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PubMed1985

Regional differences in normal and cancer-associated glycoconjugates of the human colon.

Because inherent regional differences in colonic epithelium may determine the biologic behavior of tumors originating from different sites, and inasmuch as colonic epithelial cells secrete mucins that may reflect the state of cell differentiation, colonic goblet cell mucin was analyzed with the use of fluorescein isothiocyanate-conjugated lectins and fluorescence microscopy in normal fetal and adult mucosa and in cancers of the proximal and distal colon. In the adult proximal colon only the goblet cell mucin in the upper portion of the crypts was specifically labeled by the lectin Dolichos biflorus agglutinin (DBA), whereas this gradient was progressively lost distally; mucin in the upper and lower crypts of the sigmoid colon and rectum bound the label uniformly. In fetuses less than 22 weeks of age, DBA bound only to mucin in the crypts of the distal colon. Seven of 12 (58%) cancers originating from the proximal colon bound DBA, whereas only 2 of 23 (9%) from the distal colon bound this lectin (P less than .005). Logistic regression analysis suggested that this difference may reflect the occurrence of larger tumors in the proximal colon. Regional differences in the binding of Ulex europaeus agglutinin (UEA-I) to nonneoplastic mucosa was similar to that found by others; predominant binding occurred in the proximal colon in the adult. No difference was noted for UEA-I binding to tumors of the proximal (8 of 12; 66.6%) versus distal (11 of 23; 48%) colon (P = .48). These findings may reflect regional differences in normal and tumor-related carbohydrate structures in mucin of the human colon.

Adult↗
PubMed1985

Distribution of blood group antigens A, B, H, Lewisa, and Lewisb in human normal, fetal, and malignant colonic tissue.

In humans, most blood group substances (BGS) are expressed throughout the fetal colon but are absent from the distal portion of adult colon. Cancers of the distal colon frequently reexpress BGS thereby suggesting that these antigens behave as oncofetal antigens at this organ site. We used a sensitive immunoperoxidase method with monoclonal antibodies directed against blood groups A, B, O (H), Lewisa and Lewisb to systematically evaluate BGS expression in fetal colon, normal adult colon from immediate autopsies of kidney donors, mucosa adjacent to cancer (transitional mucosa) and colorectal cancer tissues. In normal colon, BG-A, B, H, and Lewisb were expressed in proximal but not distal colon, whereas Lewisa was distributed uniformly throughout the colon. In colon cancer, and fetal colon, the proximal-distal gradient of BG-A, B, H, and Lewisb expression was abolished because of enhanced distal expression of these antigens. In cancer tissues, three patterns of altered BGS expression emerged: (a) incompatible expression of BG-A or BG-B (over 50% of patients); (b) deletion of BGS; and (c) precursor BG-H accumulation (80% of 25 tumors). BGS staining of transitional mucosa closely resembled that of the adjacent tumor except that no examples of BGS deletion were encountered in transitional mucosa. The goblet cell secretory vacuole accounted for most of the BGS expression in normal colon, but cancer cells demonstrated differentiation-dependent antigenic expression such that well-differentiated tumors expressed BGS on cell apical membranes and glandular contents, but poorly differentiated cancers exhibited diffuse cytoplasmic staining. These findings confirm the oncofetal nature of BGS in distal colon cancer, and provide immunohistochemical evidence for a diverse repertoire of altered antigen expression in colon cancer. Further investigation is needed to elucidate the possible genetic and biochemical mechanisms involved.

ABO Blood-Group System↗
PubMed1985

Management of nonfamilial adenomatous polyps and colon cancers.

There is evidence that patients with adenocarcinoma of the colon and synchronous adenomatous polyps are at an increased risk for developing metachronous colon cancer. A retrospective study was made of all patients with colon cancer at our institution and the associated Veterans Administration Hospital between 1974 and 1983 to help assess the need for more extensive colon resection in patients with colon cancer and synchronous adenomatous polyps. At our hospitals 470 new cases of colon cancer were identified. Nine percent (44/470) had colon cancer and concurrent adenomatous polyps. Seven (16%) of these 44 patients developed metachronous colon cancer, as compared with four of 426 patients without polyps at the initial surgery (p less than 0.001). Four patients without polyps at the initial surgery developed polyps at a later date; three of the four patients developed metachronous colon cancer. We believe that more extensive colon resection, such as total colectomy and ileoproctostomy, may play a role in preventing the occurrence of metachronous colon cancer in patients with colon cancer and synchronous adenomatous polyps. In addition, if adenomatous polyps develop after colon surgery, close endoscopic follow-up is required.

Adenocarcinoma↗
PubMed1995

Chemoprevention of colon carcinogenesis by phenylethyl-3-methylcaffeate.

Previous studies from this laboratory have established that caffeic acid esters present in propolis, a natural resin produced by honey bees, are potent inhibitors of human colon adenocarcinoma cell growth, carcinogen-induced biochemical changes, and preneoplastic lesions in the rat colon. The present study was designed to investigate the chemopreventive action of dietary phenylethyl-3-methylcaffeate (PEMC) on azoxymethane-induced colon carcinogenesis and to examine the modulating effect of PEMC on phosphatidylinositol-specific phospholipase C (PI-PLC), phospholipase A2, lipoxygenase (LOX), and cyclooxygenase activities in the colonic mucosa and tumor tissues in male F344 rats. At 5 weeks of age, groups of rats were fed the control (modified AIN-76A) diet, or a diet containing 750 ppm of PEMC. At 7 weeks of age, all animals except those in the vehicle (normal saline)-treated groups were given 2 weekly s.c. injections of azoxymethane at a dose rate of 15 mg/kg body weight/week. All groups were maintained on their respective dietary regimen until the termination of the experiment 52 weeks after the carcinogen treatment. Colonic tumors were evaluated histopathologically. Both colonic mucosa and tumors were analyzed for PI-PLC, phospholipase A2, cyclooxygenase, and LOX activities. The results indicate that dietary administration of PEMC significantly inhibited the incidence and multiplicity of invasive, noninvasive, and total (invasive plus noninvasive) adenocarcinomas of the colon (P < 0.05-0.004). Dietary PEMC also suppressed the colon tumor volume by 43% compared to the control diet. Animals fed the PEMC diet showed significantly decreased activities of colonic mucosal and tumor PI-PLC (about 50%), but PEMC diet had no effect on phospholipase A2. The production of 5(S)-, 8(S)-, 12(S)-, and 15(S)-hydroxyeicosatetraenoic acids via the LOX pathway from arachidonic acid was reduced in colonic mucosa and tumors (30-60%) of animals fed the PEMC diet as compared to control diet. PEMC had no effect on the formation of colonic mucosal cyclooxygenase metabolites but inhibited the formation in colonic tumors by 15-30%. The precise mechanism by which PEMC inhibits colon tumorigenesis remains to be elucidated. It is likely that the chemopreventive action may be related, at least in part, to the modulation of PI-PLC-dependent signal transduction and LOX-mediated arachidonic acid metabolism.

Animals↗
PubMed1993

[Intestinal occlusion due to a colonic lipoma. Apropos 2 cases].

Lipomas occur through the intestinal tract, from the hypopharynx to the rectum, the colon having the highest incidence, where lipomata are the commonest benign neoplasm after adenomata. Nevertheless they are uncommon. CASE REPORT. 1) A 68-year-old man presented as an emergency with abdominal pain associated with bowel obstruction. He had a 2 to 3 month history of intermittent right-sided abdominal pain, constipation spontaneously resolved. At laparotomy there was a mass of the transverse colon, next hepatic flexure. A right hemicolectomy was performed. The patient made an uneventful recovery. Histologic examination showed a lipoma of the submucosal plane. 2) A 65-year-old man presented as an emergency with lower abdominal pain associated with a prolapsed rectal polyp. He had 1 month history of passing fresh blood per rectum. Ap ast colonoscopy revealed a large polypoid lesion in the descending colon. Transanal examination revealed a polypoid lesion with a maximum diameter of 4 cm, acting as an intussuseptum. Transanal polypectomy was performed. At laparotomy there was an intussuseptum of the descending colon into the rectum: a left hemicolectomy was performed. Histology showed the polyp to be a submucosal lipoma. DISCUSSION. Lipomas are the most common benign nonepithelial tumors of the colon. Lipomata of the large bowel are reported as incidental findings in 0.3-0.5% of cases in large series of autopsies. In the wall of the intestine most lie in the submucosal plane, less frequently they are found in the subserosal plane. The commonest site for symptomatic solitary large bowel lipoma is the ascending colon, including the caecum, followed by the transverse colon, including both hepatic and splenic flexure, descending colon, sigmoid colon and rectum. The peak incidence for lipomata of the large bowel is in fifth-sixth decade. Colonic lipomas are generally asymptomatic but occasionally patients may have intermittent crampy abdominal pain secondary to intussusception of a pedunculated lipoma or with intermittent fresh rectal bleeding. On barium enema lipomas appear circular, ovoid, well demarcated, and smooth. A barium enema showing a relatively radiolucent mass, caused by the radiolucency of fat, is suggestive of a lipoma. The water enema, with water as the contrast agent, accentuates the difference in density between a lipoma and surrounding tissues. Another characteristic feature of lipomas on barium enema is said to be their fluctuation in size and shape during the study: "squeeze sign". Lipomas of the large bowel can be seen, however, by colonoscopy. On computerized tomography scan the lipoma has a uniform appearance and density. In expert hands pedunculated and sessile lesions can be removed endoscopically, but often large bowel lipomata are treated on the basis of a presumptive malignant diagnosis with exploratory laparotomy. CONCLUSION. Colonic lipomas, although unusual, continue to present difficulties in the preoperative differentiation between malignant and benign colonic neoplasm. Two cases of colonic lipomas are reported.

Aged↗
PubMed1997

Enhancement of experimental colon cancer by genistein.

Several phytochemicals and micronutrients that are present in fruits and vegetables are known to exert cancer chemopreventive effects in several organs, including the colon. Among them, the soybean isoflavonoid genistein received much attention due to its potential anticarcinogenic, antiproliferative effects and its potential role in several signal transduction pathways. The present study was designed to investigate the effect of genistein on azoxymethane (AOM)-induced colon carcinogenesis and to study its modulatory role on the levels of activity of 8-isoprostane, cyclooxygenase (COX), and 15-hydroxyprostaglandin F2alpha dehydrogenase (15-PGDH) in the colonic mucosa and colon tumors of male F344 rats. At 5 weeks of age, groups of male F344 rats were fed control (AIN-76A) diet or a diet containing 250 ppm genistein. Beginning 2 weeks later, all animals except those in the vehicle-treated groups were given weekly s.c. injections of AOM (15 mg/kg body weight) for 2 successive weeks. All rats were continued on their respective dietary regimen for 52 weeks after AOM treatment and were then sacrificed. Colon tumors were evaluated histopathologically. Colonic mucosae and tumors were analyzed for COX, 15-PGDH, and 8-isoprostane levels. Administration of genistein significantly increased noninvasive and total adenocarcinoma multiplicity (P < 0.01) in the colon, compared to the control diet, but it had no effect on the colon adenocarcinoma incidence nor on the multiplicity of invasive adenocarcinoma (P > 0.05). Also, genistein significantly inhibited the 15-PGDH activity (>35%) and levels of 8-iosoprostane (50%) in colonic mucosa and in tumors. In contrast, genistein had no significant effect on the COX synthetic activity, as measured by the rate of formation of prostaglandins and thromboxane B2 from [14C]arachidonic acid. The results of this investigation emphasize that the biological effects of genistein may be organ specific, inhibiting cancer development in some sites yet showing no effect or an enhancing effect on the tumorigenesis at other sites, such as the colon. The inhibition of 8-isoprostane levels by genistein indicates its possible antioxidant potential, which is independent of the observed colon tumor enhancement, yet this agent may also possess several biological effects that overshadow its antioxidant potential. The exact mechanism(s) of colon tumor enhancement by genistein remain to be elucidated; it is likely that its colon tumor-enhancing effects may, at least in part, be related to inhibition of prostaglandin catabolic enzyme activities.

Adenocarcinoma↗
PubMed1997

Preliminary assessment of three-dimensional magnetic resonance imaging for various colonic disorders.

BACKGROUND: Improvements in magnetic resonance imaging (MRI) technology have enabled the acquisition of three-dimensional MRI datasets in a single breath hold. We adopted this technique to make a three dimensional intraluminal and extraluminal assessment of the colon in three patients with various colonic disorders. METHODS: One patient was studied after having a double-contrast barium enema. Two patients had MRI scans after colonoscopy, which showed three colonic tumours in one and multiple polyps in the ascending colon of the other. The process of rectal filling with 1.5-2.0 L water mixed with 15-20 mL 0.5 mol/L gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA) was monitored with MR fluoroscopic sequence. Three-dimensional datasets of the contrast-filled colon were taken with patients in prone (before and after intravenous administration of 0.1 mmol/kg bodyweight Gd-DTPA) and supine positions. 64 sections with a voxel-resolution of 2.0 x 2.0 x 1.25 mm3-were taken during a 28 s breath hold. Three-dimensional maximum intensity projection, multiplanar reconstruction, and virtual colonoscopic images of the colon were created from these. FINDINGS: Analysis of the coronal source images in conjunction with multiplanar reconstructions revealed all relevant abnormalities, including diverticula, carcinomas, and polyps. Three dimensional maximum-intensity projections gave a morphological overview of the whole colon. Targeted projections, made up of a limited number of coronal source images, showed diverticula and smaller polyps more clearly. After patients were given intravenous contrast all colonic mass lesions were enhanced. Datasets obtained in prone patients gave the best intraluminal views of the colon. Virtual magnetic resonance colonoscopy showed colonic haustra as well as the ileocaecal valve, but did not show clearly the diverticula. All intraluminal mass lesions, on the other hand, were easy to see. INTERPRETATION: The potential of three-dimensional colonic MRI to provide accurate, minimally invasive, cost-effective polyp screening, as well as comprehensive colonic tumour staging, warrants further investigation.

Aged↗
PubMed1980

Inhibition of murine colon adenocarcinomas and Lewis lung carcinoma by 1-hexylcarbamoyl-5-fluorouracil.

1-Hexylcarbamoyl-5-fluorouracil (HCFU) and its parent compound 5-fluorouracil (5-FU) were tested PO for antitumor activity against mouse colon adenocarcinoma 26 (colon 26), colon adenocarcinoma 38 (colon 38), and Lewis lung carcinoma. The drugs were given orally at 2--4 days intervals for a total of ten doses. 5-FU was moderately active against colons 26 and 38 but not against Lewis lung carcinoma. In this treatment regimen the most impressive antitumor activity was obtained with HCFU against colons 26 and 38, especially colon 38 tumor. At 300 mg HCFU/kg, one out of seven mice inoculated with colon 26 and five out of ten mice inoculated with colon 38 became tumor-free. HCFU, however, was marginally effective in the prolongation of survival time of mice bearing Lewis lung carcinoma. 5-FU is approximately twice as active as HCFU against cultured cell lines from colon 26, colon 38, and Lewis lung carcinoma. Lewis lung carcinoma cells were most sensitive against HCFU, which is in contrast to the results obtained in the in vivo experiment. The IC50 value of HCFU against Lewis lung carcinoma cells was approximately half that against colon 26 and colon 38 cells. This higher sensitivity of Lewis lung cells against HCFU could be explained by the higher cellular uptake of the drug.

Adenocarcinoma↗
PubMed1984

Structure of zonulae occludentes and the permeability of the epithelium to short-chain fatty acids in the proximal and the distal colon of guinea pig.

Absorption of short-chain fatty acids has been studied in the proximal and the distal colon of anaesthetized guinea pigs. Segments were perfused with a solution similar in chemical composition to that of normal colonic fluids. In the proximal colon the permeability of the mucosa was similar for acetate, propionate and butyrate. For acetate the permeability was significantly higher in the proximal than in the distal colon, and the reverse was seen for butyrate. In the distal colon the short-chain fatty acids seem to be absorbed mainly in the undissociated form due to their lipid solubility; a paracellular pathway for the dissociated molecules is of no major importance. In the proximal colon, on the other hand, a considerable portion of acetate and propionate disappears in the ionized form. Light microscopy (semithin sections) and electron microscopy (freeze-fracture replicas) showed remarkable morphological differences between the proximal and the distal colon. "Leaky spots" with only few strands were present in the zonulae occludentes between the epithelial cells at the surface of the proximal colon. In the distal colon the junctions between the cells were more compact, and significantly more strands separated the lumen from the intercellular space. These results suggest that short-chain fatty acids could be absorbed by a paracellular pathway in the proximal colon, and not in the distal colon. In the proximal colon the number of strands of the zonulae occludentes between surface cells and that between cryptal cells was similar. On the contrary, in the distal colon significantly more strands were present between surface cells than between cryptal cells. Morphological and physiological considerations suggest that absorption of short-chain fatty acids in the crypts is negligible.

Animals↗
PubMed1998

Role of nitric oxide in the colon of patients with ulcerative colitis.

The cause of impaired motility, such as diarrhea and toxic megacolon, in patients with ulcerative colitis (UC) is unknown. Nitric oxide (NO) has been shown to be a neurotransmitter in the nonadrenergic noncholinergic (NANC) inhibitory nerves in the human gut. To assess the physiologic significance of NO in the colon of patients with UC, we investigated enteric nerve responses on lesional and normal bowel segments derived from patients with ulcerative colitis (n = 6) and patients who underwent colon resection for colonic cancers (n = 10). A mechanographic technique was used to evaluate in vitro muscle responses to electrical field stimulation (EFS) of adrenergic and cholinergic nerves before and after treatment with various autonomic nerve blockers, including NG-nitro-L-arginine (L-NNA) and L-arginine. The results showed that (1) NANC inhibitory nerves were found to act on both normal colon and UC colon; (2) the colon with UC was more strongly innervated by NANC inhibitory nerves than the normal colon; (3) L-NNA concentration-dependently inhibited the relaxation in response to EFS in the colon of both normal and UC colon; and (4) this inhibitory effect in the colon of both normal and UC patients was reversed by L-arginine; (5) NO acts more strongly in the UC colon than the normal colon. These findings suggest that NANC inhibitory nerves play an important role in the impaired motility observed in patients with UC and that NO plays an important role as a neurotransmitter in NANC inhibitory nerves of human colon.

Adolescent↗
PubMed2004

Dietary patterns and risk of colon cancer and adenoma in a cohort of men (United States).

BACKGROUND: Examining the effects of dietary patterns on cancer risk may provide insights beyond the assessment of individual foods or nutrients. DESIGN: In the health professionals follow-up cohort, associations between the 'prudent' and the 'western' dietary pattern and risk of colon cancer and adenomas were examined in 561 colon cancer cases and 1207 distal colon adenoma cases. RESULTS: Higher prudent pattern scores were only weakly and non-significantly associated with decreased risk of colon cancer or distal colon adenoma (highest versus lowest quintile: colon cancer: multivariate adjusted relative risk (RR) = 0.84 (95% confidence interval (CI) = 0.64-1.10); p(trend) = 0.37; distal adenoma: multivariate odds ratio (OR) = 0.88 (95% CI = 0.73-1.08); p(trend) = 0.12). Our findings suggest a moderately increased risk of colon cancer and distal adenoma with higher western pattern scores (colon cancer: RR = 1.27 (95% CI = 0.96-1.69), p(trend) = 0.05; distal adenoma: OR = 1.28 (95% CI = 1.05-1.56), p(trend) = 0.01). Adding body mass index, which is positively related to western pattern and thus may be considered an intermediate endpoint between western pattern and colon cancer, attenuated associations somewhat but not substantially. CONCLUSION: Our data do not provide evidence for an appreciable inverse association between higher prudent pattern scores and risk of colon cancer or distal colon adenomas, but do support a moderate positive association between higher western pattern scores and risk of colon cancer or distal colon adenomas.

Adenoma↗
PubMed1998

Regional differences in the nitrergic innervation between the proximal and the distal colon in rats.

BACKGROUND & AIMS: Functional differences in the inhibitory neural pathway between the proximal and the distal colon are unknown. METHODS: We investigated the nonadrenergic, noncholinergic (NANC) relaxation, nitric oxide synthase (NOS) synthesis, and NOS messenger RNA (mRNA) expression of the myenteric plexus in the proximal and the distal colon in rats. RESULTS: Transmural nerve stimulation of the neuromuscular preparations from the proximal colon showed greater NANC relaxations than those from the distal colon. NANC relaxations were abolished by the NO biosynthesis inhibitor (NG-nitro-L-arginine methyl ester) in the proximal and the distal colon, suggesting mediation by NO released from the myenteric plexus. The average number of NOS-immunoreactive cells was significantly higher in the tissue from the proximal colon than in the tissue from the distal colon. Western and Northern blot analyses showed a higher density of the immunoreactive NOS band and the NOS mRNA band in the tissue from the proximal colon than in that from the distal colon. CONCLUSIONS: These observations indicate that the number of NOS-containing neurons and the NOS activity are increased in the myenteric plexus of the proximal colon compared with the distal colon, resulting in greater NANC relaxation in the proximal colon. These findings may explain the physiological role of the proximal colon as an organ for fecal storage and absorption of excess fluid.

Animals↗
PubMed2003

Body mass index and colon cancer: an evaluation of the modifying effects of estrogen (United States).

OBJECTIVE: The association between body mass index (BMI) and colon cancer has been reported to be different for men and women. No prior literature has examined if estrogen influences these differences. METHODS: Using data from an incident population-based case (n = 1,972) and control (n = 2386) study of colon cancer we evaluated if estrogen modifies the association between BMI and risk of colon cancer. RESULTS: Women who were estrogen-negative (postmenopausal women not taking hormone replacement therapy, HRT) were at increased risk of colon cancer regardless of indicator of estrogen status used (i.e. estrogen-negative compared to estrogen-positive women defined as either being premenopausal or postmenopausal women using HRT, OR 1.54, 95% CI 1.23-1.93; no recent exposure to estrogens compared to current or HRT use within the past 2 years, OR 1.58, 95% CI 1.24-2.00; postmenopausal women not currently using HRT compared to postmenopausal women taking HRT, OR 1.65, 95% CI 1.29-2.12). BMI (kg/m2) was not associated with an increased risk of colon cancer among women who were estrogen-negative. However, women who were estrogen-positive experienced a greater than two-fold increase in colon cancer risk if they had a BMI of > 30 relative to those who had a BMI of <23 (for estrogen-positive, OR, 2.50, 95% CI 1.51-4.13; premenopausal, OR 2.19, 95% CI 0.94-5.07; postmenopausal using HRT, OR 3.36, 95% CI 1.58-7.13). Among men the colon cancer risk associated with BMI decreased with advancing age. Physical activity modified the increased colon cancer risk associated with a large BMI. CONCLUSIONS: These data suggest the importance of estrogen in colon cancer etiology. Being estrogen-negative resulted in a significant increased risk of colon cancer. However, BMI significantly increased the risk of colon cancer among women who were estrogen-positive. We hypothesize that estrogen up-regulates IGF-I receptors and IRS-I levels in the colon, which in turn increases susceptibility to obesity-induced increased levels of insulin. We further hypothesize that androgens may have similar effects in men given the decline in colon cancer risk associated with BMI with advancing age.

Aged↗
PubMed2005

Strong expression of methylthioadenosine phosphorylase (MTAP) in human colon carcinoma cells is regulated by TCF1/[beta]-catenin.

Methylthioadenosine phosphorylase (MTAP) is known as a ubiquitously expressed house keeping gene important in biochemical salvage processes. The MTAP gene is localized on the human chromosomal region 9p21, a region often deleted in cancer. Recently, several groups including our own have shown that MTAP serves as a tumour suppressor gene. The aim of this study was to analyse the role of MTAP in colon carcinoma and normal colon epithelium and the regulation of gene expression. To examine MTAP RNA and protein expression, we screened six colon carcinoma cell lines and human primary colon epithelial cells by RT-PCR and immunoblotting. MTAP expression was confirmed in vivo by immunohistochemical staining of normal colon tissue compared to adenoma and colon carcinoma. Interestingly, we found strong MTAP mRNA and protein expression by colon carcinoma cell lines but no expression by colonic epithelial cells. To analyse the regulation of MTAP expression, promoter studies were performed and revealed control of MTAP expression by LEF/TCF/beta-catenin. Furthermore, we demonstrated a significant correlation between MTAP protein expression and tumour progression as the intensity of MTAP protein staining increased from normal tissue to carcinoma. In addition, the recently postulated association between MTAP activity and interferon (IFN) sensitivity was confirmed in colon epithelial cells showing only little response to IFN-gamma, in contrast to the carcinoma cell lines. In summary, these data indicate for the first time that MTAP is not expressed in normal human colonic epithelium but is strongly upregulated in colon carcinoma. This finding may be of clinical significance concerning the homeostasis of normal colon epithelium and potential treatment of colon carcinoma.

Adenocarcinoma↗
PubMedDate not supplied

Inhibitory effect on the establishment of hepatic metastasis by transduction of the tissue plasminogen activator gene to murine colon cancer.

Hepatic metastasis is a major factor in limiting the prognosis of patients with colon carcinoma. Recent investigations indicate a correlation between plasminogen activator profiles and hepatic metastasis. We examined the effectiveness of tissue plasminogen activator (tPA) gene therapy using a hepatic metastasis model of murine colon carcinoma. Murine colon carcinoma Colon 26 cells transduced with an MFGtPA retroviral vector (Colon 26/tPA) or an MFGLacZ retroviral vector (Colon 26/LacZ) were injected into the liver via the superior mesenteric vein of BALB/c mice, whose survival rates were checked daily. The mean survival rate of mice with hepatic metastasis induced by Colon 26/LacZ was 23.1 days, whereas that of mice with Colon 26/tPA was >100 days. The in vitro proliferation of Colon 26/tPA was comparable with that of Colon 26/LacZ, and antitumor immunity to wild-type Colon 26 cells was not induced after an intrahepatic injection of Colon 26/tPA. We suggest that transduction of the tPA gene to murine colon cancer is useful against the establishment of hepatic metastasis.

Animals↗
PubMed2000

Protective immunity is induced in murine colon carcinoma cells by the expression of interleukin-12 or interleukin-18, which activate type 1 helper T cells.

We investigated the antitumor effects induced by the production of interleukin-12 (IL-12) or IL-18, which influence the function of T helper type 1 cells, in murine colon carcinoma cells (Colon 26). Retrovirally transduced cells with IL-12 genes that encoded both p35 and p40 (Colon 26/IL-12) lost their tumorigenicity when inoculated subcutaneously or intraperitoneally into syngeneic immunocompetent mice. Moreover, the mice that had rejected the Colon 26/IL-12 cells generated protective immunity to wild-type (wt) cells when subsequently challenged. Colon 26 cells transduced with the IL-18 gene (Colon 26/IL-18) could not form subcutaneous tumors in immunocompetent mice, and the mice became resistant to inoculated wt cells. Immunohistochemical analysis revealed that the numbers of blood vessels in Colon 26/IL-12 or Colon 26/IL-18 tumors were markedly reduced, and that the expression of adhesion molecules such as intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 increased on the endothelium in the stroma of Colon 26/IL-12 tumors. The loss of tumorigenicity of Colon 26/IL-12 or Colon 26/IL-18 cells was not observed in immunocompromised mice. However, the survival days of the immunocompromised mice inoculated with Colon 26/IL-12 but not Colon 26/IL-18 cells were significantly longer than those inoculated with wt cells. The secretion of cytokines that stimulate T helper type 1 cells from tumor cells can thereby induce an antitumor response. However, the effector cells involved in these antitumor effects could differentially migrate to the tumors, and the inhibition of angiogenesis may partially contribute to the antitumor responses observed.

Animals↗
PubMed2000

Transduction of murine colon carcinoma cells with interleukin-15 gene induces antitumor effects in immunocompetent and immunocompromised hosts.

We examined the antitumor effects caused by murine colon carcinoma cells (Colon 26) transduced with interleukin-15 (IL-15) gene. Although the in vitro proliferation rate of IL-15-secreting Colon 26 (Colon 26/IL-15) cells was not different from that of wild-type (wt) cells, small subcutaneous tumors of Colon 26/IL-15 cells that developed in syngeneic immunocompetent mice regressed spontaneously in contrast to tumors of wt cells. The mice that had eliminated tumors of Colon 26/IL-15 cells rejected wt cells when subsequently challenged. The survival of the mice that had been inoculated intraperitoneally with Colon 26/IL-15 cells was significantly prolonged compared with that of the mice injected with wt cells. However, in an experimental lung metastasis model, the survival of the mice inoculated with Colon 26/IL-15 cells remained the same as that of the mice inoculated with wt cells. The inoculation of Colon 26/IL-15 cells into immunocompromised nude or severe combined immunodeficient mice produced tumors, but the survival of the immunocompromised mice was significantly longer than that of the mice inoculated with wt cells. The nude mice inoculated with Colon 26/IL-15 cells also survived longer than the severe combined immunodeficient mice with Colon 26/IL-15 cells. Depletion of natural killer cells in nude mice with anti-asialo GM1 antibody did not influence the survival of the mice injected with Colon 26/IL-15 cells. Immunohistological examination revealed that CD31+ cells migrated into tumors of Colon 26/IL-15 cells that developed in immunocompetent and immunocompromised mice. Taken together, our results indicate that an inoculation of IL-15-producing tumor cells can produce antitumor effects that are mediated by a variety of immunocompetent cells.

Animals↗
PubMed2000

Orphanin FQ, but not dynorphin A, accelerates colonic transit in rats.

BACKGROUND & AIMS: The endogenous opiate receptor-like 1 ligand, orphanin FQ (OFQ), which structurally resembles dynorphin A, has been identified. We investigated the mechanism of action of OFQ in the colon and compared it with that of dynorphin A in vivo. METHODS: Colonic contractions were recorded via miniature force transducers implanted on the serosal surface of the rat colon. RESULTS: Intravenous administration of OFQ (0.01-3 nmol/kg) induced contractions in the rat colon in a dose-dependent manner. Colonic contractions induced by OFQ were not affected by extrinsic denervation but abolished by tetrodotoxin. Continuous infusion of OFQ (1 nmol x kg(-1) x min(-1)) and dynorphin A (100 nmol x kg(-1) x min(-1)) induced similar phasic contractions in the proximal colon. However, the contractile activity induced by the 2 peptides differed significantly in the mid and distal colon. Giant contractions induced by OFQ infusion migrated from the mid to distal colon. In contrast, dynorphin A evoked simultaneous contractions throughout the entire colon, which did not migrate aborally. Subcutaneous administration of OFQ (1-3 nmol/kg) accelerated colonic transit, whereas dynorphin A (30-100 nmol/kg) delayed colonic transit. CONCLUSIONS: The results show that OFQ accelerates colonic transit by promoting migrating colonic contractions in rats.

Animals↗