UMLS:C0699790 - FACTA Search

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Query: UMLS:C0699790 (colon cancer)
28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The immune regulation of phytohemagglutinin (PHA) and concanavalin A (Con A) mitogen responses by prostaglandin (PG)-producing suppressor monocytes was examined in 57 patients with colorectal cancer and 55 normal individuals. The blood lymphocyte responses to either PHA or Con A were significantly depressed in 74% of patients compared to normal controls. The mean PHA response for the patients was significantly lower than that for controls (17,649 versus 25,549 cpm, P = 0.02), while the mean Con A response for the patients was also depressed but not as significantly (13,551 versus 18,623 cpm, P = 0.09). The depression of immune competence was greatest in older patients and those with metastatic disease. The addition of indomethacin (1 microgram/ml) to cell cultures of both patients and normal individuals enhanced the mitogen response, suggesting that PGE-producing suppressor cells were operative in both groups. Among the patient group, however, a differential modulation of the immune response by indomethacin was observed. Thus, the addition of indomethacin restored the PHA response in patients almost to normal levels, while the Con A increase was less pronounced. Even after indomethacin treatment, the Con A proliferative response by lymphocytes was significantly depressed in patients as compared to controls (P = 0.002). To prove that indomethacin was blocking excessive PG production by suppressor monocytes in colon cancer patients, we directly measured PGE2 production by peripheral blood mononuclear cells (PBMCs) using a radioimmunoassay. PBMCs from the patients produced significantly greater amounts of PGE2 compared to controls (10.1 versus 5.1 ng/ml, P = 0.0001). This comparison was still significant after adjustment for age and sex. The increased PGE2 production appeared to be selective, since the levels of two other arachidonic acid metabolites, PGF1 alpha and thromboxane B2, were the same or less than control levels. PG-mediated immune suppression of mitogenesis thus appears to be abnormally increased in colon cancer patients, particularly for the PHA response. This abnormality was partially corrected in vitro by incubation of the PBMCs with indomethacin, a prostaglandin synthetase inhibitor.
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PMID:Prostaglandin E2-mediated suppression of cellular immunity in colon cancer patients. 622 53

p6e monoclonal antibody HNK-1 reacts exclusively with human granular lymphocytes that comprise 16 +/- 1.4% of blood mononuclear cells. In normal individuals, almost all natural killer (NK) and killer (K) cell function resides in this lymphocyte subset. The level of HNK-1+ granular lymphocytes, their stage of differentiation, and NK cell function were examined in 70 colon cancer patients and the results compared with data for 114 age-matched normal individuals. Median levels of granular lymphocytes were significantly depressed in colon cancer patients compared to controls (9% versus 16.5%, P less than 0.0001). Despite the depressed numbers of circulating HNK-1+ cells, NK cell function in the colon cancer patients was essentially the same as in normals (P = 0.78). The HNK-1+ lymphocyte level correlated exactly with NK cell function in about two thirds of normal individuals but only one third of colon cancer patients (P = 0.025). Three possible mechanisms for this dichotomy were examined. First, lymphoid cell subpopulations purified with a fluorescence-activated cell sorter (FACS) were examined for altered NK cell functional activity. HNK-1+ cells from the colon cancer patients exhibited significantly less NK functional activity compared to normals (796 versus 1046 lytic units, P = 0.04). Interestingly, the HNK-1- fraction (predominantly T lymphocytes) had increased NK cell functional activity in the colon cancer patients compared to normals (373 versus 218 lytic units, P = 0.0001). Purified monocytes did not contribute to NK cell functional activity. Second, the functional maturity of the HNK-1+ lymphocytes was correlated with NK activity. Two subsets of HNK-1+ cells were identified by surface membrane markers and purified with the FACS. The more mature HNK-1+ subset (i.e., HNK+Leu-4-M1+) exhibited almost ten times more NK cell functional activity than did the less mature cell fraction (i.e., HNK+Leu-4+M1-) cells in normal individuals (2230 versus 286 lytic units/10(7) cells). Further analysis demonstrated that the ratio of mature to immature HNK+ cells in normal individuals was 3:1, while it was decreased to a 1:1 ratio in colon cancer patients P = 0.005). Third, the influence of prostaglandin-mediated suppression on NK cell activity was examined. PGE2 did not appear to influence NK cell function, since NK cell function was unchanged in vitro in the presence of a prostaglandin synthesis inhibitor.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Heterogeneity of natural killer lymphocyte abnormalities in colon cancer patients. 658 46

Human monocytes from normal donors as well as breast or colon cancer patients were fractionated on five-step discontinuous bovine serum albumin (BSA) density gradients, and the monocytes from each fraction were allowed to mature into macrophages during a 5 day incubation period. The macrophages were then examined both for their ability to kill tumor cells after activation with lipopolysaccharide (LPS) and the quantity of prostaglandin E2 (PGE2) synthesized. When the macrophages obtained from normal donors were fractionated, fractions 2 and 4 which comprised 58% of the total cell population, were cytotoxic for tumor cells. In contrast, when the macrophages from breast cancer patients were fractionated, only the high density cells found in fraction 4 were cytotoxic. It is also conceivable that since fraction 4 comprises only 26% of the total macrophages recovered, this may be the reason unfractionated macrophages from breast cancer patients are unable to kill tumor cells. When the colon cancer patients' macrophages were fractionated on BSA density gradients, fractions 1, 2 and 4, which comprised 79% of the total cell population, were cytotoxic for tumor cells. Prostaglandin E2 synthesis was also analyzed and it was found that fraction 3 consistently synthesized increased quantities of PGE2 when compared with the other three fractions. Furthermore, since fraction 3 was non-cytotoxic for tumor cells, it is conceivable that the increased synthesis of PGE2 by fraction 3 rendered these macrophages non-cytotoxic.
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PMID:Separation of macrophages on discontinuous bovine serum albumin (BSA) density gradients: cytotoxic effects of fractionated cells from normal donors and cancer patients. 659 30

Peripheral blood mononuclear cells of patients with different tumors of the gastrointestinal tract (esophagus, stomach, colon, rectum), with Crohn's disease and healthy controls were analyzed for their capacity to produce mitogen induced interleukin-2 (I1-2). Tumor patients could be divided into two groups, one group exhibiting a nearly normal and a second group showing a significantly decreased production of I1-2. Most of the patients with a carcinoma of the colon were found in the low-producer group. Patients with Crohn's disease did not significantly differ from the relevant controls. Tumor patients with proven metastasis produced less I1-2 as compared to those with localized disease although the differences are not significant. When I1-2 containing supernatants of patients with tumors were additionally analyzed for the presence of prostaglandin E2, an inverse relationship could be demonstrated. Supernatants showing a suppressed activity of I1-2 exhibited increased amounts of PGE2, indicating a modulation of I1-2 production by prostaglandin E2.
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PMID:Interleukin-2 production in peripheral blood mononuclear cells of patients with gastrointestinal tumors. 661 Jul 65

Previous research has suggested that prostaglandins (PGs) may play a role in the development of colon cancer since tumor cells produce more PGs than normal cells. However, the exact mechanism by which PGs play a role in the development of cancer is not known. In addition, factors that influence PG synthesis are not known since they are complicated by the presence of homeostatic mechanisms. To avoid the homeostatic mechanisms, the present research was designed to examine factors that may influence PG synthesis in an in vitro system, i.e., a tissue culture. We have chosen two human colon cancer cell lines that differ in their ability to metabolize long-chain fatty acids (LCFAs), LS174T cells and HT-29 cells. We examined the effect of LCFAs on their membrane fatty acid composition, growth, and ability to release the main PGs (PGE2 and PGI). The LCFAs used were those most common in the colonic lumen [18:0, 18:2 (n-6), and 18:3 (n-3)]. In addition, we examined the effect of butyrate on the above mentioned parameters. Butyrate is produced in the colon through fermentation of dietary fibers. The data obtained suggest that although both of these tumor cell lines are of human colonic origin, they differ in their response to LCFAs and butyrate in some of the characteristics studied, such as growth, composition of membranes, and the relationship between membrane FA composition and PG synthesis. Polyunsaturated fatty acid supplementation stimulated the growth of HT-29 cells but not of LS174T cells when compared with growth in media supplemented with 18:0.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Prostaglandin synthesis in human cancer cells: influence of fatty acids and butyrate. 748 78

Eicosanoids have been implicated in colon carcinogenesis, but their role remains unclear. The levels of PGE2 are elevated in colon cancer tissues and in blood draining colon tumors. The effect of eicosanoids on the proliferation of colonic cells is unknown. We studied the effect of several prostaglandins (PGs) and leukotriene (LT)B4 on the proliferation rate of the human colon adenocarcinoma cell lines SW1116 and HT-29 and of 16,16-dimethyl PGE2 (dmPGE2) on the colon of BALB/c mice. PGs E2, F2 alpha, I2, the methyl ester of PGE2, dmPGE2, and LTB4 (10(-10), 10(-8), 10(-6) M), administered for up to 72 h, stimulated cell proliferation in SW1116 cells and all but PGF2 alpha and PGI2 stimulated proliferation in HT-29 cells. The proliferative effect was time- and concentration-dependent. However, in SW1116 cells the response to PGs was 'bell-shaped', being maximal at 10(-8) M, with the 10(-10) and 10(-6) M concentrations being less effective. In HT-29 cells, the addition of methyl groups to the PGE2 molecule increased the proliferative effect. None of these eicosanoids affected the distribution of these cells in the cell cycle or their rate of programmed cell death (apoptosis). dmPGE2 stimulated 3.6-fold the proliferation of colonocytes in normal BALB/c mice. This was determined by bivariate flow cytometric analysis of the expression of proliferating cell nuclear antigen (PCNA) in virtually pure populations of mouse colonocytes. dmPGE2 did not alter the cell cycle distribution of these cells. We conclude that several PGs as well as LTB4 stimulate the proliferation of human colon carcinoma cells in vitro, while dmPGE2 has a similar effect on mouse colonocytes in vivo. These findings raise the possibility that eicosanoids may contribute to colonic carcinogenesis by stimulating the proliferation rate of tumor cells in the colon.
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PMID:Selected eicosanoids increase the proliferation rate of human colon carcinoma cell lines and mouse colonocytes in vivo. 754 86

In this article we have reviewed and discussed the results of our investigation of lipid metabolites as modulators of epidermal growth factor (EGF) signaling pathways. We have studied epidermal growth factor-dependent mitogenesis in BALB/c 3T3 and Syrian hamster embryo (SHE) cells in culture. We observed that EGF stimulates the formation of prostaglandins in BALB/c 3T3 cells and their formation appears to be necessary for EGF dependent mitogenesis. EGF did not stimulate PGE2 formation in SHE cells and in fact, exogenously added PGE2 inhibited mitogenesis. In both cell lines, EGF stimulated the formation of lipoxygenase-derived 13(S)-hydroxyoctadecadienoic acid (13-HODE) and inhibition of 13-HODE formation attenuated mitogenesis. The addition of 13-(S)-HODE enhanced EGF-dependent mitogenesis but when added alone, the compound was not mitogenic. Other metabolites, including lipoxygenase metabolites of arachidonic acid, were either weak simulators of EGF-dependent mitogenesis or essentially inactive. The 13(S)-HODE appears to be formed by an apparently unique lipoxygenase that is regulated by the tyrosine kinase activity of the EGF receptor. The mechanisms by which lipids, particularly the lipoxygenase-derived linoleic acid metabolites, modulate the EGF signaling pathways leading to cell proliferation is discussed. The possible significance of lipoxygenase and prostaglandin H synthase-dependent metabolism of unsaturated fatty acids in breast and colon cancer is also discussed.
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PMID:Cellular proliferation and lipid metabolism: importance of lipoxygenases in modulating epidermal growth factor-dependent mitogenesis. 771 98

Prostaglandins (PG) have been implicated in the pathogenesis of cancer and play an important role in immune regulation. Colon cancer is associated with elevated levels of PGE2, while aspirin, the prototypical inhibitor of PG synthesis, appears to reduce the incidence of colon cancer by 50%. We have observed that in human colon cancer the expression of HLA class I and II antigens is reduced or lost; loss of HLA antigens is suspected to be a mechanism by which the malignant cell escapes the immune surveillance. We investigated the effect of these eicosanoids on the expression of HLA antigens in human colon adenocarcinoma cell lines. PGE2 down-regulated the expression of the class II antigen HLA-DR in SW1116 cells (65% reduction at 2.8 x 10(-8) M). This effect was dose- and time-dependent, reversible, and specific (PGF2 alpha and LTB4 had no effect; the expression of carcinoembryonic antigen and class I genes were not affected). Aspirin induced the expression of HLA-DR in HT29 cells, a cell line not expressing constitutively HLA-DR. The reduction of HLA-DR by PGE2 was accompanied by reduced messenger RNA (mRNA) levels of HLA-DR alpha and reduced transcription of the corresponding gene. In contrast to HLA-DR, none of these three eicosanoids affected the expression of HLA class I genes, as assessed via determination of protein expression by fluorescence flow cytometric analysis and evaluation of the corresponding class I mRNA levels. We conclude that PGE2 specifically down-regulates the expression of HLA-DR, while it does not affect the expression of class I antigens.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Prostaglandin E2 down-regulates the expression of HLA-DR antigen in human colon adenocarcinoma cell lines. 772 22

Human epidemiological and laboratory animal model studies have suggested that nonsteroidal antiinflammatory drugs reduce the risk of development of colon cancer and that the inhibition of colon carcinogenesis is mediated through the alteration in cyclooxygenase metabolism of arachidonic acid. Curcumin, which is a naturally occurring compound, is present in turmeric, possesses both antiinflammatory and antioxidant properties, and has been tested for its chemopreventive properties in skin and forestomach carcinogenesis. The present study was designed to investigate the chemopreventive action of dietary curcumin on azoxymethane-induced colon carcinogenesis and also the modulating effect of this agent on the colonic mucosal and tumor phospholipase A2, phospholipase C gamma 1, lipoxygenase, and cyclooxygenase activities in male F344 rats. At 5 weeks of age, groups of animals were fed the control (modified AIN-76A) diet or a diet containing 2000 ppm of curcumin. At 7 weeks of age, all animals, except those in the vehicle (normal saline)-treated groups, were given two weekly s.c. injections of azoxymethane at a dose rate of 15 mg/kg body weight. All groups were continued on their respective dietary regimen until the termination of the experiment at 52 weeks after the carcinogen treatment. Colonic tumors were evaluated histopathologically. Colonic mucosa and tumors were analyzed for phospholipase A2, phospholipase C gamma 1, ex vivo prostaglandin (PG) E2, cyclooxygenase, and lipoxygenase activities. The results indicate that dietary administration of curcumin significantly inhibited incidence of colon adenocarcinomas (P < 0.004) and the multiplicity of invasive (P < 0.015), noninvasive (P < 0.01), and total (invasive plus noninvasive) adenocarcinomas (P < 0.001). Dietary curcumin also significantly suppressed the colon tumor volume by > 57% compared to the control diet. Animals fed the curcumin diet showed decreased activities of colonic mucosal and tumor phospholipase A2 (50%) and phospholipase C gamma 1 (40%) and levels of PGE2 (> 38%). The formation of prostaglandins such as PGE2, PGF2 alpha, PGD2, 6-keto PGF1 alpha, and thromboxane B2 through the cyclooxygenase system and production of 5(S)-, 8(S)-, 12(S)-, and 15(S)-hydroxyeicosatetraenoic acids via the lipoxygenase pathway from arachidonic acid were reduced in colonic mucosa and tumors of animals fed the curcumin diet as compared to control diet. Although the precise mechanism by which curcumin inhibits colon tumorigenesis remains to be elucidated, it is likely that the chemopreventive action, at least in part, may be related to the modulation of arachidonic acid metabolism.
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PMID:Chemoprevention of colon carcinogenesis by dietary curcumin, a naturally occurring plant phenolic compound. 781 55

Nonsteroidal antiinflammatory drugs (NSAIDs) have considerable potential as chemopreventive agents for colorectal cancer. Recent case-control drug surveillance and large cohort studies found that patients with regular aspirin use had a reduced incidence of colorectal cancer and/or decreased death rate from this disease. Several different NSAIDs reduce formation of both colon adenomatous polyps (the precursor lesion of colon cancer) and cancers in experimental animals given known carcinogens. Perhaps most convincing are reports that the NSAID sulindac promotes regression and inhibits recurrence of adenomatous colon polyps in patients with adenomatous polyposis coli. The best characterized pharmacologic effect of the NSAIDs is their reduction of prostaglandin synthesis by inhibiting prostaglandin synthetase PGE2, which catalyzes the formation of prostaglandin precursors from arachidonic acid. Several lines of evidence are contrary to the concept that inhibition of prostaglandin synthesis is central to the NSAIDs' chemopreventive effects. Relatively high levels of prostaglandins have been reported to inhibit tumor cell growth both in vivo and in vitro, and to inhibit differentiation in some tumor cell lines. We evaluated comparative chemopreventive effects on colon tumor formation in an azoxymethane (AOM)-induced colon carcinogenesis rat model using the NSAIDs piroxicam, sulindac, and sulindac sulfone, a metabolite of sulindac which lacks the anti-prostaglandin synthetase activity typically associated with NSAID-induced gastrointestinal toxicities. The results demonstrate that sulindac sulfone, a compound lacking anti-prostaglandin synthetase activity, inhibits AOM-induced colon cancer in rats. Substantial dose-dependent reductions in both tumor burden and tumor multiplicity were observed in the sulindac sulfone-treated animals.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Do NSAIDs exert their colon cancer chemoprevention activities through the inhibition of mucosal prostaglandin synthetase? 853 96

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