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Introduction: Familial adenomatous polyposis (FAP), a hereditary disorder of the gastrointestinal tract, is an autosomal dominant inherited condition caused by germline mutations in the adenomatous polyposis coli (APC) gene. It is characterized by the development of hundreds to thousands of colorectal adenomatous polyps, which, if left untreated, can eventually develop into colorectal carcinomas. Representative extracolonic tumors in FAP include multiple duodenal adenomas and desmoid tumors. Moreover, multiple fundic gland polyps are frequently identified in the stomachs of patients with FAP. Case Presentation: Herein, we report the two cases. A 52-year-old woman who underwent total colectomy for FAP, and pancreatoduodenectomy was initiated on esomeprazole for the treatment of anastomotic erosion. Esophagogastroduodenoscopy performed 42 months later showed an increased number and size of gastric fundic gland polyps, which subsequently decreased after replacing esomeprazole with ranitidine. Similarly, a 39-year-old woman with FAP was initiated on vonoprazan for the treatment of reflux symptoms. Esophagogastroduodenoscopy and colonoscopy performed 14 months later indicated an increase in the number of gastric fundic gland polyps and colorectal polyps, which subsequently decreased after vonoprazan discontinuation. In these two cases, the increase and decrease in the number and size of fundic gland polyps and colon adenoma were associated with serum gastrin levels. Conclusion: Gastric fundic gland polyps and colon polyps may rapidly increase in number and size due to increased gastrin levels induced by proton pump inhibitor/potassium-competitive acid blocker use. Hence, these drugs should be prescribed with caution.

Abstract Aspirin, a nonsteroidal anti-inflammatory drug, has been proven effective in a clinical trial of carcinogenesis blockade. However, various modes of action have been reported for these effects. Thus, in this study, we aimed to present reasonable mode of actions as a proof of concept for human trials, especially trials for patients with familial adenomatous polyposis (FAP). Aspirin treatment at 1000 ppm inhibited intestinal tumorigenesis in FAP model Min mice. As a mode of action, aspirin regulated β-catenin signaling, inflammation, and oxidative stress both in vivo and in vitro. Furthermore, we examined novel markers predictive of aspirin treatment based on liquid biopsy. Here, we demonstrated that aspirin reduced the levels of reactive carbonyl species in the serum of Min mice. These data are expected to be of use for proof of concept of aspirin human trials and implied for the prediction of aspirin efficacy.

Abstract Normal epithelial cells exert their competitive advantage over RasV12-transformed cells and eliminate them into the apical lumen via cell competition. However, the internal or external factors that compromise cell competition and provoke carcinogenesis remain elusive. In this study, we examine the effect of sequential accumulation of gene mutations, mimicking multi-sequential carcinogenesis on RasV12-induced cell competition in intestinal epithelial tissues. Consequently, we find that the directionality of RasV12-cell extrusion in Wnt-activated epithelia is reversed, and transformed cells are delaminated into the basal lamina via non-cell autonomous MMP21 upregulation. Subsequently, diffusively infiltrating, transformed cells develop into highly invasive carcinomas. The elevated production of MMP21 is elicited partly through NF-κB signaling, blockage of which restores apical elimination of RasV12 cells. We further demonstrate that the NF-κB-MMP21 axis is significantly bolstered in early colorectal carcinoma in humans. Collectively, this study shows that cells with high mutational burdens exploit cell competition for their benefit by behaving as unfit cells, endowing them with an invasion advantage.

Abstract Background Patients with familial adenomatous polyposis (FAP) have a lifetime risk of developing duodenal adenomas approaching 100%, and the relative risk for duodenal cancer compared with the general population is high. We conducted a retrospective study to investigate the progression of non-ampullary duodenal adenomas (NADAs) and risk factors for advanced lesions in patients with FAP. Methods Of 248 patients with 139 pedigrees at 2 institutes, we assessed 151 patients with 100 pedigrees with a pathogenic germline variant in the adenomatous polyposis coli gene, excluding mosaic variants. We evaluated the prevalence of NADAs in patients with FAP, the progression of these adenomas to advanced adenoma during the observation period, and the risk factors for the lifetime development of high-grade dysplasia (HGD), large (≥ 10 mm) duodenal adenomas, and Spiegelman stage IV. Results During the median observation period of 7 years, the incidences of patients with NADAs, with more than 20 polyps, with polyps ≥ 10 mm, with HGD, and with stage IV at the last esophagogastroduodenoscopy were increased 1.6-fold, 1.7-fold, 5-fold, 22-fold, and 9-fold, respectively. Intramucosal cancer occurred in three patients (2%), but no patients developed invasive cancer during the observation period because we performed endoscopic intervention for advanced adenomas. Stage progression was observed in 71% of 113 patients. Stage IV was more common in women, patients with a history of colectomy, and those with a 3’ side mutation in their adenomatous polyposis coli gene. Conclusions NADAs in patients with FAP frequently become exacerbated. Our findings suggest that patients with FAP who develop duodenal adenomas should be surveyed to prevent the development of duodenal cancer.

Cowden syndrome (CS)/PTEN hamartoma tumor syndrome (PHTS) is a rare autosomal dominantly inherited condition caused by germline pathogenesis. It is associated with multiple hamartomatous lesions occurring in various organs and tissues, including the gastrointestinal tract, skin, mucous membranes, breast, thyroid, endometrium, and brain. Macrocephaly or multiple characteristic mucocutaneous lesions commonly develop in individuals in their 20s. This syndrome is occasionally diagnosed in childhood due to the occurrence of multiple gastrointestinal polyps, autism spectrum disorders, and intellectual disability. CS/PHTS can be diagnosed taking the opportunity of multigene panel testing in patients with cancer. Appropriate surveillance for early diagnosis of associated cancers is required because patients have a high risk of cancers including breast, thyroid, colorectal, endometrial, and renal cancers. Under these circumstances, there is growing concern regarding the management of CS/PHTS in Japan, but there are no available practice guidelines. To address this situation, the guideline committee, which included specialists from multiple academic societies, was organized by the Research Group on Rare and Intractable Diseases granted by the Ministry of Health, Labour, and Welfare, Japan. The present clinical guidelines explain the principles in the diagnosis and management of CS/PHTS, together with four clinical questions and the corresponding recommendations, incorporating the concept of the Grading of Recommendations Assessment, Development, and Evaluation system. Herein, we present an English version of the guideline, some of which have been updated, to promote seamless implementation of accurate diagnosis and appropriate management of pediatric, adolescent, and adult patients with CS/PHTS.

Abstract Background Prostate cancer is one of the most common cancers among men worldwide and the fourth most common cause of death. The number of prostate cancer cases and deaths is increasing every year because of population aging. This study aimed to clarify the risk of developing prostate cancer due to fluctuations in Prostate Specific Antigen (PSA) levels in patients without a history of prostate cancer using large medical information data. Results This retrospective cohort included 1707 male patients aged 60 years or older who had a PSA level measurement date (2-PSA) within 3 months or more and 2 years from the first PSA level measurement date (1-PSA) in the database between 2008 and 2019. We subtracted 1-PSA from 2-PSA and designated patients with a higher 2-PSA than 1-PSA to the “up” group (n = 967) and patients with a lower 2-PSA than 1-PSA to the “down” group (n = 740). By using Cox proportional hazards model, a significant increase in prostate cancer risk was observed in the up group compared with the down group (adjusted hazard ratio [HR] = 1.82, 95% confidence interval [CI] = 1.21–2.72; adjusted for patient background factors). Subgroup analysis showed that patients with PSA levels

Abstract Objective Although there is increasing evidence to suggest the cost‐effectiveness of aspirin use to prevent colorectal cancer (CRC) in the general population, no study has assessed cost‐effectiveness in patients with familial adenomatous polyposis (FAP), who are at high risk of developing CRC. We examined the cost‐effectiveness of preventive use of low‐dose aspirin in FAP patients who had undergone polypectomy in comparison with current treatment practice. Design We developed a microsimulation model that simulates a hypothetical cohort of the Japanese population with FAP for 40 years. Three scenarios were created based on three intervention strategies for comparison with no intervention, namely intensive downstaging polypectomy (IDP) of colorectal polyps at least 5.0 mm in diameter, IDP combined with low‐dose aspirin, and total proctocolectomy with ileal pouch‐anal anastomosis (IPAA). Cost‐effective strategies were identified using a willingness‐to‐pay threshold of USD 50,000 per QALY gained. Results Compared with no intervention, all strategies resulted in extended QALYs (21.01–21.43 QALYs per individual) and showed considerably reduced colorectal cancer mortality (23.35–53.62 CRC deaths per 1000 individuals). Based on the willingness‐to‐pay threshold, IDP with low‐dose aspirin was more cost‐effective than the other strategies, with an incremental cost‐effectiveness ratio of $57 compared with no preventive intervention. These findings were confirmed in both one‐way sensitivity analyses and probabilistic sensitivity analyses. Conclusion This study suggests that the strategy of low‐dose aspirin with IDP may be cost‐effective compared with IDP‐only or IPAA under the national fee schedule of Japan.

Juvenile polyposis syndrome (JPS) is a rare disease characterized by multiple hamartomatous polyps within the gastrointestinal tract. SMAD4 or BMPR1A is known as a causative gene of JPS. Approximately 75% of newly diagnosed cases have an autosomal-dominantly inherited condition, whereas 25% are sporadic without previous history of polyposis in the family pedigree. Some patients with JPS develop gastrointestinal lesions in childhood and require continuous medical care until adulthood. JPS is classified into three categories according to phenotypic features of polyp distributions, including generalized juvenile polyposis, juvenile polyposis coli, and juvenile polyposis of the stomach. Juvenile polyposis of the stomach is caused by germline pathogenic variants of SMAD4 with a high risk leading to gastric cancer. Pathogenic variants of SMAD4 are also associated with hereditary hemorrhagic telangiectasia-JPS complex, inducing regular cardiovascular survey. Despite growing concerns regarding the managing JPS in Japan, there are no practical guidelines. To address this situation, the guideline committee was organized by the Research Group on Rare and Intractable Diseases granted by the Ministry of Health, Labor and Welfare involving specialists from multiple academic societies. The present clinical guidelines explain the principles in the diagnosis and management of JPS with three clinical questions and corresponding recommendations based on a careful review of the evidence and involve incorporating the concept of the Grading of Recommendations, Assessment, Development, and Evaluation system. Herein, we present the clinical practice guidelines of JPS to promote seamless implementation of accurate diagnosis and appropriate management of pediatric, adolescent, and adult patients with JPS.

Abstract Background Colibactin is a genotoxin produced by Escherichia coli and other Enterobacteriaceae that is believed to increase the risk of colorectal cancer (CRC) of their symbiosis hosts, including human. A peptidase ClbP is the key enzyme for activation of colibactin. Inhibition of ClbP is considered to impede maturation of precolibactin into genotoxic colibactin. Therefore, ClbP-specific inhibitors could potentially prevent the onset of CRC, one of the leading causes of cancer-related deaths in the world. This study intends to establish an efficient screening system for identifying inhibitors that are specific to ClbP. Methods Two types of assays were applied in the screening procedure: a probe assay and an LC–MS assay. For the probe assay, we employed the synthesized probe which we described in our previous report. This probe can be hydrolyzed efficiently by ClbP to release a fluorophore. Hence it was applied here for detection of inhibition of ClbP. For the LC–MS assay, formation of the byproduct of precolibactin maturation process, N-myristoyl-D-asparagine, was quantified using a liquid chromatography–mass spectrometry (LC–MS) technique. The probe assay can be performed much faster, while the LC–MS assay is more accurate. Therefore, our method employed the two assays in sequence to screen a large number of compounds for inhibition of ClbP. Results A library of 67,965 standard compounds was evaluated by the screening method established in the current study, and one compound was found to show a moderate inhibitory activity against ClbP. Conclusion A simple screening method for ClbP-specific inhibitors was established. It was proven to be reliable and is believed to be useful in developing potential prophylactic agents for CRC.

Smoking is a known risk factor for the development of colorectal polyps. Even in familial adenomatous polyposis and serrated polyposis syndrome, smoking is a risk factor of the development of polyps. Here, we report a case of monozygotic twins with atypical colorectal polyposis showing lots of hyperplastic polyps and adenomas and describe how the polyposis developed differently in the brothers based on the presence or absence of smoking. The case was of a set of monozygotic male twins, and the twins were in their 50s. The younger brother smoked 40 cigarettes a day since he was 16 years old. The older brother had smoked about 25 cigarettes a day since he was 16 years old but stopped smoking after he was diagnosed with polyposis. As we previously reported, we managed to remove polyps as much as possible from both twins without surgery. The median number of removed polyps (IQR: 25–75%) per colonoscopy for 20 years was 9.0 (3.5–14.8) in the older brother and 20.5 (7.5–35.5) in the younger brother. There was a significant difference between the twins (p < 0.01). Additionally, genetic tests found that the twins carried a rare missense variant of BRCA2, and this variation has not been previously reported. In conclusion, these monozygotic twins with atypical colorectal polyposis showing a new variant of BRCA2 suggest that smoking is related to the development of colorectal polyps. Further analysis will be required for the identified BRCA2 variant in possible involvement in the development of atypical polyposis.

Background: Recent advances have been achieved in the genetic diagnosis and therapies against malignancies due to a better understanding of the molecular mechanisms underlying carcinogenesis. Since active preventive methods are currently insufficient, the further development of appropriate preventive strategies is desired. Methods: We searched for drinks that reactivate the functions of tumor-suppressor retinoblastoma gene (RB) products and exert anti-inflammatory and antioxidant effects. We also examined whether lactic acid bacteria increased the production of the cancer-specific anti-tumor cytokine, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), in human, and examined whether the RB-reactivating drinks with lactic acid bacteria decreased azoxymethane-induced rat colon aberrant crypt foci (ACF) and aberrant crypts (ACs) in vivo. Results: Kakadu plum juice and pomegranate juice reactivated RB functions, which inhibited the growth of human colon cancer LIM1215 cells by G1 phase arrest. These juices also exerted anti-inflammatory and antioxidant effects. Lactiplantibacillus (L.) pentosus S-PT84 was administered to human volunteers and increased the production of TRAIL. In an in vivo study, Kakadu plum juice with or without pomegranate juice and S-PT84 significantly decreased azoxymethane-induced rat colon ACF and ACs. Conclusions: RB is one of the most important molecules suppressing carcinogenesis, and to the best of our knowledge, this is the first study to demonstrate that natural drinks reactivated the functions of RB. As expected, Kakadu plum juice and pomegranate juice suppressed the growth of LIM1215 cells by reactivating the functions of RB, and Kakadu plum juice with or without pomegranate juice and S-PT84 inhibited rat colon ACF and ACs. Therefore, this mixed juice has potential as a novel candidate for cancer prevention.

Abstract Background The Escherichia coli strain that is known to produce the genotoxic secondary metabolite colibactin is linked to colorectal oncogenesis. Therefore, understanding the properties of such colibactin-positive E. coli and the molecular mechanism of oncogenesis by colibactin may provide us with opportunities for early diagnosis or prevention of colorectal oncogenesis. While there have been major advances in the characterization of colibactin-positive E. coli and the toxin it produces, the infection route of the clb + strain remains poorly characterized. Results We examined infants and their treatments during and post-birth periods to examine potential transmission of colibactin-positive E. coli to infants. Here, analysis of fecal samples of infants over the first month of birth for the presence of a colibactin biosynthetic gene revealed that the bacterium may be transmitted from mother to infant through intimate contacts, such as natural childbirth and breastfeeding, but not through food intake. Conclusions Our finding suggests that transmission of colibactin-positive E. coli appears to be occurring at the very early stage of life of the newborn and hints at the possibility of developing early preventive measures against colorectal cancer.

Abstract Introduction Colibactin is a small genotoxic molecule produced by enteric bacteria, including certain Escherichia coli (E. coli) strains harbored in the human large intestine. This polyketide-peptide genotoxin is considered to contribute to the development of colorectal cancer. The colibactin-producing (clb +) microorganisms possess a 54-kilobase genomic island (clb gene cluster). In the present study, to assess the distribution of the clb gene cluster, genotyping analysis was carried out among E. coli strains randomly chosen from the Japan Collection of Microorganisms, RIKEN BRC, Japan. Findings The analysis revealed that two of six strains possessed a clb gene cluster. These clb + strains JCM5263 and JCM5491 induced genotoxicity in in vitro micronucleus (MN) tests using rodent CHO AA8 cells. Since the induction level of MN by JCM5263 was high, a bacterial umu test was carried out with a cell extract of the strain, revealing that the extract had SOS-inducing potency in the umu tester bacterium. Conclusion These results support the observations that the clb gene cluster is widely distributed in nature and clb + E. coli having genotoxic potencies is not rare among microorganisms.

Abstract Background Evidence from epidemiological and experimental studies has shown that the etiology of colorectal cancer (CRC) is related to lifestyle, mainly diet. At the same time, there are many foods and beverages that have been shown to provide protection against CRC. We turned our attention to a traditional Japanese food, brown algae, that contains carotenoids and various functional polyphenols, especially fucoxanthin (FX) and fucoxanthinol (FxOH). Results Both FX and FxOH treatments induced apoptosis in a dose-dependent and time-dependent manner as detected by annexin V / propidium iodide and the presence of a subG1 population in human colon cancer HCT116 cells. This apoptotic effect of FxOH was stronger than that of FX. We also found that nuclear factor-kappa B (NF-κB) transcriptional activity was significantly increased by treatment with ≥5 μM FxOH. Thus, we cotreated the cells with FxOH plus NF-κB inhibitor, and the results demonstrated that this cotreatment strongly enhanced the induction of apoptosis compared with the effects of FxOH or NF-κB inhibitor treatment alone and resulted in X-linked inhibitor of apoptosis (IAP) downregulation. Conclusions This study suggested that FxOH is a more potent apoptosis-inducing agent than FX and that its induction of apoptosis is enhanced by inhibiting NF-κB transcriptional activity via suppression of IAP family genes.

Edible plant-derived nanovesicles have been explored as effective materials for preventing colorectal cancer (CRC) incidence, dependent on gene status, as a K-Ras-activating mutation via the macropinocytosis pathway. Approximately 70% of CRC harbors the p53 mutation, which is strongly associated with a poor prognosis for CRC. However, it has not been revealed whether p53 inactivation activates the macropinocytosis pathway or not. In this study, we investigated parental cells, wild-type or null for p53 treated with Citrus limon L.-derived nanovesicles, as potential materials for CRC prevention. Using ultracentrifugation, we obtained C. limon L.-derived nanovesicles, the diameters of which were approximately 100 nm, similar to that of the exosomes derived from mammalian cells. C. limon L.-derived nanovesicles showed inhibitory effects on cell growth in not p53-wild, but also in p53-inactivated CRC cells. Furthermore, we revealed that the macropinocytosis pathway is activated by p53 inactivation and C. limon L.-derived nanovesicles were up taken via the macropinocytosis pathway. Notably, although C. limon L.-derived nanovesicles contained citrate, the inhibitory effects of citrate were not dependent on the p53 status. We thus provide a novel mechanism for the growth inhibition of C. limon L.-derived nanovesicles via macropinocytosis and expect to develop a functional food product containing them for preventing p53-inactivation CRC incidence.

Fucoxanthin (Fx) is a major xanthophyll in Undaria pinnatifida (wakame) and is one of the potent carotenoids against cancer development. However, the cancer preventive function of high fucoxanthin (Fx-high) wakame itself has not been well investigated. Therefore, we cultivated Fx-high wakame and investigated the effect of this alga on a AOM/DSS carcinogenesis mouse model. Fx-high wakame (Fx 30 mg/kg body weight) significantly decreased the number of cells that compose the tumor microenvironment compared to mice without wakame. The number of colorectal cancer stem cell-like CD44high/EpCAMhigh cells, cancer-associated fibroblast-like αSMAhigh cells, tumor-associated macrophage-like and dendritic cell-like CD206high cells were significantly decreased 0.6-, 0.5-, and 0.5-fold, respectively, and apoptotic cell-like cleaved caspase-3high cells were significantly increased 1.7-fold by Fx-high wakame. Moreover, salivary glycine was decreased 0.4-fold by Fx-high wakame. Our results imply that Fx-high wakame could prevent formation of the tumor microenvironment with a salivary predictor of the Fx-high wakame function.

Fucoxanthin (Fx) is a marine carotenoid with anti-inflammatory and anti-cancer properties in various animal models of carcinogenesis. However, there is currently no information on the effects of Fx in animal models of pancreatic cancer. We investigated the chemopreventive effects of Fx in C57BL/6J mice that received allogenic and orthotopic transplantations of cancer cells (KMPC44) derived from a pancreatic cancer murine model (Ptf1aCre/+; LSL-krasG12D/+). Using microarray, immunofluorescence, western blot, and siRNA analyses, alterations in cancer-related genes and protein expression were evaluated in pancreatic tumors of Fx-administered mice. Fx administration prevented the adenocarcinoma (ADC) development of pancreatic and parietal peritoneum tissues in a pancreatic cancer murine model, but not the incidence of ADC. Gene and protein expressions showed that the suppression of chemokine (C-C motif) ligand 21 (CCL21)/chemokine receptor 7 (CCR7) axis, its downstream of Rho A, B- and T-lymphocyte attenuator (BTLA), N-cadherin, αSMA, pFAK(Tyr397), and pPaxillin(Tyr31) were significantly suppressed in the pancreatic tumors of mice treated with Fx. In addition, Ccr7 knockdown significantly attenuated the growth of KMPC44 cells. These results suggest that Fx is a promising candidate for pancreatic cancer chemoprevention that mediates the suppression of the CCL21/CCR7 axis, BTLA, tumor microenvironment, epithelial mesenchymal transition, and adhesion.

Cigarette smoking and alcohol consumption are major risk factors for lifestyle-related diseases. Although it has been reported that the combination of these habits worsens risks, the underlying mechanism remains elusive. Reactive carbonyl species (RCS) cause chemical modifications of biological molecules, leading to alterations in cellular signaling pathways, and total RCS levels have been used as a lipid peroxidation marker linked to lifestyle-related diseases. In this study, at least 41 types of RCS were identified in the lipophilic fraction of plasma samples from 40 subjects using liquid chromatography/electrospray ionization tandem mass spectrometry (LC/ESI-MS/MS). Higher levels of 10 alkanals, 5 trans-2-alkenals, 1 cis-4-alkenal, and 3 alkadienals were detected in the smoking/drinking group (N = 10) as compared to those with either habit (N = 10 each) or without both habits (N = 10) in the analysis of covariances adjusted for age and BMI. The levels of 3 alkanals, 1 trans-2-alkenal, 1 alkadienal, and 1 4-hydroxy-2-alkenal in the smoking/drinking group were significantly higher than those in the no-smoking/drinking and no-smoking/no-drinking groups. These results strongly indicate that the combination of cigarette smoking and alcohol drinking synergistically increases the level and variety of RCS in the circulating blood, and may further jeopardize cellular function.

Summary: The generation of tumor-initiating cells during colon carcinogenesis is associated with the dysregulation of Wnt signaling, which is known to act on Lgr5-positive intestinal stem cells. Here, using single-cell qPCR analysis, we identified a subset of Lgr5-positive stem cells that emerged during tumorigenesis in a mouse model of colon cancer. These tumor-specific Lgr5-positive cells expressed low levels of Ceacam1 and increased levels of a specific subset of Wnt targets and showed enhanced tumorigenicity. Among the Wnt targets that were specifically expressed, the long isoform of Tcf1 was required for the proliferation of tumor organoids and drove a unique Wnt target gene expression profile. Tcf1 expression increased at an early stage of colon carcinogenesis and was associated with the nuclear accumulation of β-catenin, underscoring the importance of the induction of Tcf1 expression in generating tumorigenic colon stem cells. : Shiokawa et al. show that a tumorigenic subpopulation of Lgr5-positve cells emerges during colon tumorigenesis. The tumorigenic Lgr5-positive cells express a distinct subset of Wnt target genes. The long isoform of Tcf1 dictates the unique expression profile of the Wnt targets and mediates generation of colon tumorigenic stem cells.

Weight loss, often observed in the elderly, is associated with increased risks of various diseases. No large and long-term human study has been conducted to demonstrate the health maintenance-related effects of lactic acid bacteria preparations. To reveal the potential benefit of long-term lactic acid, the effects of bacteria-based probiotics for health maintenance were examined. This observational study included the participants from a previous clinical study designed to evaluate the effects of wheat bran biscuits or Lactobacillus preparation, 3 g/day biolactis powder (BLP), in preventing colorectal tumor. The participants were provided an option to continue treatment with BLP on an outpatient basis after completion of the study. The 380 patients who completed the study were contacted and asked to participate in the present study and those who consented were surveyed for cancer incidence, treatment compliance, lifestyle, weight, and other variables. Informed consent was obtained from 237 of the 380 (62.4%) patients. The mean follow-up period was 7913 days (21.7 years). Cancer developed in 24 of 128 (18.8%) patients in the BLP extension group and 24 of 109 (22.0%) patients in the non-BLP extension group (risk ratio 0.88 [95% confidence interval 0.53–1.47]). Although no significant difference was observed, the cumulative cancer incidence rose at a slightly lower rate in the BLP extension group. Both groups showed a significant weight decrease over the course of 20 years, although the decrease in the BLP extension group was only 1.4 kg, compared with 2.8 kg in the non-BLP extension group. Very long-term treatment with a Lactobacillus probiotic preparation suppressed weight loss in the elderly.

Osteopontin (OPN) is a secreted phosphoglycoprotein, and is a transcriptional target of aberrant Wnt signaling. OPN is upregulated in human colon cancers, and is suggested to enhance cancer progression. In this study, the effect of deficiency of OPN on intestinal tumor development in Apc-deficient Min mice was investigated. At 16 weeks of age, the number of small intestinal polyps in Min/OPN(+/−) and Min/OPN(−/−) mice was lower than that of Min/OPN(+/+) mice. Colorectal tumor incidences and multiplicities in Min/OPN(+/−) and Min/OPN(−/−) mice were significantly lower than those in Min/OPN(+/+) mice, being 48% and 0.6 ± 0.8, 50% and 0.8 ± 0.9 vs. 80% and 1.6 ± 1.7, respectively. OPN expression in colorectal tumors was strongly upregulated in Min/OPN(+/+) compared to adjacent non-tumor parts, but was decreased in Min/OPN(+/−) and not detected in Min/OPN(−/−). Targets of OPN, matrix metalloproteinases (MMPs)-3, -9, and -13 were lowered by OPN deficiency. Macrophage marker F4/80 in colorectal tumors was also lowered by OPN deficiency. MMP-9 expression was observed in tumor cells and tumor-infiltrating neutrophils. These results indicate that induction of OPN by aberrant Wnt signaling could enhance colorectal tumor development in part by upregulation of MMP-3, -9, and -13 and infiltration of macrophage and neutrophils. Suppression of OPN expression could contribute to tumor prevention, but complete deficiency of OPN may cause some adverse effects.

Genetic rearrangement of the ROS1 receptor tyrosine kinase was recently identified as a distinct molecular signature for human non-small cell lung cancer (NSCLC). However, direct evidence of lung carcinogenesis induced by ROS1 fusion genes remains to be verified. The present study shows that EZR-ROS1 plays an essential role in the oncogenesis of NSCLC harboring the fusion gene. EZR-ROS1 was identified in four female patients of lung adenocarcinoma. Three of them were never smokers. Interstitial deletion of 6q22-q25 resulted in gene fusion. Expression of the fusion kinase in NIH3T3 cells induced anchorage-independent growth in vitro, and subcutaneous tumors in nude mice. This transforming ability was attributable to its kinase activity. The ALK/MET/ROS1 kinase inhibitor, crizotinib, suppressed fusion-induced anchorage-independent growth of NIH3T3 cells. Most importantly, established transgenic mouse lines specifically expressing EZR-ROS1 in lung alveolar epithelial cells developed multiple adenocarcinoma nodules in both lungs at an early age. These data suggest that the EZR-ROS1 is a pivotal oncogene in human NSCLC, and that this animal model could be valuable for exploring therapeutic agents against ROS1-rearranged lung cancer.

Epidemiological studies have shown that serum triglyceride (TG) levels are linked with risk of development of cancer, including colorectal and pancreatic cancers, and their precancerous lesions. Thus, it is assumed that serum TG plays an important role in carcinogenesis, and the key enzyme lipoprotein lipase (LPL), which catalyzes the hydrolysis of plasma TG, may therefore be involved. Dysregulation of LPL has been reported to contribute to many human diseases, such as atherosclerosis, chylomicronaemia, obesity, and type 2 diabetes. Recently, it has been reported that LPL gene deficiency, such as due to chromosome 8p22 loss, LPL gene polymorphism, and epigenetic changes in its promoter region gene, increases cancer risk, especially in the prostate. In animal experiments, high serum TG levels seem to promote sporadic/carcinogen-induced genesis of colorectal and pancreatic cancers. Interestingly, tumor suppressive effects of LPL inducers, such as PPAR ligands, NO-1886, and indomethacin, have been demonstrated in animal models. Moreover, recent evidence that LPL plays important roles in inflammation and obesity implies that it is an appropriate general target for chemopreventive and chemotherapeutic agents.