La récidive tumorale est l'un des principaux obstacles à surmonter à l'avenir pour améliorer la survie globale des patients atteints de cancer du côlon (CCR). Les échecs thérapeutiques observés chez les patients sont compatibles avec une accumulation de cellules souches cancéreuses (CSCs) résistantes aux médicaments. Dans cette étude, nous démontrons que le récepteur nucléaire PXR (NR1I2) agit comme un régulateur important de la chimiorésistance des CSCs coliques et de leur capacité à initier la rechute tumorale après traitement. Nous avons d'abord montré que l'expression de PXR augmente avec celle de certains marqueurs des CSCs dans des cellules cancéreuses de patients CCR traitées par chimiothérapies. Nous avons constaté que PXR est préférentiellement exprimé dans les CSCs coliques et qu'il contribue à l'enrichissement des CSCs après chimiothérapies in vitro et in vivo. Par des approches de transcriptomiques, nous avons observé qu'au sein des CSCs coliques, PXR contrôle l'expression d'un large réseau de gènes marqueurs des CSCs coliques, ainsi que des gènes impliqués dans la résistance aux médicaments ou à l'apoptose, ou impliqués dans la dissémination métastatique. Enfin, l'inhibition de PXR par interférence à ARN diminue la survie et auto-renouvèlement des cellules souches cancéreuses du côlon in vitro, ainsi que leur capacité à résister à la chimiothérapie après xénogreffes, conduisant à des retards importants de rechute tumorale après traitements par chimiothérapies in vivo. Cette étude suggère fortement que l'inhibition ciblée de PXR peut représenter une stratégie de traitement néo-adjuvant afin de diminuer la résistance aux médicaments et la récidive des patients CCR via la sensibilisation des cellules souches cancéreuses aux chimiothérapies classiques. / Tumor recurrence is one of the major obstacles to overcome in the future to improve overall survival of patients with colon cancer. High rates and patterns of therapeutic failure seen in patients are consistent with a steady accumulation of drug-resistant cancer stem cells (CSCs). Here, we demonstrate that the nuclear receptor PXR (NR1I2) acts as a key regulator of colon CSC chemoresistance and of their ability to generate post-treatment tumor relapse. We first determined that the enrichment of PXR paralleled that of CSC markers upon treatment of colon cancer cells with standard of care chemotherapy. We found that PXR was highly expressed in colorectal cancer cells displaying CSC markers and function and that it was instrumental for the emergence of CSCs following chemotherapy in vitro and in vivo. mRNA profiling experiments in colon CSCs indicated that PXR transcriptionally controls a large network of genes including markers of stemness, genes involved in resistance to drug/apoptosis or migration/invasion. Finally, PXR down-regulation altered the survival and self-renewal of colon CSCs in vitro and hampered their capacity to resist chemotherapy in vivo, leading to significant delays of post-chemotherapy tumor relapse. This study strongly suggests that targeting PXR may represent a novel treatment strategy to prevent drug resistance and recurrence through the sensitization of CSCs to standard chemotherapy. Taken together, our data strongly suggest that PXR plays an instrumental role in the so-called "intrinsic" pan-resistance of CSCs against therapy.

Artificial urinary sphincters have been used for decades for treatment of urinary incontinence. A commonly used device, the AMS 800 consists of a urethral cuff, pump and an abdominal reservoir. Notable complications of this system include scrotal or labial hematomas, infection or erosion of the cuff and rarely migration of its components. Although there are few reported cases related to effects from pump migration, those documenting reservoir related complications are even rarer. We present a case of reservoir migration adjacent to the ascending colon causing ischemic changes mimicking colonic neoplasm. Our patient, a 66-year old male with medical history of adenocarcinoma of prostate status post radical prostatectomy, had been having abdominal pain for a month. A CT scan showed cecal and proximal ascending colonic irregular nodular thickening suggestive of colonic mass. It also revealed a low-density structure next to the ascending colon abutting into area of the mass. A follow up colonoscopy showed a fungating, ulcerated mass extending from cecum to ascending colon concerning for a malignancy of which biopsy was also done. The patient then underwent right open hemicolectomy. During surgery, a balloon reservoir was seen in the abdominal cavity with its adherence to the right colon but not eroding into it. The surgeon dissected the balloon, repositioned and re-peritonealized it before closing the abdomen. The colonoscopic and surgical pathology instead demonstrated findings of ischemic colitis with mucosal ulceration in cecum and ascending colon limited to the mucosa but no evidence of cancer. Retrospective chart review revealed history of artificial urinary sphincter implantation for urinary incontinence related to radical prostatectomy for adenocarcinoma eight years prior. With manufacturer suggested implant location of the reservoir in prevesical space, the possibility of migration needs to be accounted for. Although there are not many reports of artificial sphincter reservoir related complications, there are cases documenting inflatable penile prosthesis reservoir erosion into abdominal and pelvic structures. As the CT scan demonstrated reservoir indentation into the ascending colon, it likely led to chronic irritation of the adjacent colonic wall due to mass effect. It is hypothesized that constant pressure on colonic wall likely led to localized ischemia. This resulted in localized inflammation including submucosal edema, which can create a mass-like appearance when severe. This case emphasizes that, while preliminary radiographic imaging and even gross colonoscopy findings may be suggestive of a malignancy, it is imperative to await biopsy results to confirm the diagnosis of a malignant neoplasm. Our case report emphasizes the consideration of diagnoses other than colon cancer when faced with a colonic mass especially in the setting of implanted intra-abdominal foreign body to avoid unnecessary surgery and related complications.

Oshima N, Yamada Y, Nagayama S, Kawada K, Hasegawa S, et al. (2014) Induction of Cancer Stem Cell Properties in Colon Cancer Cells by Defined Factors. PLoS ONE 9(7): e101735. doi:10.1371/journal.pone.0101735 / 京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第18547号 / 医博第3940号 / 新制||医||1006(附属図書館) / 31447 / 京都大学大学院医学研究科医学専攻 / (主査)教授 千葉 勉, 教授 野田 亮, 教授 武藤 学 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Colorectal cancer is the third most common cancer and the fourth most common cause of cancer-related death in the world. The global burden of colorectal cancer is also expected to increase by 60%, to over 2.2 million new cases and 1.1 million annual deaths, by the year 2030. Jackfruit is known for its packed nutrition including many antioxidants: vitamin C, carotenoids and flavanones. It has also been used in traditional medicine due to its potential protection against many chronic diseases. However, there is limited research studying the potential effect of jackfruit on colorectal cancer. Here, we used a well-established AOM/DSS mice model to investigate the impact of jackfruit-derived extracts on colitis-associated colorectal cancer. After 6-week treatment with diet containing 480 ppm jackfruit-derived extracts, the mice showed significantly alleviated colon tumorigenesis with a 46% decrease in tumor numbers of each mouse compared to vehicle group (2.1 ± 0.31 for 480 ppm jackfruit-derived fraction group vs 3.9 ± 0.67 for vehicle group, P < 0.05). The expression of the pro-inflammatory cytokines (Il-6 and Inf- γ) and pro-tumorigenic genes (Axin2, Vegf, Myc and Pcna) was also decreased in the group consuming 480 ppm jackfruit-derived extracts compared to the vehicle group. Together the results suggest that the consumption of jackfruit-derived extracts could protect against colitis-associated colorectal carcinogenesis in mice.

<p>Colorectal cancer is one of the leading causes of cancer deaths in the United States and multiple modifiable factors contribute to colorectal carcinogenesis. Gut microbiota are believed to play key roles in colon cancer development. Dietary factors may modulate gut microbiota composition, which may potentially have impact on carcinogenesis. Thus, it is reasonable to develop dietary interventions to effectively prevent colorectal cancer development through alteration of gut microbiota. In this thesis, the first objective is to evaluate the effect of vitamin E forms and metabolites, i.e., δ-tocotrienol (δTE), γ-tocotrienol (γTE) and δTE-13’-COOH (δTE-13’), respectively, on gut microbiota in mice. Healthy male balb/c mice were supplemented with a δTE/γTE mixture or δTE-13’ by gavage for two weeks, while control mice received soybean oil. We isolated DNAs from fecal samples and used 16S rRNA gene sequencing to evaluate the impact of these compounds on gut microbiota compositions. Further, we also examined the effect on short chain fatty acids (SCFAs). We observed that supplementation of δTE-13’ increased microbial richness using the Faith index. On the other hand, supplementation did not separate the microbial communities from the control group. But, these compounds managed to alter the relative abundances of several taxa that might present chemopreventive activities against colon cancer. Specifically, <i>Desulfovibrio</i>, a sulfur-reducing bacterium, was decreased after δTE/γTE supplementation. <i>Eubacterium coprostanoligenes</i> group, a group of microbes that can reduce circulating cholesterol, was increased after δTE/γTE supplementation. In addition, several members from the <i>Lachnospiraceae</i> family were elevated under δTE/γTE and δTE-13’ supplementation, and these microbes are known to produce SCFAs and maintain colonic health. However, the measurement of SCFAs showed that supplementation of δTE/γTE and δTE-13’ did not change SCFAs compared with controls. In the second project, I investigated anti-proliferative effects of combining δTE or δTE-13’ with sodium butyrate (NaBu) on human colorectal carcinoma HCT116 cells. Our data showed promising additive effects against cell growth. Collectively, these results indicate that δTE/γTE and δTE-13’ can modulate gut microbiota under healthy conditions, which provides insights into potential chemopreventive activities of these vitamin E forms. Our cell-based studies also showed additive anticancer effects of combining δTE or δTE-13’ with NaBu, which provides rationale to further develop combination of butyrate producers with vitamin E forms for cancer prevention.</p>

The NAD-dependent deacetylase SIRT1 regulates several factors involved in stress response and cell survival but its function in cancer is largely unknown. Research suggests that SIRT1 influences several transcription factors and molecules that are important components of pathways often deregulated in cancer. Our experiments have shown that SIRT1 knock down by short hairpin RNA accelerates tumor xenograft formation by HCT116 colon cancer cells, whereas SIRT1 overexpression inhibits tumor formation. We have also found that, pharmacological inhibition of SIRT1 stimulates cell proliferation under conditions of growth factor deprivation suggesting a tumor suppressive function of SIRT1. Paradoxically, SIRT1 inhibition sensitizes the same cells to apoptosis by chemotherapeutic drugs. Immunohistochemical staining of a colon tumor microarray revealed high SIRT1 expression levels in normal colon mucosa and benign adenomas. SIRT1 overexpression was observed in nearly 25% of stage I/II/III colorectal adenocarcinomas but rarely found in advanced stage IV tumors. Furthermore, about 30% of carcinomas showed lower than normal SIRT1 expression. These results suggest a pleiotropic effect of SIRT1 in cancer, i.e., anti-proliferative as well as anti-apoptotic. Further experiments along these lines and examination of a larger patient cohort could provide a rationale for the use of SIRT1 activators and inhibitors in the prevention and treatment of cancer.

No description available.

Nutritional factors play an important role in the prevention and promotion of colorectal cancer. Vitamin E is a generic term that describes a group of lipid-soluble chain-breaking antioxidants that includes tocopherols and tocotrienols. Vitamin E occurs in nature as eight structurally related forms that include four tocopherols and four tocotrienols. Vitamin E is a potent membrane-soluble antioxidant. Antioxidants like vitamin E (tocopherols) may prevent colon cancer through several different cellular and molecular mechanisms. Vitamin E in the American diet is primarily available in plant-oil rich foods such as vegetable oils, seeds and nuts and these foods vary widely in their content of α-tocopherol and γ-tocopherol [1]. Vitamin E may help prevent colon cancer by decreasing the formation of mutagens arising from the oxidation of fecal lipids, by decreasing oxidative stress in the epithelial cells of the colon and by molecular mechanisms that influence cell death, cell cycle and transcriptional events. Most epidemiological, experimental and clinical studies have evaluated the α-isoform and not the γ-isoform of vitamin E. Recent epidemiological, experimental and mechanistic evidence suggests that γ-tocopherol may be a more potent cancer chemopreventive agent than α-tocopherol. The differences in chemical reactivity, metabolism and biological activity may contribute to these differences in the effects of γ-tocopherol when compared with α-tocopherol. The rationale supporting the development of γ-tocopherol as a colorectal cancer preventive agent is reviewed here.

The purpose of this investigation was to determine how dietary levels of α-tocopherol, γ-tocopherol and iron influence oxidative stress and ras-p21 levels in the colon. Rats were fed diets deficient in tocopherols (-E) or supplemented with either 0.156 mmol of α-tocopherol (AE)/kg diet or 0.156 mmol of γ-tocopherol (GE)/kg of diet. Half the rats in each of these three groups received dietary iron at a level of 35 mg/kg diet and the other half at eight times this level (280 mg/kg diet). Rats fed the AE diets had higher levels of Vitamin E in feces, colonocytes, plasma and liver than did rats fed the GE diets. Dietary iron levels did not influence tocopherol levels in plasma, liver or feces. For colonocytes, high dietary iron decreased tocopherol levels. The ratio of γ-tocopherol (in the GE groups) to α-tocopherol (in the AE groups) was 0.13 for plasma, 0.11 for liver, 0.28 for colonocytes and 0.51 for feces. The plasma ratio is not, therefore, predictive of the ratio in colonocytes and feces. High levels of dietary iron increased levels of fecal lipid hydroperoxides. Moreover, rats fed the GE diets had lower levels of fecal lipid hydroperoxides than rats fed the AE diets. The levels of ras-p21 were significantly lower in rats fed the GE diets compared with rats fed the AE diets. The γ-tocopherol may, therefore, play a significant role in preventing colon cancer. High levels of dietary iron were found to promote oxidative stress in feces and colonocytes.

Ethanol and n-hexane extracts obtained from the leaves and inflorescences of Gnaphalium gracile, were tested at different concentrations to evaluate their antineoplastic activities on pancreatic, colon, and prostate cancer cell lines by examining mitochondrial function. The polar extracts of both, leaves and inflorescences which contain gnaphalin, quercetin, and 3-methoxy quercetin, exhibited cytotoxicity against every cell line tested with EC50 values ranging between 20.23±1.185 µg/mL and 70.71±1.1419 µg/mL. The most remarkable values were observed in pancreatic cancer Panc 28 and androgen-dependent prostate LnCaP cells, with EC50 values of 20.23±1.185 and ˂25µg/mL, and androgen-independent prostate cancer PC-3, colon HCT-116 and pancreatic MIA PaCa cells with values ranging between 28.84±1.1766 and 34.41±1.057 µg/mL. The non-polar extract derived from leaves demonstrated significant cytotoxicity towards colon cancer HCT-116 cells, with an EC50 of 39.46±1.0617 µg/mL. However, the non-polar extract from the inflorescences did not have an appreciable effect on cell proliferation of any of the cell lines tested except for androgen-independent prostate cancer PC-3 cells with an EC50 of 62.05±1.237 µg/mL. The data obtained support the traditional use of G. gracile and suggest the polar extracts from aerial parts, as an interesting source for the development of novel antineoplastic agents.