced hepatic inflammation and fibrosis. Therefore, IDO may have a protective effect against hepatic fibrosis, at least in this HFD-induced liver injury model.

Vα14 natural killer T (iNKT) cells activated by alpha-galactosylceramide (GalCer) secrete a large amount of cytokines. Toll-like receptors (TLRs) play a critical role in the innate immune responses via the recognition of pathological antigen. Previously we demonstrated that the iNKT cells activated by GalCer augmented LPS-induced NO production in peritoneal cells. In this study, we examined the effect of GalCer and TLR agonists by IFN-γ production from splenocytes. Splenocytes pretreated with GalCer induced TLR3, 4, 7/8 and 9 agonists in vitro, resulting in the enhancement of IFN-γ mRNA expression. In particular, IFN-γ stimulated by GalCer and LPS was increased in NK cells and CD8 T cells and inhibited by a neutralizing anti-IL-12 antibody. Pretreatment with GalCer enhanced the phosphorylation of IκB-α induced by LPS stimulation. The present study showed that co-stimulation of GalCer and TLR agonists powerfully induced the production of IFN-γ from splenocytes.

Toll-like receptor (TLR) agonists have been shown to have anti-tumor activity in basic research and clinical studies. However, TLR agonist monotherapy in cancer treatment dose not sufficiently eliminate tumors. Activation of the innate immune response by TLR agonists and other pathogen-associated molecular patterns is effective for driving adaptive immunity via interleukin (IL)-12 or IL-1, but is counteracted by the simultaneous induction of immunosuppressive cytokines and other molecules, including IL-10, tumor growth factor-β, and induced nitric oxide synthase (iNOS). In the present study, we evaluated the anticancer effect of the TLR7 agonist, imiquimod (IMQ), in the absence of iNOS. The administration of IMQ in iNOS-knockout (KO) mice implanted with tumor cells significantly suppressed tumor progression as compared to that in wild-type mice and improved the survival rate. Moreover, injection with IMQ enhanced the tumor antigen-specific Th1 response in iNOS-KO mice with tumors. The enhancement of the antigen-specific Th1 response was associated with an increase in IL-2 and IL-12b expressions in the tumor-draining lymph nodes. Combination therapy with IMQ and an iNOS inhibitor also significantly inhibited tumor growth in the established tumor model. Finally, our results indicated that the enhancement of iNOS expression through the administration with TLR agonists impairs host anti-tumor immunity, while the inhibition of iNOS could enhance the therapeutic efficacy of TLR agonists via the increase in Th1 immune response.

Inflammatory response is required to proceed the optimal liver regeneration after liver injury. Recent reports demonstrated that inflammasomes are involved in the innate immune response. Several NOD-Like receptors (NLRs) participated in the formation of the inflammasomes. NACHT, LRR, and PYD domain-containing protein 3 (NALP3) belongs to the NLR families and recognizes adenosine triphosphate (ATP), crystals, and reactive oxygen species. The present study examined the effect of inflammasomes on the process of liver regeneration using NALP3 knockout (KO) mice. The activation of inflammasomes in the liver was induced after 70% partial hepatectomy (PHx). The liver-to-body weight ratio was significantly decreased in NALP3-KO mice compared to that in WT mice after PHx. The number of Ki67-positive cells and the expression of Cyclin D1 and E1 after PHx were reduced in NALP3-KO mice compared to WT mice. The expression of pro-inflammatory cytokines (IL-1β, TNF-α, and IL-6) were decreased in the remnant liver of NALP3-KO mice compared to WT mice. Flow cytometric analysis revealed that the expression of chemokines was decreased and the accumulation of CD11b-positive cells was suppressed in NALP3-KO mice after PHx. The treatment with ATP, which is a ligand to NALP3, increased the liver-to-body weight ratio in WT mice. These results indicate that NALP3 signaling is required for the induction of inflammatory response and the development of liver regeneration after PHx.

In the present study, we examined the role of indoleamine 2,3-dioxygenase (IDO) in the development of CCl4-induced hepatic fibrosis. The liver fibrosis induced by repetitive administration with CCl4 was aggravated in IDO-KO mice compared to WT mice. In IDO-KO mice treated with CCl4, the number of several inflammatory cells and the expression of pro-inflammatory cytokines increased in the liver. In the results, activated hepatic stellate cells (HSCs) and fibrogenic factors on HSCs increased after repetitive CCl4 administration in IDO-KO mice compared to WT mice. Moreover, the treatment with l-tryptophan aggravated the CCl4-induced hepatic fibrosis in WT mice. Our findings demonstrated that the IDO deficiency enhanced the inflammation in the liver and aggravated liver fibrosis in repetitive CCl4-treated mice.