Mapping Nanomechanical Properties of Basal Surfaces in Metastatic Intestinal 3D Living Organoids with High-Speed Scanning Ion Conductance Microscopy.

Studying mechanobiology is increasing of scientific interests in life science and nanotechnology since its impact on cell activities (e.g., adhesion, migration), physiology, and pathology. The role of apical surface (AS) and basal surface (BS) of cells played in mechanobiology is significant. The mechanical mapping and analysis of cells mainly focus on AS while little is known about BS. Here, high-speed scanning ion conductance microscope as a powerful tool is utilized to simultaneously reveal morphologies and local elastic modulus (E) of BS of genotype-defined metastatic intestinal organoids. A simple method is developed to prepare organoid samples allowing for long-term BS imaging. The multiple nano/microstructures, i.e., ridge-like, stress-fiber, and E distributions on BS are dynamically revealed. The statistic E analysis shows softness of BS derived from eight types of organoids following a ranking: malignant tumor cells > benign tumor cells > normal cells. Moreover, the correlation factor between morphology and E is demonstrated depending on cell types. This work as first example reveals the subcellular morphologies and E distributions of BS of cells. The results would provide a clue for correlating genotype of 3D cells to malignant phenotype reflected by E and offering a promising strategy for early-stage diagnosis of cancer.

The specific deletion of cyclooxygenase-1 in megakaryocytes/platelets reduces intestinal polyposis in ApcMin/+ mice.

Clinical and experimental evidence sustain the role of cyclooxygenase (COX)-1 in intestinal tumorigenesis. However, the cell type expressing the enzyme involved and molecular mechanism(s) have not been clarified yet. We aimed to elucidate the role of platelet COX-1 (the target of low-dose aspirin in humans) in intestinal tumorigenesis of ApcMin/+ mice, considered a clinically relevant model. To realize this objective, we generated an ApcMin/+ mouse with a specific deletion of Ptgs1(COX-1 gene name) in megakaryocytes/platelets (ApcMin/+;pPtgs1-/-mice) characterized by profound inhibition of thromboxane(TX)A2 biosynthesis ex vivo (serum TXB2; by 99%) and in vivo [urinary 2,3-dinor-TXB2(TXM), by 79%]. ApcMin/+ mice with the deletion of platelet COX-1 showed a significantly reduced number (67%) and size (32%) of tumors in the small intestine. The intestinal adenomas of these mice had decreased proliferative index associated with reduced COX-2 expression and systemic prostaglandin(PG)E2 biosynthesis (urinary PGEM) vs. ApcMin/+mice. Extravasated platelets were detected in the intestine of ApcMin/+mice. Thus, we explored their contribution to COX-2 induction in fibroblasts, considered the primary polyp cell type expressing the protein. In the coculture of human platelets and myofibroblasts, platelet-derived TXA2 was involved in the induction of COX-2-dependent PGE2 in myofibroblasts since it was prevented by the selective inhibition of platelet COX-1 by aspirin or by a specific antagonist of TXA2 receptors. In conclusion, our results support the platelet hypothesis of intestinal tumorigenesis and provide experimental evidence that selective inhibition of platelet COX-1 can mitigate early events of intestinal tumorigenesis by restraining COX-2 induction.

New insights in gastrointestinal "pediatric" neoplasms in adult patients: pancreatoblastoma, hepatoblastoma and embryonal sarcoma of the liver. A practical approach by GIPPI-GIPAD Groups.

Pediatric solid neoplasms are rare and very different from those observed in adults. The majority of them are referred to as embryonal because they arise as a result of alterations in the processes of organogenesis or normal growth and are characterized by proliferation of primitive cells, reproducing the corresponding tissue at various stages of embryonic development. This review will focus on embryonal gastrointestinal pediatric neoplasms in adult patients, including pancreatoblastoma, hepatoblastoma, and embryonal sarcoma of the liver. Although they are classically considered pediatric neoplasms, they may (rarely) occur in adult patients. Hepatoblastoma represents the most frequent liver neoplasm in the pediatric population, followed by hepatocellular carcinoma and embryonal sarcoma of the liver; while pancreatoblastoma is the most common malignant pancreatic tumor in childhood. Both in children and adults, the mainstay of treatment is complete surgical resection, either up front or following neoadjuvant chemotherapy. Unresectable and/or metastatic neoplasms may be amenable to complete delayed surgery after neoadjuvant chemotherapy. However, these neoplasms display a more aggressive behavior and overall poorer prognosis in adults than in children, probably because they are diagnosed in later stages of diseases.

An adverse outcome pathway for small intestinal tumors in mice involving chronic cytotoxicity and regenerative hyperplasia: a case study with hexavalent chromium, captan, and folpet.

Small intestinal (SI) tumors are relatively uncommon outcomes in rodent cancer bioassays, and limited information regarding chemical-induced SI tumorigenesis has been reported in the published literature. Herein, we propose a cytotoxicity-mediated adverse outcome pathway (AOP) for SI tumors by leveraging extensive target species- and site-specific molecular, cellular, and histological mode of action (MOA) research for three reference chemicals, the fungicides captan and folpet and the transition metal hexavalent chromium (Cr(VI)). The gut barrier functions through highly efficient homeostatic regulation of SI epithelial cell sloughing, regenerative proliferation, and repair, which involves the replacement of up to 1011 cells per day. This dynamic turnover in the SI provides a unique local environment for a cytotoxicity mediated AOP/MOA. Upon entering the duodenum, cytotoxicity to the villous epithelium is the molecular initiating event, as indicated by crypt elongation, villous atrophy/blunting, and other morphologic changes. Over time, the regenerative capacity of the gut epithelium to compensate declines as epithelial loss accelerates, especially at higher exposures. The first key event (KE), sustained regenerative crypt proliferation/hyperplasia, requires sufficient durations, likely exceeding 6 or 12 months, due to extensive repair capacity, to create more opportunities for the second KE, spontaneous mutation/transformation, ultimately leading to proximal SI tumors. Per OECD guidance, biological plausibility, essentiality, and empirical support were assessed using modified Bradford Hill considerations. The weight-of-evidence also included a lack of induced mutations in the duodenum after up to 90 days of Cr(VI) or captan exposure. The extensive evidence for this AOP, along with the knowledge that human exposures are orders of magnitude below those associated with KEs in this AOP, supports its use for regulatory applications, including hazard identification and risk assessment.

177Lu-DOTATATE Peptide Receptor Radionuclide Therapy: Dose Response in Small Intestinal Neuroendocrine Tumors.

INTRODUCTION: Peptide receptor radionuclide therapy (PRRT) has during the last few years been frequently used in patients with progressive, disseminating, well-differentiated neuroendocrine tumors (NETs). OBJECTIVE: To study whether the absorbed dose in small intestinal NET (SI-NET) metastases from PRRT with 177Lu-DOTATATE is related to tumor shrinkage. MATERIALS AND METHODS: Dosimetry for 1 tumor was performed in each of 25 SI-NET patients based on sequential SPECT/CT 1, 4, and 7 days after 177Lu-DOTATATE infusion. The SPECT data were corrected for the partial volume effect based on previous phantom measurements, and the unit density sphere model from OLINDA was used for absorbed dose calculations. Morphological therapy response was assessed by CT/MRI regarding tumor diameter, tumor volume, total liver tumor volume, liver volume, and overall tumor response according to RECIST 1.1. Plasma chromogranin A and urinary 5-hydroxy-indole-acetic-acid were measured during PRRT and follow-up to assess biochemical response. RESULTS: At the time of best response with respect to tumor diameter and volume shrinkage, the median absorbed dose was 128.6 Gy (range 28.4-326.9) and 140 Gy (range 50.9-487.4), respectively. All metrics regarding tumor shrinkage and biochemical response were unrelated to the absorbed dose. A correlation was, however, found between the administered radioactivity and the tumor volume shrinkage (p = 0.01) and between the administered radioactivity and RECIST 1.1 response (p = 0.01). CONCLUSIONS: It was not possible to demonstrate a tumor dose-response relationship in SI-NET metastases with the applied dosimetry method, contrary to what was previously shown for pancreatic NETs.

[The standardized mortality numbers of patients with gastrointestinal tumors and cardiovascular diseases in four wine regions and in one not-wine region of Hungary between 2000-2010]. / A gastrointestinalis daganatok és szív-ér rendszeri betegségek standardizált halálozási arányszámai Magyarország négy borvidékén és egy nem borvidéken 2000­2010 között.

INTRODUCTION: Eating habits act on mortalities from gastrointestinal tumors and cardiovascular diseases. AIM: To investigate the role of wine drinking on these mortalities in Hungary. METHOD: The standardized mortality data of people from 206,159 subjects died of gastrointestinal tumors and cardiovascular diseases between 2000-2010 were compared in four wine regions: Tokaj (white), Eger (red), Balaton (white), Szekszárd/Villány (red) and in Hódmezovásárhely (not-wine region). RESULTS: The significantly smallest number of tumors (664) occurred in Tokaj, but the cardiovascular mortality here was the highest (5955). On the other hand, the fewest cardiovascular mortality occurred in Szekszárd/Villány (3907), but showing here (831) and in Eger (934) the highest values of tumor death. CONCLUSIONS: The protective effect of red wine on cardiovascular mortality was verified. Surprisingly, the low value of gastrointestinal mortality in "Tokaj" - besides the higher level of selenium in tap water - shows some hidden features of these white wines. Orv Hetil. 2017; 158(25): 992-998.

Jejunal Gastrointestinal Stromal Tumor Presenting as Hemorrhagic Shock.

Gastrointestinal stromal tumors (GISTs) are rare tumors of the gastrointestinal (GI) tract. Intermittent GI bleeding is the most common manifestation. Massive GI bleeding leading to syncopal episodes and hemorrhagic shock is a rare presentation of these tumors. Herein, we describe a case of a jejunal GIST presenting as massive bleeding.

[The Research Progress in the Diagnosis and Treatment of Primary Intestinal Diffuse Large B-cell Lymphoma--Review].

Primary intestinal diffuse large B-cell lymphoma (PI-DLBCL) is clinically rare, but in recent years, with the gradual maturity of pathology and molecular biology technology, its incidence rate and diagnosis rate have also increased. Due to the lack of specificity of the clinical symptoms of PI-DLBCL, it is easy to misdiagnose and miss the diagnosis, and there is no consensus on the best treatment of PI-DLBCL in clinical practice. Therefore, by retrieving the latest literature at home and abroad, this review systematically discusses the pathogenesis, clinical manifestations, diagnostic criteria, treatment and prognosis of PI-DLBCL, in order to improve the understanding of rare PI-DLBCL in hematology and oncology, and provide reference for basic research and clinical diagnosis and treatment of PI-DLBCL.

Orally administered docetaxel-loaded chitosan-decorated cationic PLGA nanoparticles for intestinal tumors: formulation, comprehensive in vitro characterization, and release kinetics.

Intestinal cancers are the third most lethal cancers globally, beginning as polyps in the intestine and spreading with a severe metastatic tendency. Chemotherapeutic drugs used in the treatment of intestinal tumors are usually formulated for parenteral administration due to poor solubility and bioavailability problems. Pharmaceutically, clinical failure due to a drug's wide biodistribution and non-selective toxicity is one of the major challenges of chemotherapy. In addition, parenteral drug administration in chronic diseases that require long-term drug use, such as intestinal tumors, is challenging in terms of patient compliance and poses a burden in terms of health economy. Especially in the field of chemotherapy research, oral chemotherapy is a subject that has been intensively researched in recent years, and developments in this field will provide serious breakthroughs both scientifically and socially. Development of orally applicable nanodrug formulations that can act against diseases seen in the distant region of the gastrointestinal tract (GIT), such as intestinal tumor, brings with it a series of difficulties depending on the drug and/or GIT physiology. The aim of this study is to develop an oral nanoparticle drug delivery system loaded with docetaxel (DCX) as an anticancer drug, using poly(lactic-co-glycolic acid) (PLGA) as nanoparticle material, and modified with chitosan (CS) to gain mucoadhesive properties. In this context, an innovative nanoparticle formulation that can protect orally administered DCX from GIT conditions and deliver the drug to the intestinal tumoral region by accumulating in mucus has been designed. For this purpose, DCX-PLGA nanoparticles (NPs) and CS/DCX-PLGA NPs were prepared, and their in vitro characteristics were elucidated. Nanoparticles around 250-300 nm were obtained. DCX-PLGA NPs had positive surface charge with CS coating. The formulations have the potential to deliver the encapsulated drug to the bowel according to the in vitro release studies in three different simulated GIT fluids for approximately 72 h. Mucin interaction and penetration into the artificial mucus layer were also investigated in detail, and the mucoadhesive and mucus-penetration characteristics of the formulations were examined. Furthermore, in vitro release kinetic studies of the NPs were elucidated. DCX-PLGA NPs were found to be compatible with the Weibull model, and CS/DCX-PLGA NPs were found to be compatible with the Peppas-Sahlin model. Within the scope of in vitro cytotoxicity studies, the drug-loaded NPs showed significantly higher cytotoxicity than a DCX solution on the HT-29 colon cell line, and CS/DCX-PLGA showed the highest cytotoxicity (p < 0.05). According to the permeability studies on the Caco-2 cell line, the CS/DCX-PLGA formulation increased permeability by 383% compared to free DCX (p < 0.05). In the light of all results, CS/DCX-PLGA NPs can offer a promising and innovative approach as an oral anticancer drug-loaded nanoformulation for intestinal tumors.

Prevalence of microsatellite instable and Epstein-Barr Virus-driven gastroesophageal cancer in a large Belgian cohort.

Introduction: Patients with gastroesophageal adenocarcinoma (GEC) with microsatellite instability-high (MSI-H) or Epstein Barr Virus positivity (EBV+) might be good candidates for immunotherapy. Incidences of about 10% have been reported for both features, but are dependent on geographical region and disease stage. Aim: The aim is to study the prevalence of MSI-H and EBV+ in a Belgian single center cohort of patients with GEC. Methods: We retrospectively assessed the files of all patients with a newly diagnosed GEC between August, 1st 2018 and February, 29th 2020 at the University Hospitals Leuven, Belgium. Microsatellite instability (MSI) status was determined using immunohistochemistry (IHC) and polymerase chain reaction (PCR). EBV+ was assessed using in situ hybridization (ISH). A case report is provided to illustrate the importance of testing for MSI in GEC. Results: 247 gastroesophageal adenocarcinomas were included in this analysis. 62 (56% stage IV) of those were tested for EBV, but only 1 turned out to be EBV positive (1.6%). 116 patients (44.0% stage IV) were tested for MSI, of which 11 were MSI-H (9.5%). Half of the MSI-H tumors identified were at the gastroesophageal junction (GEJ). A patient with MSI-H metastatic GEC obtained a complete response with nivolumab, which persisted after discontinuation of treatment. Conclusion: While we confirm that about 10% of GECs are MSI-H, the incidence of EBV+ in our cohort (1.6%) is clearly lower than expected. Given the important prognostic and predictive implications, every gastroesophageal cancer should be tested for MSI.

Biotin controls intestinal stem cell mitosis and host-microbiome interactions.

Diet is a key regulator of metabolism and interacts with the intestinal microbiome. Here, we study the role of the Drosophila intestinal stem cell (ISC)-specific biotin transporter Smvt in midgut homeostasis, infection-induced regeneration, and tumorigenesis. We show that Smvt-transported biotin in ISCs is necessary for ISC mitosis. Smvt deficiency impairs intestinal maintenance, which can be rescued by the human Smvt, encoded by SLC5A6. ISC-specific, Smvt-silenced flies exhibit microbial dysbiosis, whereby the growth of Providencia sneebia, an opportunistic pathogen, is favored. Dysbiosis correlates with increased Nox expression, reactive oxygen species (ROS), and enterocyte apoptosis. Flies acquire biotin from their diet and microbiota. We show that, when dietary biotin is scarce, biotin-producing commensals, e.g., E. coli, can rescue reduced ISC mitosis. Smvt and commensals also control intestinal tumor growth. Our findings suggest that direct modification of the gut microbiome by biotin can serve as an approach for the treatment of dysbiosis-promoted diseases and tumorigenesis control.

Antioxidants Promote Intestinal Tumor Progression in Mice.

Dietary antioxidants and supplements are widely used to protect against cancer, even though it is now clear that antioxidants can promote tumor progression by helping cancer cells to overcome barriers of oxidative stress. Although recent studies have, in great detail, explored the role of antioxidants in lung and skin tumors driven by RAS and RAF mutations, little is known about the impact of antioxidant supplementation on other cancers, including Wnt-driven tumors originating from the gut. Here, we show that supplementation with the antioxidants N-acetylcysteine (NAC) and vitamin E promotes intestinal tumor progression in the ApcMin mouse model for familial adenomatous polyposis, a hereditary form of colorectal cancer, driven by Wnt signaling. Both antioxidants increased tumor size in early neoplasias and tumor grades in more advanced lesions without any impact on tumor initiation. Importantly, NAC treatment accelerated tumor progression at plasma concentrations comparable to those obtained in human subjects after prescription doses of the drug. These results demonstrate that antioxidants play an important role in the progression of intestinal tumors, which may have implications for patients with or predisposed to colorectal cancer.

Bridging the Species Gap: Morphological and Molecular Comparison of Feline and Human Intestinal Carcinomas.

Limited availability of in vivo experimental models for invasive colorectal cancer (CRC) including metastasis and high tumor budding activity is a major problem in colorectal cancer research. In order to compare feline and human intestinal carcinomas, tumors of 49 cats were histologically subtyped, graded and further characterized according to the human WHO classification. Subsequently, feline tumors were compared to a cohort of 1004 human CRC cases. Feline intestinal tumors closely resembled the human phenotype on a histomorphological level. In both species, adenocarcinoma not otherwise specified (ANOS) was the most common WHO subtype. In cats, the second most common subtype of the colon (36.4%), serrated adenocarcinoma (SAC), was overrepresented compared to human CRC (8.7%). Mucinous adenocarcinoma (MAC) was the second most common subtype of the small intestine (12.5%). Intriguingly, feline carcinomas, particularly small intestinal, were generally of high tumor budding (Bd) status (Bd3), which is designated an independent prognostic key factor in human CRC. We also investigated the relevance of feline CTNNB1 exon 2 alterations by Sanger sequencing. In four cases of feline colonic malignancies (3 ANOS, 1 SAC), somatic missense mutations of feline CTNNB1 (p.D32G, p.D32N, p.G34R, and p.S37F) were detected, indicating that mutational alterations of the WNT/ß-catenin signaling pathway potentially play an essential role in feline intestinal tumorigenesis comparable to humans and dogs. These results indicate that spontaneous intestinal tumors of cats constitute a useful but so far underutilized model for human CRC. Our study provides a solid foundation for advanced comparative oncology studies and emphasizes the need for further (molecular) characterization of feline intestinal carcinomas.

Vitamin D and the nutritional environment in functions of intestinal stem cells: Implications for tumorigenesis and prevention.

Sporadic colon cancer accounts for ∼80% of CRC, with high incidence in western societies strongly linked to dietary patterns. The only mouse model for sporadic CRC results from feeding mice a purified rodent western-style diet (NWD1), establishing mouse intake of several common nutrients that mimic for each its level consumed in western populations at higher risk for colon cancer (higher fat, lower vitamin D3, calcium, methyl donors and fiber). This causes sporadic colon and small intestinal tumors at an incidence and frequency similar to that of humans. NWD1 perturbs intestinal cell maturation and Wnt signaling throughout villi and colonic crypts before tumors are detected. Surprisingly, feeding NWD1 decreases mouse Lgr5hi intestinal stem cell contribution to homeostasis and tumorigenesis, associated with extensive Lgr5hi cell transcriptional reprogramming, with nutrient levels interactive in these effects. There is a key impact of the lower vitamin D3 in NWD1 and its signaling through the Vdr. The DNA mismatch repair pathway is elevated in Lgr5hi cells by lower vitamin D3 and/or calcium in NWD1, reducing accumulation of relevant somatic mutations detected by single cell exome sequencing. There are also alterations in metabolic pathways, including down-regulation of oxidative phosphorylation. In compensation for compromise of Lgr5hi cells, NWD1 also reprograms cells derived from the Bmi1+ population, defined as those cells marked in Bmi1creERT2, Rosa26tom mice following tamoxifen injection, and at least a portion of these cells then function and persist as stem-like cells in mucosal homeostasis and tumorigenesis. The data establish a key role of the nutrient environment, and vitamin D signaling, in defining contribution of at least two different stem cell populations to mucosal homeostasis and tumorigenesis. This raises significant questions regarding impact of variable human diets on which and how multiple potential intestinal stem cell populations function in the human and give rise to tumors. Moreover, genetic and epigenetic changes in long-lived stem cells have important implications for understanding the effects of vitamin D and other nutrients on intestinal homeostasis and on intervention strategies for altering probability of tumor development.

Small Intestinal Tumors: A Rare Case of Tubulovillous Adenoma in Duodenum.

The small intestine is a relatively privileged organ; primary tumors are uncommon among malignancies of the gastrointestinal tract, with an average annual incidence rate of 9.9 per million people. Among these uncommon tumors, duodenal tumors are even rarer with an average incidence rate of 0.4% only. Histopathological examination mostly shows villous type. Tubulovillous histology is extremely rare with an incidence of less than 1% of all duodenal tumors. These tumors are either found incidentally or during screening for familial disorders such as familial adenomatous polyposis or Gardner's syndrome. Patients usually have symptoms such as diarrhea and abdominal pain along with weight loss over a period of months. Itching over the whole body and progressive yellow discoloration of sclera and skin (jaundice) can also be present when tumor compresses the common bile duct (CBD) and causes obstruction, especially in the region of ampulla of Vater. Examination of the abdomen may or may not reveal a mass lesion. Abdominal radiography and ultrasound show intra- and extra-hepatic biliary dilatation along with distention of CBD and growth at the lower end of CBD. Endoscopic retrograde cholangiopancreatography (ERCP) is, however, the investigation of choice as it not only allows direct visualization of a biliary tree but biopsy specimens can also be taken. Palliative procedures like placing a stent in the common bile duct to relieve obstruction can be done or a drain can be placed to drain bile. The definitive treatment is the Whipple procedure involving gastrojejunostomy, choledochojejunostomy, and cholecystectomy. Our case is unique as the patient had duodenal tubulovillous adenoma, a very rare tumor among the already uncommon duodenal tumors. The patient underwent Whipple procedure, T tube was placed, and feeding jejunostomy was done. An uneventful recovery occurred.

Innovative Disease Model: Zebrafish as an In Vivo Platform for Intestinal Disorder and Tumors.

Colorectal cancer (CRC) is one of the world's most common cancers and is the second leading cause of cancer deaths, causing more than 50,000 estimated deaths each year. Several risk factors are highly associated with CRC, including being overweight, eating a diet high in red meat and over-processed meat, having a history of inflammatory bowel disease, and smoking. Previous zebrafish studies have demonstrated that multiple oncogenes and tumor suppressor genes can be regulated through genetic or epigenetic alterations. Zebrafish research has also revealed that the activation of carcinogenesis-associated signal pathways plays an important role in CRC. The biology of cancer, intestinal disorders caused by carcinogens, and the morphological patterns of tumors have been found to be highly similar between zebrafish and humans. Therefore, the zebrafish has become an important animal model for translational medical research. Several zebrafish models have been developed to elucidate the characteristics of gastrointestinal diseases. This review article focuses on zebrafish models that have been used to study human intestinal disorders and tumors, including models involving mutant and transgenic fish. We also report on xenograft models and chemically-induced enterocolitis. This review demonstrates that excellent zebrafish models can provide novel insights into the pathogenesis of gastrointestinal diseases and help facilitate the evaluation of novel anti-tumor drugs.

Endometrioid adenocarcinoma arising from colon endometriosis.

Endometriosis-associated intestinal tumors represent the malignant transformation of gastrointestinal endometriosis. Approximately 50 cases have been reported in the literature. They are most commonly found among women aged 30-60 years, whereas exogenous hormone therapy and obesity are primary risk factors for the malignant transformation of endometriotic lesions. Clinical features simulate a primary colonic carcinoma. A high index of suspicion in conjunction with careful histological and immunohistochemical examination (CK7, CK20, CDX2, CD10, ER, and PR) is important for establishing a correct diagnosis. In this article, a rare case of a postmenopausal woman with no risk factors and conflicting clinical presentation, diagnosed with endometriosis-associated intestinal tumor, is described.

Adenomatous Polyposis Coli Defines Treg Differentiation and Anti-inflammatory Function through Microtubule-Mediated NFAT Localization.

Adenomatous polyposis coli (APC) is a polarity regulator and tumor suppressor associated with familial adenomatous polyposis and colorectal cancer development. Although extensively studied in epithelial transformation, the effect of APC on T lymphocyte activation remains poorly defined. We found that APC ensures T cell receptor-triggered activation through Nuclear Factor of Activated T cells (NFAT), since APC is necessary for NFAT's nuclear localization in a microtubule-dependent fashion and for NFAT-driven transcription leading to cytokine gene expression. Interestingly, NFAT forms clusters juxtaposed with microtubules. Ultimately, mouse Apc deficiency reduces the presence of NFAT in the nucleus of intestinal regulatory T cells (Tregs) and impairs Treg differentiation and the acquisition of a suppressive phenotype, which is characterized by the production of the anti-inflammatory cytokine IL-10. These findings suggest a dual role for APC mutations in colorectal cancer development, where mutations drive the initiation of epithelial neoplasms and also reduce Treg-mediated suppression of the detrimental inflammation that enhances cancer growth.

Targeting Zfp148 activates p53 and reduces tumor initiation in the gut.

The transcription factor Zinc finger protein 148 (Zfp148, ZBP-89, BFCOL, BERF1, htß) interacts physically with the tumor suppressor p53, but the significance of this interaction is not known. We recently showed that knockout of Zfp148 in mice leads to ectopic activation of p53 in some tissues and cultured fibroblasts, suggesting that Zfp148 represses p53 activity. Here we hypothesize that targeting Zfp148 would unleash p53 activity and protect against cancer development, and test this idea in the APCMin/+ mouse model of intestinal adenomas. Loss of one copy of Zfp148 markedly reduced tumor numbers and tumor-associated intestinal bleedings, and improved survival. Furthermore, after activation of ß-catenin-the initiating event in colorectal cancer-Zfp148 deficiency activated p53 and induced apoptosis in intestinal explants of APCMin/+ mice. The anti-tumor effect of targeting Zfp148 depended on p53, as Zfp148 deficiency did not affect tumor numbers in APCMin/+ mice lacking one or both copies of Trp53. The results suggest that Zfp148 controls the fate of newly transformed intestinal tumor cells by repressing p53 and that targeting Zfp148 might be useful in the treatment of colorectal cancer.

Chemopreventive Action of Anthocyanin-rich Black Soybean Fraction in APC (Min/+) Intestinal Polyposis Model.

BACKGROUND: Anthocyanins have been shown to inhibit cancer cell growth by suppressing oxidative stress and inflammatory responses. The purpose of this study was to investigate the effects of an anthocyanin-rich extract (AE) from black soybean coat on intestinal carcinogenesis. METHODS: Apc (Min/+) mice were fed a diet of 0.2% or 0.5% AE for 7 weeks. We analyzed the number of intestinal tumors, oxidative stress and inflammatory markers associated with ß-catenin and cytosolic phospholipase A2 (cPLA2) signals. The number of intestinal tumors, and cellular expression of ß-catenin were determined. RESULTS: The number of intestinal tumors was significantly lower in mice fed a 0.5% AE diet compared to those of the other groups. Cytosolic ß-catenin expression was significantly decreased in the AE supplemented groups compared to that of the control animals. In addition, mucosa expression of cyclooxygenase-2 and cPLA2 were also significantly decreased in the 0.5% AE group, by 32% and 62%, respectively, compared to the control group. CONCLUSIONS: These results suggest that dietary AE reduced the development of intestinal tumors, possibly through the ability to suppress oxidative stresses, decreasing inflammatory responses mediated by ß-catenin associated signals.