deoxycholic-acid and Colorectal-Neoplasms

Topics: Biomarkers, Tumor; Colorectal Neoplasms; Deoxycholic Acid; Feces; Humans; Lithocholic Acid; Risk Factors

Newmark et al. (J Natl Cancer Inst 1984; 72:1323-8) hypothesized that supplementation with calcium would decrease the concentration of bile acids in aqueous phase feces and that such a reduction would reduce the risk of malignant disease in the bowel. A randomized trial was therefore undertaken to examine the effects of calcium supplementation on fecal biochemistry. A total of 68 men between 40 and 60 years of age volunteered to participate after having been selected randomly from population lists in Scarborough, a city in the Toronto area, Ontario, Canada. Participants were randomly assigned to receive a daily supplement of 3 g of calcium carbonate or a sucrose placebo for a period of 1 week. Fecal samples were collected for 2 days prior to supplementation and for the last 2 days of supplementation. Records of all foods consumed were kept throughout the study period. The average concentration of total soluble bile acids fell in the placebo group (-11.2 g/ml) but increased slightly in the calcium group (1.4 g/ml). Similar patterns of change were observed for deoxycholic acid (placebo, -3.0 g/ml; calcium, 4.5 g/ml). The distribution of changes in total bile acids and deoxycholic acid differed between randomization groups at the 10 percent level of significance in univariate analysis. After adjustment for initial stool chemistry and initial levels and changes in nutrient intake, no reduction in fecal bile acid levels was observed in association with calcium supplementation. In fact, a statistically significant (p = 0.05) increase in deoxycholic acid concentration remained in the calcium supplemental group. Thus, this study was unable to support the hypothesis that calcium supplementation alters aqueous phase bile acids in the manner hypothesized to be consistent with protection from colorectal cancer.

Topics: Adult; Bile Acids and Salts; Calcium; Colorectal Neoplasms; Deoxycholic Acid; Double-Blind Method; Feces; Humans; Male; Middle Aged

To identify potential diagnostic biomarkers of colorectal cancer (CRC) using serum metabolomic technology for minimally invasive and efficient screening for CRC.. Serum samples from 79 healthy individuals and 82 CRC patients were analyzed by metabolomics using ultra-high-performance liquid chromatography-tandem highresolution mass spectrometry (UHPLC-HRMS). The differential metabolites between the two groups were analyzed using principal component analysis and orthogonal partial least squares discriminant analysis (OPLS-DA). Receiver operating characteristic curve (ROC) analysis was performed to identify the differential metabolites with good diagnostic performance (AUC>0.80) for CRC, and targeted bile acid metabolomics was used to verify the selected bile acids as biomarkers.. Serum metabolic profiles differed significantly between the healthy individuals and CRC patients, and a total of 82 differential metabolites (mostly fatty acids and glycerophospholipids) were selected. ROC analysis identified 10 differential metabolites, including adenine, bilirubin, ACar 12:0, ACar 10:1, ACar 9:0, PC 18:2e, deoxycholic acid, chenodeoxycholic acid, ACar 14:1 and palmitoylcarnitine. One of these metabolites was significantly up-regulated and 9 were down-regulated in the serum of CRC patients (. Metabolic disorders of fatty acids and glycerophospholipids are closely related wigh tumorigenesis of CRC. Ten differential metabolites show good performance for CRC diagnosis, and the panel consisting 7 of these metabolites has important diagnostic value for CRC. Deoxycholic acid and chenodeoxycholic acid may serve as potential diagnostic biomarkers of CRC.

Topics: Bile Acids and Salts; Biomarkers; Chenodeoxycholic Acid; Colorectal Neoplasms; Deoxycholic Acid; Fatty Acids; Glycerophospholipids; Humans; Metabolome; Metabolomics

A high-fat diet (HFD) leads to long-term exposure to gut microbial metabolite secondary bile acids, such as deoxycholic acid (DCA), in the intestine, which is closely linked to colorectal cancer (CRC). Evidence reveals that vasculogenic mimicry (VM) is a critical event for the malignant transformation of cancer. Therefore, this study investigated the crucial roles of DCA in the regulation of VM and the progression of intestinal carcinogenesis. The effects of an HFD on VM formation and epithelial-mesenchymal transition (EMT) in human CRC tissues were investigated. The fecal DCA level was detected in HFD-treated Apc

Topics: Adult; Aged; Animals; Apoptosis; Bile Acids and Salts; Carcinogenesis; Cell Movement; Cell Proliferation; Colorectal Neoplasms; Deoxycholic Acid; Diet, High-Fat; Epithelial-Mesenchymal Transition; Feces; Female; Gastrointestinal Microbiome; HCT116 Cells; Humans; Intestinal Mucosa; Male; Mice; Middle Aged; Neovascularization, Pathologic; Signal Transduction; Vascular Endothelial Growth Factor Receptor-2

Topics: Colorectal Neoplasms; Deoxycholic Acid; Humans; Intestines; Nanofibers; Silicon Dioxide; Tumor Microenvironment

Micro-RNA-21 (miR-21) is a vital regulator of colorectal cancer (CRC) progression and has emerged as a potential therapeutic target in CRC treatment. Our study using real-time PCR assay found that a secondary bile acid, lithocholic acid (LCA), stimulated the expression of miR21 in the CRC cell lines. Promoter activity assay showed that LCA strongly stimulated miR21 promoter activity in HCT116 cells in a time- and dose-dependent manner. Studies of chemical inhibitors and miR21 promoter mutants indicated that Erk1/2 signaling, AP-1 transcription factor, and STAT3 are major signals involved in the mechanism of LCA-induced miR21 in HCT116 cells. The elevation of miR21 expression was upstream of the phosphatase and tensin homolog (PTEN) inhibition, and CRC cell proliferation enhancement that was shown to be possibly mediated by PI3K/AKT signaling activation. This study is the first to report that LCA affects miR21 expression in CRC cells, providing us with a better understanding of the cancer-promoting mechanism of bile acids that have been described as the very first promoters of CRC progression.

Topics: Cell Line, Tumor; Chenodeoxycholic Acid; Cholic Acid; Colorectal Neoplasms; Deoxycholic Acid; Detergents; HCT116 Cells; HT29 Cells; Humans; Lithocholic Acid; MAP Kinase Signaling System; MicroRNAs; Mitogen-Activated Protein Kinase 3; PTEN Phosphohydrolase; STAT3 Transcription Factor

Colorectal cancer (CRC) is a prevalent and fatal cancer. Oral administration provided the potential for in situ treatment of the colorectal cancer. However, drugs couldn't be well-absorbed mainly due to its degradation in the gastric area and poor intestinal permeability. In this study, we synthesized deoxycholic acid and hydroxybutyl decorated chitosan nanoparticles (DAHBC NPs) as oral curcumin (CUR) delivery system for colorectal cancer treatment. DAHBC with lower critical solution temperature (LCST) below 37 °C (27-33 °C) was obtained. DAHBC NPs were correspondingly stable in simulated gastric conditions (pH 1.2, 37 °C), due to the offset of size change between pH-responsive expansion and thermo-responsive shrinkage. In simulated intestinal tract (pH 7.0-7.4, 37 °C), DAHBC NPs exhibited burst release of CUR owing to the onefold effect of thermo-responsive shrinkage. DAHBC27 NPs showed the minimum CUR leakage (~10%) in simulated gastric conditions, because a furthest temperature-sensitive shrinkage caused by the lowest LCST offset the expansion in acid environment. DAHBC27 NPs induced ~10-fold increased (P < 0.05) CUR absorption by paracellular transport pathway, compared to the free CUR. Thus, DAHBC NPs stabilized in the gastric environment may be a promising oral drugs delivery system for effective in situ colorectal cancer therapy.

Topics: Administration, Oral; Adsorption; Caco-2 Cells; Chitosan; Colorectal Neoplasms; Curcumin; Deoxycholic Acid; Drug Carriers; Drug Liberation; Drug Stability; Gastric Mucosa; Hemolysis; Humans; Intestinal Absorption; Materials Testing; Nanoparticles; Temperature

Increased levels of intestinal bile acids (BAs) are a risk factor for colorectal cancer (CRC). Here, we show that the convergence of dietary factors (high-fat diet) and dysregulated WNT signaling (APC mutation) alters BA profiles to drive malignant transformations in Lgr5-expressing (Lgr5

Topics: Animals; Bile Acids and Salts; Cell Line; Cell Proliferation; Colorectal Neoplasms; Deoxycholic Acid; Gene Expression Regulation, Neoplastic; Humans; Intestinal Neoplasms; Intestines; Liver; Mice; Mice, Inbred C57BL; Neoplastic Stem Cells; Organoids; Receptors, Cytoplasmic and Nuclear; Risk Factors; Signal Transduction; Taurocholic Acid; Wnt Signaling Pathway

To achieve a clinically rational regimen for cancer chemoprevention with improved efficacy and safety, the combination effect of celecoxib and newly developed oral angiogenesis inhibitor, LHD4, on chemoprevention was evaluated. The chemopreventive effects of celecoxib, LHD4, and the combination of celecoxib and LHD4 were evaluated in a murine colorectal carcinogenesis model. After 17 experimental weeks, mouse colon tissues were collected and examined in terms of polyp volume and degree of carcinogenesis, inflammation, and angiogenesis. Mice in the celecoxib-treated or LHD4-treated groups had total polyp volumes of 47.0±9.7 and 120.1±45.2 mm, respectively, which represented decreases of 65.6 and 22.3% from the control (154.5±33.5 mm). However, the polyp volume in the combination group was 22.8±9.3 mm, a decrease of 85.2% from the control. In the comparison of carcinogenesis, the percentage of normal tissue (i.e. excluding proliferative tissue) was found to be 40.6% in the control, 51.7% in the celecoxib, 56.9% in the LHD4, and 81.7% in the combination group. In accordance with attenuated carcinogenesis, both inflammation and angiogenesis were also well controlled. Together, these results suggest that the combinatory use of celecoxib and a newly developed oral heparin conjugate could be a promising regimen for chemoprevention by intervening in both inflammation and angiogenesis.

Topics: Administration, Oral; Angiogenesis Inhibitors; Animals; Anticarcinogenic Agents; Azoxymethane; Carcinogenesis; Celecoxib; Colon; Colonic Polyps; Colorectal Neoplasms; Cyclooxygenase Inhibitors; Deoxycholic Acid; Dextran Sulfate; Drug Therapy, Combination; Heparin, Low-Molecular-Weight; Inflammation; Male; Mice, Inbred ICR; Neovascularization, Pathologic; Pyrazoles; Sulfonamides; Tumor Burden

Colorectal cancer is one of the leading causes of cancer deaths. It correlates to a high fat diet, which causes an increase of the secondary bile acids including deoxycholate (DOC) in the intestine. We aimed to determine the effects of DOC on intestinal carcinogenesis in Apc (min/+) mice, a model of spontaneous intestinal adenomas. Four-week old Apc (min/+) mice were treated with 0.2 % DOC in drinking water for 12 weeks. The number and size of tumors were measured, and tissue sections were prepared for the evaluation of intestinal carcinogenesis, cell proliferation, and apoptosis. The activation of Wnt signaling was detected in the intestinal tumor cells of the Apc (min/+) mice, and also in the human colon samples. DOC increased the number of intestine tumors by 165.1 % compared with that in untreated Apc (min/+) mice mainly in the middle and distal segments of the small intestine and colon. The numbers of all sizes of tumors in the small intestine were increased. Intestinal carcinogenesis was confirmed in 75 % mice in DOC treated-Apc (min/+) mice compared with 0 % in untreated mice. This was accompanied by promoting tumor cell proliferation and decreasing apoptosis, and increasing the percentage of β-catenin positive cells and its nuclear expression in intestinal tumor cells of Apc (min/+) mice, and also up-regulating the expression of cyclin D1. In addition, the activation of Wnt signaling also played in modulating human colon carcinogenesis. Our studies suggest that DOC enhances the multiplicity of intestinal tumor, and accelerates intestinal adenoma-adenocarcinoma sequence in Apc (min/+) mice mediated by stimulating tumor cell proliferation and decreasing apoptosis through enhancing Wnt signaling.

Topics: Adenocarcinoma; Adenoma; Animals; Blotting, Western; Colorectal Neoplasms; Deoxycholic Acid; Disease Models, Animal; Disease Progression; Genes, APC; Humans; Immunohistochemistry; In Situ Nick-End Labeling; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Wnt Signaling Pathway

All-trans retinoic acid (RA)-incorporated nanoparticles were prepared using deoxycholic acid-conjugated dextran (DexDA). Anticancer activity of RA-incorporated DexDA nanoparticles were tested in vitro and in vivo.. RA-incorporated nanoparticles were prepared by dialysis. Antiproliferative and anti-invasive potential of RA-incorporated nanoparticles were studied using CT26 colorectal carcinoma cells.. RA-incorporated nanoparticles have small particle sizes of around 70-300 nm and spherical shapes. The higher drug-feeding ratio and higher substitution degree of deoxycholic acid in the conjugates resulted in higher drug contents, lower loading efficiency, and larger particle size. RA release rate became slower at higher drug contents and higher substitution degree of deoxycholic acid in the DexDA conjugates. The antiproliferation activity, anti-invasive activity, and matrix metalloproteinase 2 expression of RA-incorporated nanoparticles against CT26 cells in vitro was similar to RA. However, RA-incorporated nanoparticles had superior antimetastatic activity in an animal pulmonary metastatic model of CT26 cells compared to RA itself.. RA-incorporated nanoparticles showed similar anticancer activity in vitro and superior antimetastatic activity in vivo in a pulmonary metastatic model of CT26 cells. We suggest that RA-incorporated nanoparticles are promising vehicles for efficient delivery of RA.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Survival; Colorectal Neoplasms; Deoxycholic Acid; Dextrans; Mice; Nanoparticles; Neoplasm Invasiveness; Neoplasm Metastasis; Particle Size; Polymers; Tretinoin

Procyanidins are oligomers of flavanol subunits present in large amounts in fruits and vegetables. Their consumption is associated with health benefits against colonic inflammation and colorectal cancer (CRC). Large procyanidins (with more than three subunits) are not absorbed by intestinal epithelial cells but could exert biological actions through their interactions with the cell membrane. This study investigated the capacity of hexameric procyanidins (Hex) to prevent oncogenic events initiated by deoxycholic acid (DCA), a secondary bile acid linked to the promotion of CRC. Hex interacted with Caco-2 cell membranes preferentially at the water-lipid interface. Hex (2.5-20 μM) inhibited DCA-triggered increase in cellular calcium, NADPH oxidase activation, and oxidant production. DCA promoted the activation of protein kinase B (Akt), of the mitogen-activated protein kinases ERK1/2 and p38, and of the downstream transcription factor AP-1. This activation was not triggered by calcium or oxidant increases. Hex caused a dose-dependent inhibition of DCA-mediated activation of all these signals. DCA also triggered alterations in the cell monolayer morphology and apoptotic cell death, events that were delayed by Hex. The capacity of large procyanidins to interact with the cell membrane and prevent those cell membrane-associated events can in part explain the beneficial effects of procyanidins on CRC.

Topics: Antioxidants; Apoptosis; Bile; Caco-2 Cells; Calcium; Cell Membrane; Cell Survival; Colorectal Neoplasms; Deoxycholic Acid; Dose-Response Relationship, Drug; Enzyme Activation; Humans; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; NADPH Oxidases; Oxidants; p38 Mitogen-Activated Protein Kinases; Polymerization; Proanthocyanidins; Proto-Oncogene Proteins c-akt; Signal Transduction

Cancer chemotherapy is often limited, since more than one molecule is usually involved with the cancer pathogenesis. A combination of therapeutic drugs would be a promising approach to overcome the complexity of tumors. In this study, a conjugate (DA3) of deoxycholic acid and low molecular weight polyethylenimine (PEI 1.8 kDa), which has a property that mimics that of cell penetrating peptides (CPPs), was used for simultaneous delivery of an anticancer drug and siRNA. When complexed with siRNA, DA3 showed significantly higher target gene silencing efficiency than PEI 25 kDa. The gene silencing efficiency of DA3 was maintained even in the presence of endocytosis inhibitors, suggesting that the polymeric carrier can mediate an endocytosis-independent macromolecular transduction similar to CPPs. The capability of forming a micelle-like core-shell structure enables the conjugates to encapsulate and dissolve paclitaxel (PTX), a water-insoluble drug. The drug-loaded cationic micelles can then interact with siRNA to form stable complexes (PTX/DA3/siRNA). The PTX/DA3/siRNA showed significantly enhanced inhibition of cancer cell growth. When administered into tumor-bearing animals, the PTX/DA3/siRNA demonstrated significant suppression of tumor growth, providing potential usefulness in clinical settings.

Topics: Animals; Antineoplastic Agents, Phytogenic; Cell-Penetrating Peptides; Colorectal Neoplasms; Deoxycholic Acid; Drug Delivery Systems; Endocytosis; Gene Silencing; HCT116 Cells; Humans; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Micelles; Molecular Weight; Paclitaxel; Polyethyleneimine; RNA, Small Interfering; Solubility

COX-2 is a major regulator implicated in colonic cancer. However, how COX-2 signaling affects colonic carcinogenesis at cellular level is not clear. In this article, we investigated whether activation of COX-2 signaling by deoxycholic acid (DCA) in primary human normal and cancer associated fibroblasts play a significant role in regulation of proliferation and invasiveness of colonic epithelial cancer cells. Our results demonstrated while COX-2 signaling can be activated by DCA in both normal and cancer associated fibroblasts, the level of activation of COX-2 signaling is significantly greater in cancer associated fibroblasts than that in normal fibroblasts. In addition, we discovered that the proliferative and invasive potential of colonic epithelial cancer cells were much greater when the cells were co-cultured with cancer associated fibroblasts pre-treated with DCA than with normal fibroblasts pre-treated with DCA. Moreover, COX-2 siRNA attenuated the proliferative and invasive effect of both normal and cancer associate fibroblasts pre-treated with DCA on the colonic cancer cells. Further studies indicated that the activation of COX-2 signaling by DCA is through protein kinase C signaling. We speculate that activation of COX-2 signaling especially in cancer associated fibroblasts promotes progression of colonic cancer.

Topics: Caco-2 Cells; Cell Proliferation; Colorectal Neoplasms; Cyclooxygenase 2; Deoxycholic Acid; Fibroblasts; HCT116 Cells; HT29 Cells; Humans; Neoplasm Invasiveness; Signal Transduction

There is evidence indicating that bile acid is a promoter of colorectal cancer. Deoxycholic acid modifies apoptosis and proliferation by affecting intracellular signaling and gene expression. We are interested in revealing the relationship between deregulated miRNAs and deoxycholic acid in colorectal cancer development. We found that miR-199a-5p was expressed at a low level in human primary colonic epithelial cells treated with deoxycholic acid compared with control, and miR-199a-5p was significantly down-regulated in colorectal cancer tissues. The miR-199a-5p expression in colorectal cancer cells led to the suppression of tumor cell growth, migration and invasion. We further identified CAC1, a cell cycle-related protein expressed in colorectal cancer, as a miR-199a-5p target. We demonstrated that CAC1 is over-expressed in malignant tumors, and cellular CAC1 depletion resulted in cancer growth suppression. HCT-8 cells transfected with a miR-199a-5p mimic or inhibitor had a decrease or increase in CAC1 protein levels, respectively. The results of the luciferase reporter gene analysis demonstrated that CAC1 was a direct miR-199a-5p target. The high miR-199a-5p expression and low CAC1 protein expression reverse the tumor cell drug resistance. We conclude that miR-199a-5p can regulate CAC1 and function as a tumor suppressor in colorectal cancer. Therefore, the potential roles of deoxycholic acid in carcinogenesis are to decrease miR-199a-5p expression and/or increase the expression of CAC1, which contributes to tumorigenesis in patients with CRC. These findings suggest that miR-199a-5p is a useful therapeutic target for colorectal cancer.

Topics: 3' Untranslated Regions; Adenocarcinoma; Adult; Aged; Aged, 80 and over; Animals; Antibiotics, Antineoplastic; Apoptosis; Base Sequence; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Survival; Colorectal Neoplasms; Cullin Proteins; Deoxycholic Acid; Doxorubicin; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Female; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Humans; Kaplan-Meier Estimate; Male; Mice; Mice, Inbred BALB C; Mice, Nude; MicroRNAs; Middle Aged; RNA Interference; Transcriptome; Tumor Burden; Xenograft Model Antitumor Assays

Deoxycholic acid (DCA) has been shown to promote proliferation of colonic carcinoma cells in many fundamental studies. However, no large-scale prospective clinical study providing direct evidence for an association of DCA with progress of colorectal tumor development in humans has been reported to date. To address this question, we conducted a two-step epidemiological study applying enzyme-linked immunosorbent assays to measure fecal cholic acid (CA) and DCA concentrations. Firstly, we compared bile acid concentrations of fecal samples from 366 patients who had multiple colorectal tumors removed endoscopically (tumor group) with those from 24 controls without abnormality in their large intestine (control group). Secondly, the tumor group was followed-up to evaluate the association between fecal bile acid concentrations and recurrence of colorectal tumors four years later. Fecal DCA level in the tumor group were significantly higher than that in the controls, whereas there was no difference in CA levels between the two groups. In the tumor group, a subgroup with high DCA level had higher recurrence risk of large adenomas (> 3 mm) four years later than the low DCA subgroup (odds ratio:1.85, 95% confidence interval: 1.12-3.05). This trend was observed more strongly in the left side colon. In conclusion, a high fecal DCA concentration may be a promoter of colorectal tumor enlargement.

Topics: Adult; Aged; Case-Control Studies; Cohort Studies; Colon; Colorectal Neoplasms; Cross-Sectional Studies; Deoxycholic Acid; Enzyme-Linked Immunosorbent Assay; Feces; Female; Humans; Male; Middle Aged; Neoplasm Recurrence, Local; Prognosis; Prospective Studies; Randomized Controlled Trials as Topic

Elevated deoxycholic acid (DCA), mutations in the adenomatous polyposis coli (APC) gene and chronic inflammation are associated with increased risk of colorectal cancer. APC status was manipulated to determine whether DCA mediates inflammatory molecules in normal or initiated colonic mucosa. DCA increased steady state mRNA and protein levels of CXCL8 in cells which do not express wild-type APC. Steady-state CXCL8 mRNA and protein were suppressed when cells with conditional expression of wild-type APC were exposed to DCA. Immunostaining did not detect CXCL8 in normal human colonic mucosa. CXCL8 was expressed in adenomatous polyps and adenocarcinomas. CXCL8 expression correlated with nuclear beta-catenin localization in epithelial cells of adenomas, but was associated with endothelial cells and neutrophils in the adenocarcinomas. DCA-mediated CXCL8 promoter-reporter activity was elevated in a mutant APC background. Wild-type APC suppressed this effect. Mutation of activator protein-1 (AP-1) or nuclear factor kappa B (NF-kappaB) sites suppressed the activation of the CXCL8 promoter-reporter by DCA. Chromatin immunoprecipitation revealed that AP-1 and NF-kappaB binding to the 5'-promoter of CXCL8 was induced by DCA. The beta-catenin transcription factor was bound to the 5'-promoter of CXCL8 in the absence or presence of DCA. Phenotypic assays determined that DCA-mediated invasion was blocked by antibody-directed against CXCL8 or wild-type APC. CXCL8 exposure led to matrix metalloproteinase-2 production and increased invasion on laminin-coated filters. These data suggest that DCA-mediated CXCL8 occurs in initiated colonic epithelium and neutralizing CXCL8 could reduce the invasive potential of tumors.

Topics: Base Sequence; Cell Line, Tumor; Chromatin Immunoprecipitation; Colorectal Neoplasms; Deoxycholic Acid; DNA Primers; Gene Expression Regulation, Neoplastic; Genes, APC; Humans; Immunohistochemistry; Interleukin-8; RNA, Messenger; Transcription, Genetic

Ileal bile acid binding protein (IBABP) is the only cytosolic protein known to bind and transport bile acids. Because IBABP is reportedly up-regulated in colorectal cancer, it has been suggested as a link between bile acids and the risk of colorectal cancer. However, in this study, we show that IBABP is not up-regulated. Rather, a novel transcript of the IBABP gene, which encodes an additional 49 NH(2)-terminal amino acid residues, is up-regulated in colorectal cancer (P < 0.001). The novel transcript, called IBABP-L, is also distinct from IBABP because its transcription is controlled by nuclear factor-kappaB (NF-kappaB) rather than by the farnesoid X receptor. Most significantly, IBABP-L is necessary for the survival of HCT116 colon cancer cells in the presence of physiologic levels of the secondary bile acid deoxycholate. Collectively, the studies point toward a unique bile acid response pathway involving NF-kappaB and IBABP-L that could be useful for diagnosis and could potentially be targeted for therapeutic benefit.

Topics: Adenocarcinoma; Amino Acid Sequence; Caco-2 Cells; Cell Survival; Chenodeoxycholic Acid; Colorectal Neoplasms; Deoxycholic Acid; Gene Expression Regulation, Neoplastic; HCT116 Cells; Humans; Hydroxysteroid Dehydrogenases; Molecular Sequence Data; NF-kappa B; Promoter Regions, Genetic; Protein Isoforms; Transcription, Genetic; Up-Regulation

We have established a medium-term colorectal carcinogenesis rat model initiated with 1,2-dimethylhydrazine (DMH) followed by dextran sodium sulfate (DSS) treatment, featuring induction of neoplastic lesions within 10 weeks. In the present study, we examined its ability to detect modification of colon lesion development with 10- or 20-week experimental periods. F344 male rats were given three subcutaneous injections of DMH (40 mg/kg b.w.) in a week followed by free access to drinking water containing 1% DSS for a week. One week after this regimen, basal diet alone, basal diet containing 0.04% nimesulide or 2% lactoferrin as known inhibitors, 0.3% deoxycholic acid (DCA) as a promoter or 1.5% 1-hydroxyanthraquinone (1-HA) as a carcinogen were supplied. At week 10, the incidence and multiplicity of combined adenomas and adenocarcinomas were significantly (P < 0.05 or 0.01) decreased by nimesulide and lactoferrin, and values for adenomas were significantly (P < 0.01) increased in the 1-HA group. There was no clear change in the DCA group. At week 20, multiplicity and volume of the tumors were significantly (P < 0.01 or 0.05) decreased by nimesulide, but no effect was now evident with lactoferrin. Multiplicity and volume of tumors were significantly (P < 0.01) increased in 1-HA group and a similar tendency was apparent (P = 0.08) with DCA. It is concluded that this system offers a useful tool for detection of colorectal carcinogenesis modifiers within 10-20 weeks, pending further studies for verification employing other model chemicals.

Topics: 1,2-Dimethylhydrazine; Animals; Anthraquinones; Carcinogenicity Tests; Colorectal Neoplasms; Deoxycholic Acid; Dextran Sulfate; Lactoferrin; Male; Precancerous Conditions; Rats; Rats, Inbred F344

Conjugated linoleic acid (CLA) has anti-carcinogenic effects in a variety of cancers including colon cancer. Secondary bile acids on the other hand are known as tumour promoters in colon cancer with effects on protein kinase C (PKC) and nuclear factor kappa B (NF-kappaB) signalling pathways. The aim of this study was to examine acute and chronic, isomer-specific effects of CLA on bile salt-induced PKC and NF-kappaB signal transduction in human colon cancer cells. HCT116 cells were treated with 100 mumol/l and 50 mumol/l cis-9,trans-11-CLA and trans-10,cis-12-CLA for 24 h and 14 days, respectively. The cells were then transfected with DNA coding for PKC beta1-EGFP (enhanced green fluorescent protein), PKC delta-EGFP or PKC zeta-EGFP fusion protein and activated with deoxycholic acid (DCA), phorbol myristate acetate (PMA) or C2-ceramide. PKC translocation was observed using real-time photomicroscopy and fluorescent microscopy and NF-kappaB analyses by gel shift assays. Chronic c-9,t-11-CLA and t-10,c-12-CLA treatment inhibited DCA-induced PKC beta1 and PKC delta translocation and also inhibited NF-kappaB activation. Acute CLA treatment had no effect on PKC or NF-kappaB activation. In conclusion this study indicates that chronic CLA treatment inhibits DCA-induced PKC and NF-kappaB activation in colon cancer cells. These data suggest mechanisms by which CLA may influence the course of colonic cancer.

Topics: Colorectal Neoplasms; Deoxycholic Acid; Electrophoretic Mobility Shift Assay; Green Fluorescent Proteins; HCT116 Cells; Humans; Linoleic Acids, Conjugated; NF-kappa B; Protein Kinase C; Protein Kinase C beta; Protein Kinase C-delta; Signal Transduction; Tetradecanoylphorbol Acetate; Transfection

Elevated levels of bile acids have been implicated in the abnormal morphogenesis of the colonic epithelium thus contributing to colorectal cancer (CRC). Alternatively sodium butyrate (NaB) produced by anaerobic fermentation of dietary fibre is regarded as being protective against colon cancer. Bile acids such as deoxycholic acid (DCA) are thought to mediate some of their actions by differentially activating protein kinase C (PKC). We examined the effects of DCA on the subcellular localisation of PKC-beta(1), -epsilon and -delta and whether these responses could be modulated by NaB. HCT116 cells endogenously express PKC-epsilon and -delta but not PKC-beta. DCA treatment results in endogenous PKC-epsilon translocation but not PKC-delta after 1 hr. To study the subcellular localisation of PKC isoforms in response to DCA in real time, PKC-beta(1), PKC-epsilon and PKC-delta functionally intact green fluorescent protein (GFP) fusion constructs were used. Stimulation with 300 microM DCA induces rapid translocation of PKC-beta(1)-GFP and PKC-epsilon-GFP but not PKC-delta-GFP from the cytosol to the plasma membrane in 15 min. Interestingly, pretreatment with 4mM NaB does not modify the response of the PKC isoenzymes to DCA as PKC-beta(1)-GFP and PKC-epsilon-GFP translocates to the plasma membrane in 15 min whereas PKC-delta-GFP localisation remains unaltered. Immunofluorescence shows that PKC-beta(1)-GFP and PKC-epsilon-GFP cells treated with DCA colocalise with the cytoskeletal elements actin and tubulin adjacent to the plasma membrane. Our findings demonstrate that the differential activation of the PKC isoenzymes by DCA may be of critical importance for the functional responses of colonic epithelial cells. Supplementary material for this article can be found on the International Journal of Cancer website at http://www.interscience.wiley.com/jpages/0020-7136/suppmat/index.html.

Topics: Butyrates; Cell Culture Techniques; Colon; Colorectal Neoplasms; Cytoskeleton; Deoxycholic Acid; Detergents; Enzyme Activation; Epithelium; Humans; Isobutyrates; Isoenzymes; Protein Kinase C

Deoxycholic acid induced programmed cell death and an imbalance with cell proliferation may favour colorectal tumourigenesis according to 'in vitro' studies, but information is lacking on the relationships occurring 'in vivo' in humans.. To evaluate whether serum deoxycholic acid is associated with programmed cell death and cell proliferation in colonic mucosa.. In 10 patients with colorectal adenomas, we measured fasting serum levels of bile acids; and, in normal colonic mucosa, programmed cell death by the TUNEL technique and cell proliferation by immunohistochemical staining with anti-Ki67. Total and compartmental indices for both activities were calculated.. Among serum bile acids, only total deoxycholic acid (median: 0.89 micromol/L +/- 0.54 95% CI), showed a significant positive correlation with the total and basal compartments PCD Index (r = 0.68, p < 0.05). Total proliferation index showed no correlation with either total PCD Index, or bile acids. Within the median compartment of the crypt, cell proliferation was negatively associated with all unconjugated bile acids.. The positive association between deoxycholic acid and programmed cell death in the basal compartment of the crypt, and the negative association of cell proliferation and unconjugated bile acids in the median compartment, do not seem to support the co-carcinogenic effect of deoxycholic acid.

Topics: Adenoma; Aged; Antibodies, Antinuclear; Antibodies, Monoclonal; Apoptosis; Bile Acids and Salts; Cell Proliferation; Colorectal Neoplasms; Deoxycholic Acid; Female; Humans; Immunohistochemistry; In Situ Nick-End Labeling; Intestinal Mucosa; Ki-67 Antigen; Male; Middle Aged

The ratio of deoxycholic acid to chenodeoxycholic acid in the serum of 62 men was inversely related to body mass index and to saturated fat intake after adjustment for body mass index, smoking, and age conversely, this ratio was associated positively with the intake of fibre from grains.

Topics: Adult; Age Factors; Body Mass Index; Chenodeoxycholic Acid; Colorectal Neoplasms; Deoxycholic Acid; Dietary Fats; Epidemiologic Studies; Humans; Male; Middle Aged; Risk Factors; Smoking

Butyrate has an antitumorigenic effect on colorectal cancer cell lines. Dietary sodium gluconate (GNA) promotes butyrate production in the large intestine. Accordingly, we examined the effect of dietary GNA on tumorigenesis in the large intestine in rats. Male Fisher-344 rats (n = 32) were divided into 4 groups: 2 diets (with or without 50 g GNA/kg basal diet) x 2 treatments (with or without carcinogen administration). Colonic tumors were induced by 3 intraperitoneal injections of azoxymethane (15 mg/kg body wt, 1 time/wk) and dietary deoxycholic acid (2 g/kg basal diet). The experiment was conducted for 33 wk except for a few rats. Ingestion of GNA increased cecal butyrate concentration at the end of experiment (P < 0.01). No tumor development occurred in the untreated groups. Ingestion of GNA decreased the incidence of tumors in rats administered the carcinogen (37.5 vs. 100%, P < 0.05). Ingestion of GNA also decreased the mean number of tumors per rat (0.5 +/- 0.8 vs. 2.8 +/- 1.5, P < 0.01). beta-Catenin accumulation and TdT-mediated dUTP nick end labeling (TUNEL) positive cells in tumors were histochemically examined. The results of this study suggested that the antitumorigenic effect of GNA may involve the stimulation of apoptosis through enhanced butyrate production in the large intestine.

Topics: Adenocarcinoma; Adenoma; Animals; Apoptosis; Azoxymethane; beta Catenin; Butyrates; Carcinogens; Cecum; Colon; Colorectal Neoplasms; Cytoskeletal Proteins; Deoxycholic Acid; Diet; Gluconates; Immunohistochemistry; In Situ Nick-End Labeling; Intestines; Male; Organ Size; Rats; Rats, Inbred F344; Trans-Activators

We have previously developed an enzyme-linked immunosorbent assay (ELISA) to measure stool decay-accelerating factor (DAF) and found that stool DAF concentrations were significantly elevated in patients with colorectal cancer, suggesting that the measurement of stool DAF may be valuable for the detection of colorectal cancer. In order to refine the assay for the measurement of stool DAF, we investigated 1) effects of centrifugation of stool samples, 2) effects of detergents, and 3) adequate combination of various anti-DAF monoclonal antibodies for the ELISA system using only monoclonal antibodies. We found that high-speed centrifugation could be omitted and that only the removal of large undigested food residues by centrifugation of short duration in a low-speed benchtop microcentrifuge sufficed to adequately prepare the stool samples. Addition of 2 detergents, octyl beta-glucoside and sodium deoxycholate, known to solubilize glycosyl-phosphatidylinositol-anchored proteins such as DAF, did not influence stool DAF values. By using 2 mouse anti-DAF monoclonal antibodies (clone 4F11 and 1C6), we were able to achieve a stable ELISA for the measurement of stool DAF using a uniform source of antibodies. The results should allow us to consistently apply the DAF assay for routine use in the detection of colorectal cancer.

Topics: Aged; Aged, 80 and over; Antibodies, Monoclonal; CD55 Antigens; Centrifugation; Colorectal Neoplasms; Deoxycholic Acid; Detergents; Enzyme-Linked Immunosorbent Assay; Feces; Female; Glucosides; Humans; Male; Middle Aged

Prolonged large bowel transit time and an associated increase in the proportion of deoxycholic acid (DCA) in serum and bile have been implicated in the development of cholesterol-rich gallstones and colon cancer. Prolongation of intestinal transit also increases intracolonic pH that, we hypothesized, should favor the solubilization and absorption of newly formed DCA within the colon. To test this hypothesis, we performed in vitro studies on homogenized cecal aspirates (obtained at colonoscopy) that were incubated anaerobically with [14C]cholic acid for 16 h after which the pH was adjusted to between 4.0 and 7.0 in 0.5-pH unit steps. The resultant reaction mixtures were centrifuged to separate the supernatant from the precipitate, and the specific activity of [14C]DCA was quantitated in both phases. As the pH in the aspirates was manipulated from 4.0 to 7.0, the proportion of newly formed, labeled DCA increased in the supernatant and fell in the precipitate, particularly at a hydrogen ion concentration of <100 x 10(-7) (equivalent to pH 5.0-7.0). These results show that the solubility of DCA in colonic contents increases with increasing pH. If solubility is rate limiting, this should lead to increased absorption that, in turn, would explain why the proportion of DCA in serum and bile increases with the prolongation of large bowel transit time.

Topics: Cecum; Centrifugation; Chemical Precipitation; Cholelithiasis; Colorectal Neoplasms; Deoxycholic Acid; Humans; Hydrogen-Ion Concentration; Intestinal Absorption; Solubility; Suction

Butyrate is produced in the colon by fermentation of dietary fibre and induces apoptosis in colon adenoma and cancer cell lines, which may contribute to the protective effect of a high fibre diet against colorectal cancer (CRC). However, butyrate is present in the colon together with unconjugated bile acids, which are tumour promoters in the colon. We show here that bile acids deoxycholate (DCA) and chenodeoxycholate (CDCA), at levels present in the colon, gave a modest increase in cell proliferation and decreased spontaneous apoptosis in AA/C1 adenoma cells. Bile acids significantly inhibited the induction of apoptosis by butyrate in AA/C1 cells. However, the survival-inducing effects of bile acids on AA/C1 cells could be overcome by increasing the concentration of sodium butyrate. These results suggest that dysregulation of apoptosis in colonic epithelial cells by dietary factors is a key factor in the pathophysiology of CRC.

Topics: Adenoma; Apoptosis; Bile Acids and Salts; Butyrates; Cell Division; Cell Survival; Chenodeoxycholic Acid; Colorectal Neoplasms; Deoxycholic Acid; Dietary Fiber; DNA; Dose-Response Relationship, Drug; Humans; Time Factors; Tumor Cells, Cultured

A prospective study of 7079 people aged 45-74 recruited through general practices in South Wales, Herefordshire and Edinburgh, Scotland was undertaken to test the hypothesis that faecal bile acids are implicated in the causation of large bowel cancer. The population was recruited between 1974 and 1980 and the response rate for stool collection was 67%. Bile acid analyses were performed on those cases that presented by 1990. It was decided in advance to examine the hypothesis separately for left- and right-sided bowel cancer because of known epidemiological differences between the two sites and to exclude the cases presenting within 2 years of the stool sample from the analyses because the cancer could have been present at recruitment and might have possibly affected faecal bile acid concentrations. Each case (n = 51 left-sided and 8 right-sided) was matched with three controls by age (within 5 years), sex, place of residence and time of providing the stool sample (within 3 months). Statistical analyses using conditional logistic regression showed no significant differences between the left-sided cases and controls for any of the concentrations of individual bile acids, total bile acid concentrations, faecal neutral steroids, percentage bacterial conversion and the ratio of lithocholic acid to deoxycholic acid concentrations. There was a statistically significant (P = 0.021) association of the presence of chenodeoxycholic acid (5/8 samples) in the right-sided cases compared with the controls (3/23), odds ratio 6.26 (95% confidence interval 1.19, 32.84). A high proportion of primary bile acids has also been found in other studies of patients with a genetic predisposition to proximal bowel cancer, however this pattern may also occur in low risk groups, such as Indian vegetarians, suggesting that they may predispose to right-sided bowel cancer only in the presence of other, as yet unknown factors. If bile acids are involved in the causation of large bowel cancer, they may be part of a complex set of interacting factors.

Topics: Aged; Bile Acids and Salts; Colorectal Neoplasms; Deoxycholic Acid; Feces; Female; Functional Laterality; Humans; Lithocholic Acid; Male; Middle Aged; Prospective Studies

Increases in fecal bile acids may play a role in colorectal carcinogenesis. The authors tested the hypothesis that high concentrations of primary and secondary bile acids are more common in patients with colon cancer than in patients with other gastrointestinal diseases.. In this retrospective study the secondary bile acid deoxycholic acid and the primary bile acid cholic acid were measured in the feces by enzyme-linked immunoabsorbent assay in 63 patients with colorectal cancer, 24 patients with gastric cancer, 11 patients with biliary disorders, and 47 healthy volunteers.. Preoperatively, the mean deoxycholic acid values tended to be higher and the cholic acid values were significantly lower in patients with colorectal cancer than in healthy subjects. Patients with other gastrointestinal diseases had lower deoxycholic acid and cholic acid values than healthy subjects. In healthy subjects the deoxycholic acid to cholic acid ratio ranged from 0.10 to 2.86 (mean, 0.88), but in almost two-thirds, the ratio did not exceed 1. In contrast, the mean preoperative ratio in patients with colorectal cancer was 2.26 (range, 0.06-7.17; P < 0.0001) and tended to be higher in patients with advanced cancer and in those with sigmoid and rectal tumors. If 1.1 is taken as the upper limit of normal for deoxycholic acid to cholic acid ratio, 67 percent of patients with colorectal cancer had an abnormal value preoperatively.. A high deoxycholic acid concentration and deoxycholic acid to cholic acid ratio may be indicators of colorectal cancer. Further study is needed to improve sensitivity and specificity, perhaps by combining fecal bile acid measurements with other tests, and a large prospective trial may be warranted to determine whether these measurements have value in screening for this common cancer.

Topics: Adult; Aged; Aged, 80 and over; Biliary Tract Diseases; Biomarkers, Tumor; Cholic Acid; Colorectal Neoplasms; Deoxycholic Acid; Enzyme-Linked Immunosorbent Assay; Feces; Female; Humans; Male; Middle Aged; Retrospective Studies; Sensitivity and Specificity; Stomach Neoplasms

Bile acids are important in the etiology of colorectal cancer. Bile acids induce apoptosis in colonic goblet cells at concentrations comparable to those found in fecal water after high-fat meals. Preliminary evidence indicated that cells of the normal-appearing (nontumorous) portion of the colon epithelium of colon cancer patients are more resistant to bile salt-induced apoptosis than are cells from normal individuals. In the present study, 68 patients were examined, and biopsies were taken at 20 cm from the anal verge, cecum, and descending colon. The patients included 17 individuals with a history of colorectal cancer, 37 individuals with adenomas, and 14 individuals who were neoplasia free. The mean bile salt-induced apoptotic index among normal individuals was 57.6 +/- 3.47 (SE), which differed significantly (P < 0.05) from the mean value of 36.41 +/- 3.12 in individuals with a history of colon cancer. The correlation between independent observers was 0.89 (P < 0.001), indicating good interobserver reliability. Components of variance comparing interindividual versus intraindividual sources of variation suggested that site-to-site variability, both between regions of the colon and for adjacent biopsies, was larger than the interpatient variability for individuals with a history of neoplasia. Therefore, there was "patchiness" of the susceptibility of regions of the colon to bile acid-induced apoptosis in individuals with a history of neoplasia (a patchy field effect). There was no obvious correlation of low-apoptotic index regions with regions in which previous neoplasias had been found and removed. On the other hand, for normal, i.e., neoplasia-free, individuals, there was relatively less intraindividual variation compared to interindividual variation. Our assay shows an association between resistance to bile acid-induced apoptosis, measured at 20 cm from the anal verge, and colon cancer risk. Thus, this assay may prove useful as a biomarker of colon cancer risk.

Topics: Adenoma; Anal Canal; Apoptosis; Bile Acids and Salts; Biological Assay; Colon, Sigmoid; Colonic Neoplasms; Colonic Polyps; Colorectal Neoplasms; Deoxycholic Acid; Dietary Fats; Disease Susceptibility; Drug Resistance; Feces; Humans; Intestinal Mucosa; Observer Variation; Quality Control; Rectum; Risk

It is unclear whether neutral steroids and bile acids are involved in large bowel carcinogenesis. This study was conducted to compare the concentration of these faecal constituents at the different stages of the adenoma-carcinoma sequence. Neutral sterols and free bile acid concentrations were determined from stool samples collected form patients with large bowel cancer (n = 47), large adenoma > or = 1 cm (n = 42), small adenoma (n = 24), and controls (n = 104). The distribution of tertiles between cases and controls was analysed using odds ratio (OR), with 95% confidence interval (CI), comparing (two-sided tests) the second tertile (OR2) and the third tertile (OR3) to the first one. Persistence of primary bile acids appeared as a protective factor against cancer: (OR = 0.09, 95% CI 0.02-0.54). High values of cholesterol were associated with cancer risk (OR2 = 5.8, 95% CI 1.3-26.6; OR3 6.4, 95% CI 1.3-31.4). High values of cholesterol were more frequently observed in patients with large adenomas than in controls (OR2 = 8.5, 95% CI 1.9-37.5; OR3 = 4.3, 95% CI 0.9-20.9). Neutral sterols, cholesterol especially, may play a role in adenoma growth and adenoma transformation into carcinoma. Persistence of primary bile acids may afford protection.

Topics: Adenocarcinoma; Adult; Aged; Bile Acids and Salts; Biomarkers, Tumor; Case-Control Studies; Cholesterol; Colorectal Neoplasms; Confidence Intervals; Deoxycholic Acid; Europe; Feces; Female; Humans; Male; Middle Aged; Odds Ratio; Reference Values; Risk Assessment; Sensitivity and Specificity; Severity of Illness Index; Sterols

Experimental dietary studies of human colorectal carcinogenesis are usually based on the AIN-76A diet, which is dissimilar to human food in source, preparation, and content. The aims of this study were to examine the feasibility of preparing and feeding rats the diet of a specific human population at risk for colorectal neoplasia and to determine whether changes in the colonic morphology and metabolic contents would differ from those resulting from a standard rat diet. The mean daily food intake composition of a previously evaluated adenoma patient case-control study was used for the "human adenoma" (HA) experimental diet. Foods were prepared as for usual human consumption and processed by dehydration to the physical characteristics of an animal diet. Sixty-four female Sprague-Dawley rats were randomized and fed ad libitum the HA or the AIN-76A diet. Every eight weeks, eight rats from each group were sacrificed, and the colons and contents were examined. Analysis of the prepared food showed no significant deleterious changes; food intake and weight gain were similar in both groups. Compared with the controls, the colonic contents of rats fed the HA diet contained significantly less calcium, concentrations of neutral sterols, total lipids, and cholic and deoxycholic acids were increased, and there were no colonic histological changes other than significant epithelial hyperproliferation. This initial study demonstrated that the HA diet can be successfully processed for feeding to experimental animals and is acceptable and adequate for growth but induces significant metabolic and hyperproliferative changes in the rat colon. This dietary model may be useful for studies of human food, narrowing the gap between animal experimentation and human nutritional research.

Topics: Adenoma; Animals; Bile Acids and Salts; Calcium; Colon; Colorectal Neoplasms; Deoxycholic Acid; Diet; Disease Models, Animal; Epithelium; Fatty Acids; Female; Rats; Rats, Sprague-Dawley; Weight Gain

Topics: Animals; Chemoprevention; Colon; Colorectal Neoplasms; Deoxycholic Acid; Humans; Lithocholic Acid; Rats; Sulfates; Ursodeoxycholic Acid

The short chain fatty acids acetate, propionate and butyrate are produced when dietary fibre is fermented by the colonic bacteria. We have previously shown that sodium butyrate induces apoptosis in 3 colorectal tumour cell lines. We have extended our study to 3 adenoma and 4 carcinoma cell lines and investigated whether propionate and acetate also induce apoptosis. All 3 short chain fatty acids induced apoptosis at physiological concentrations, but of the 3, butyrate was the most effective. Since these fatty acids are produced as a result of bacterial fermentation of dietary fibre, this may in part explain the correlation between a high-fibre diet and low colorectal cancer incidence. Sodium butyrate induced apoptosis in all 7 of the cell lines studied; however, 2 of the 4 carcinoma cell lines (PC/JW/FI and S/KS/FI) were more resistant to butyrate-induced apoptosis than the 3 adenoma cell lines, suggesting that at least some carcinomas may evolve mechanisms to protect the cells from the induction of apoptosis. The bile acid deoxycholic acid has previously been reported as a possible tumour promoter in the large intestine and its levels are reduced by dietary fibre. Concentrations of between 10 nM and 0.1 mM had no effect on either the proliferation or apoptosis of colonic tumour cells in vitro. However, a significant induction of apoptosis was obtained at a concentration of 0.5 mM. These results may have significance for the aetiology of colorectal cancer.

Topics: Acetates; Adenoma; Apoptosis; Butyrates; Carcinoma; Colorectal Neoplasms; Deoxycholic Acid; DNA Damage; DNA, Neoplasm; Fatty Acids, Volatile; Humans; In Vitro Techniques; Propionates; Tumor Cells, Cultured

A positive association between deoxcholic acid (DCA) in the serum and colorectal adenomas, the precursors of colorectal cancer has recently been found, which supported the hypothesis of a pathogenic role of DCA in colonic carcinogenesis. This approach was based on the hypothesis that DCA formed in the colon is absorbed into the portal venous blood and exhibits a constant spillover to the systemic circulation. To further substantiate this hypothesis this study investigated whether in the serum of adenoma patients DCA was higher in the unconjugated fraction, which originates directly from the colon. DCA was found to be 2.8-fold higher in the unconjugated fraction of patients with colorectal adenomas than in controls (0.89 v 0.32 mumol/l, p < 0.0025), 1.9-fold in the total DCA fraction (1.89 v 0.95 mumol/l, p < 0.0001), and 1.4-fold in the conjugated fraction (0.67 v 0.47 mumol/l, p < 0.05). It was further found that the bacterial isomerisation product 3 beta-DCA was twofold higher in the unconjugated fraction of adenoma patients than in controls (0.08 v 0.04 mumol/l, p = 0.27), 1.8-fold in the total iso-DCA fraction (0.11 v 0.06 mumol/l, p < 0.05), and 1.5-fold in the conjugated iso-DCA fraction (0.03 v 0.02 mumol/l, p = 0.68). The data suggest that the positive association between the serum DCA concentration and colorectal adenoma as described previously results from the DCA fraction that is absorbed from the colon. This further supports a pathogenic role of DCA in the carcinogenesis of colorectal cancer.

Topics: Adenoma; Bile Acids and Salts; Cocarcinogenesis; Colorectal Neoplasms; Deoxycholic Acid; Humans; Male; Middle Aged

Bile acids are believed to play a role in the etiology of colorectal cancer. To investigate a possible relationship between bile acids and colorectal tumors, duodenal bile acids were analyzed in 18 patients with colorectal adenomas, 18 patients with colorectal carcinoma and 18 control subjects. Using high performance liquid chromatography and immobilized 3 alpha-hydroxysteroid dehydrogenase in column form, significant increases in the proportion of chenodeoxycholic acid and significant decreases in the proportion of deoxycholic acid and lithocholic acid were found in the bile of patients with colorectal adenoma or carcinoma compared with the control subjects. The data support the concept that bile acids have a role to play in the development of large bowel tumors.

Topics: Adenoma; Aged; Bile Acids and Salts; Carcinoma; Chenodeoxycholic Acid; Colorectal Neoplasms; Deoxycholic Acid; Duodenum; Female; Humans; Intestinal Secretions; Lithocholic Acid; Male; Middle Aged

Topics: Adenoma; Colorectal Neoplasms; Deoxycholic Acid; Humans

Epidemiological and animal studies have suggested that the secondary bile acid deoxycholic acid is cocarcinogenic in colorectal cancer, but this hypothesis was not confirmed by case-control studies investigating fecal bile acids.. Individual serum bile acid concentrations were investigated in 25 men and 25 women with colorectal adenomas and in an equal number of age- and sex-matched controls by gas-liquid chromatography.. Deoxycholic acid levels were significantly higher in the sera of men with colorectal adenomas (1.70 +/- 0.59 vs. 1.16 +/- 0.39 mumol/L, P < 0.0005) and in a combined analysis of both sexes (1.47 +/- 0.78 vs. 1.08 +/- 0.39 mumol/L, P < 0.0025). Six- and 12-month follow-up measurements of deoxycholic acid concentrations in a subgroup of 22 men and 17 women showed higher serum levels in men with adenomas, indicating that measurement of deoxycholic acid concentration may be a reliable parameter to investigate its pathogenetic role in colonic neoplasia.. The data of this study support the hypothesis that deoxycholic acid may play a role in the pathogenesis of colorectal cancer.

Topics: Adenoma; Adult; Aged; Bile Acids and Salts; Colorectal Neoplasms; Deoxycholic Acid; Female; Follow-Up Studies; Humans; Male; Middle Aged; Osmolar Concentration; Reference Values; Sex Characteristics

Colorectal cancer is a disease of elderly subjects. A decreased ileal absorption of bile acids in elderly subjects may lead to an increased exposure of the colonic mucosa to secondary bile acids. This may contribute to an enhanced risk of colorectal cancer. In this study fasting and postprandial conjugated and unconjugated serum levels of cholic, chenodeoxycholic, and deoxycholic acid in 12 elderly and 12 younger subjects were investigated. Intestinal transit time, gallbladder emptying and jejunal bacterial flora were also studied in both age groups. Fasting levels of conjugated and unconjugated serum bile acids were similar in both age groups. Postprandial levels of all individual conjugated bile acids increased to a significantly higher extent in the younger subjects. Postprandial unconjugated serum bile acid levels did not differ significantly between both age groups, although unconjugated deoxycholic levels tended to increase to higher levels in the elderly. Results of jejunal bacterial counts, gallbladder emptying and intestinal transit time were similar in both groups. These data suggest that conjugated bile acids are reabsorbed less effectively in elderly subjects.

Topics: Adult; Aged; Aged, 80 and over; Aging; Bile Acids and Salts; Chenodeoxycholic Acid; Cholic Acid; Cholic Acids; Colorectal Neoplasms; Deoxycholic Acid; Eating; Fasting; Female; Gastrointestinal Transit; Humans; Intestinal Absorption; Jejunum; Male; Middle Aged

An association between colorectal cancer and previous peptic ulcer surgery is reported. In a prospective screening study, 100 asymptomatic patients (80 men and 20 women) who had undergone truncal vagotomy at least 10 years previously were investigated by barium enema, colonoscopy and gallbladder ultrasonography. Control data were obtained from forensic autopsy subjects. The incidence of neoplasms greater than or equal to 1.0 cm in the vagotomized group was 14 per cent (11 adenomas, 3 carcinomas) and 3 per cent in controls (P = 0.01). Duodenal bile obtained at endoscopy from 21 vagotomized patients with normal gallbladders and from 21 control patients undergoing endoscopy was analysed by high performance liquid chromatography. The mean percentage of cholic (CA), chenodeoxycholic (CDCA), deoxycholic (DCA) and lithocholic (LCA) acids in the bile of vagotomized patients was 32.3, 45.6, 20.7 and 1.4 per cent respectively compared with 45.3, 36.2, 17.9 and 0.7 per cent respectively in controls. The increased proportions of CDCA and LCA and decreased proportions of CA in the duodenal bile of vagotomized patients were significant (P less than 0.001; P = 0.02; P = 0.007). Abnormalities in bile acid metabolism may help to explain the increased risk of colorectal neoplasia 10 years after truncal vagotomy.

Topics: Bile Acids and Salts; Chenodeoxycholic Acid; Cholic Acids; Colorectal Neoplasms; Deoxycholic Acid; Female; Humans; Lithocholic Acid; Male; Middle Aged; Peptic Ulcer; Prospective Studies; Risk Factors; Vagotomy, Truncal

A hypothesis is presented to account for the dietary induction and promotion of colorectal cancer. The principal agents are the secondary bile acids, lithocholic and deoxycholic acids, the vitamin K group and ferrous iron complexes. These metabolites may interact to subvert the normal free radical generating mechanisms involved in mucosal defence. Diets high in fat and red meat and low in fibre support a Bacteroides-dominated colonic microflora, which both synthesis and utilises vitamin K2 isoprenalogues or menaquinones as enzyme co-factors. Iron(II) complexes such as haemin from the breakdown of dietary haemoglobin and myoglobin also serve as growth factors for these bacteria and provide a rich source of haem-iron for intestinal uptake. Biliary secretion is stimulated by dietary fat and bile acids are essential for the intestinal uptake of vitamin K and possibly of iron complexes such as haemin. In the mature colonocyte, vitamin K and haemin may initiate redox cycling reactions which liberate superoxide (O2-.). Bile acids can activate the membrane bound phospholipase to liberate arachidonate and diacylglycerol. This leads in turn to the production of more O2-. which can enter the microcirculation and acts as a potent chemoattractant for the neutrophils that line the lamina propria. The released diacylglycerol can activate protein kinase C in the neutrophil membrane to switch on the respiratory burst oxidase system generating yet more O2-. and may stimulate the proliferation of transformed stem cells by a similar protein kinase C mediated mechanism.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Colon; Colorectal Neoplasms; Deoxycholic Acid; Diet; Free Radicals; Humans; Lithocholic Acid; Oxidation-Reduction; Vitamin K