p27KIPI Expression inversely correlates with microsatellite instability and TGF-β receptor type II...
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A636 AGA ABSTRACTS • G2618 THE ASSOCIATION OF LIFESTYLE AND DIETARY FACTORS WITH THE DEVELOPMENT OF PRECANCEROUS LESIONS IN H. PYLORI-INFECTED SUBJECTS IN CHINA. SR Lin*. JY Sung, ALM Yu, JYL Ching, LY Zhou*, CCH Lam, RT Wang*, WK Leung, JWY Lau, EKW Ng, W Chao, SCS Chung. Beijing Medical University* and Chinese University of Hong Kong. Epidemiological studies suggest that the risk of gastric cancer is increased with high intake of salty food, lack of fresh vegetable and fruit, consumption of tobacco and alcohol. AIM To assess the association of lifestyle and dietary habits and the risk of developing precancerous gastric lesions in H. pylori-infected subjects. METHOD A population-based endoscopy screening study for gastric cancer was conducted in a high cancer prevalent area in Yantai county of China. Healthy volunteer subjects with H. pylori infection were identified by biopsy urease test and histology. They were interviewed individually using a structured questionnaire on diet and other lifestyle factors. These factors were correlated to the risk of developing intestinal metaplasia and gastric atrophy. RESULTS Among 514 subjects interviewed (mean age: 52_+8.4 year, M:F=I:I.6), histological examination showed superficial gastritis in 11 (2.1%), chronic active gastritis in 201 (39.1%), intestinal metaplasia in 193 (37.5%) and gastric atrophy in 109 (21.2%) subjects. The consumption of salty fish, dry fish, pickle vegetable, fresh fruit, milk, raw meat and water supply from community well showed no correlation with the development of intestinal metaplasia and gastric atrophy. Smoking was associated with an increased risk of developing intestinal metaplasia (OR: 1,59, 95%CI 1.03-2.44 P=0.032) and gastric atrophy (OR:1.69, 95%CI 1.03-2.79, P=0.036). Alcohol consumption was associated with a significant increased risk of developing intestinal metaplasia (OR: 1.74, 95%CI 1.12-2.69, P=0.013) but an insignificant increase in gastric atrophy (OR: 1.62, 95%CI 0.97-2.70 P=0.067). CONCLUSION With the exception of tobacco and alcohol consumption, the importance of the aforementioned dietary and lifestyle factors in the development of precancerous gastric lesions in the 1t. pylori-infected population was not confirmed. • G2619 p27 KIPI EXPRESSION INVERSELY CORRELATES WITH MICROSATELLITE INSTABILITY AND TGF-13 RECEPTOR TYPE II MUTATIONS IN SPORADIC COLON CANCER. Done Fene Liu. William M Grady, Ashwani Rajput, Sanford Markowitz, Joseph Willis. University Hospitals of Cleveland and Case Western Reserve University, Cleveland, OH. Background: TGF-[3 is a potent inhibitor of colon epithelial cell growth, and mutations that inactivate the type II TGF-I3 receptor (Rll) have been identified in 80 - 90% of colon cancers that have microsatellite instability (MSI). p27 is a nuclear cyclin dependent kinase, which inhibits cell cycle progression and has in some cell types been shown to be induced by TGF-13 and also in part moderate TGF-13 stimulated grade inhibition. Decreased p27 expression has also been shown to characterize colon cancer with poor prognosis. Purpose: The purpose of this study was to determine if absent p27 expression in colon cancer reflects mutations in TGF-13 receptors by examining p27 expression in tumors with documented RII mutations as well as with MSI and hence presumed RII mutations. Materials and Methods: Twenty-six colon cancers from patients with nonfamilial cancer were obtained. The specimens were routinely processed for pathologic diagnosis. The cancers were microdissected from formalin, fixed paraffin-embedded sections for MSI and TGF-13 RII mutation analysis using PCR based techniques. MSI was identified if at least 2/5 loci studied showed instability. Expression of p27 was determined by performing immunostaining. Results: p27 expression was demonstrated in 19/26 cases (73%). p27 expression was detected in 93% (n=13/14) of cases without MSI and in 50% (n=6/12) of cases with MSI (p<0.05). A subset of these cases were analyzed for TGF-I3 RII mutations, p27 expression was shown in 75% (n=12/16) of cases with wild type TGF-13 RII but in only 50% (n=3/6) of cases with TGF-I3 RII mutations. Conclusions: MSI and TGF-13 RII mutations are associated with an increased liklihood of absence of p27 expression in colon cancer suggesting that in vivo growth inhibitory signals from TGF-~ may be important in the regulation of the cell cycle inhibitor p27. G2620 CELLULAR MITOGENESIS IS INHIBITED BY SELECTIVE CYCLOOXYGENASE-2 (COX-2) INHIBITOR-S. W, Longo; B. Erickson; J. Mazuski; N. Panesar; Y. Deshpande; D. Kaminski, St. Louis, MO. Background: Various studies indicate that non-steroidal, antiinflammatory drugs alter the incidence of colorectal cancer, a process which may be mediated by alterations in cyclooxygenase (COX), a key enzyme in arachidonic acid metabolism. The COX enzymes are well recognized. COX-I is generally constitutive and cytoprotective, and COX-2 is inducible in response to various stimuli. Aim: The present study was undertaken to GASTROENTEROLOGY Vol. 114, No. 4 determine the effects of specific COX-1 and COX-2 inhibitors on epithelial proliferation of intestinal cells. Methods: A continuously proliferating rat intestinal cell line (IEC-18) and a rat colon cancer cell line (WB 2054) which expresses COX-2 constitutively, were used for these experiments. The cells were seeded onto microwells in serum-containing medium at 1,000 cells per well. After 24 hours, the cells were exposed for 48 hours to either the COX-1 inhibitor valerylsalicylicacid (VSA), the COX-2 inhibitor SC-58125, Indomethacin (Indo), or a serum-free environment. Cells were allowed to incorporate 3H thymidine for the final six hours, and the amount of isotope incorporated into the cells was determined. Results are expressed as the counts per minute (cpm) 3H thymidine incorporated. Serum PGE2 levels were measured using an RIA. Statistical significance was set at p<0.05. Results are from five different experiments. IEC-18 Control VSA SC-58125 Indo Serum (50uM) (50 ug/mi) (100 uM) Free cpm 8200 6956 3631 7321 3225 Std 11342 1100 887 1254 590 p-value !0.20 0.01 0.74 0.02 WB Control !VSA SC-58125 lndo Serum 2054 (50uM) (50 ug/ml) (100 uM) Free cpm 66,554 58,561 22,424 53,523 19,775 Std 23,421 31,200 13,844 24,490 3500 p-value 0.44 0.01 0.66 0.02 Results: SC-58125, but not VSA or Indo inhibited the proliferation of both intestinal epithelial ceils and malignant cells. This effect was similar to that seen when the cells were placed into serum-free medium. SC-58125 and Indo but not VSA significantly inhibited PGE 2 levels in proliferating IEC-18 but not WB 2054 cells. Conclusions: A differential effect on intestinal cell mitogenesis was seen with different COX inhibitors. COX-2 inhibition, as compared to the COX-1 inhibitor appeared to significantly inhibit both epithelial cell restitution and carcinogenesis. COX-2 inhibitors may be specific inhibitors of epithelial cell mitogenesis. G2621 CIGARETTE SMOKING AND GASTRIC EPITHELIAL CELL APOPTOSIS: ROLE OF EPIDERMAL GROWTH FACTOR. L. Ma, J.Y.C. Chow, H. Y. Wang and C.H. Cho. Department of Pharmacology, Faculty of Medicine, The University of Hong Kong, Hong Kong, China Previous studies have shown that cigarette smoking potentiated lesion formation by challenge with 70% of ethanol and also delayed acetic acid- induced ulcer healing in rats by either augmenting the aggressive factors or/and depressing the protective mechanisms. However, effects of cigarette smoke exposure alone on gastric mucosa are still undefined. Aim: To study the effects of cigarette smoking on the basal condition of gastric mucosa in rats. Methods: Male Sprague-Dawley rats (180-200 g) were exposed to different concentrations of cigarette smoke (0, 2 or 4%) for 1-hr period given once daily for 3 or 6 days. During these periods, gastric blood flow, serum and gastric mucosal EGF levels were assessed. In addition, gastric epithelial cell proliferation and apoptosis were also determined by immuno- histochemical method for the incorporation of 5-bromo-2'-deoxyuridine (BrdU) and TdT-mediated dUTP-biotin nick end labeling (TUNEL), respectively, in the formalin fixed- and paraffin-embedded sections. Results: Cigarette smoke exposure decreased serum EGF level which was accompanied with a reduction of basal gastric blood flow. It also increased gastric epithelial cell apoptosis together with an increase in epithelial cell proliferation. Intravenous administration of EGF (20 /ag/kg) before each cigarette smoke exposure reversed the reduced gastric blood flow and increased epithelial cell apoptosis induced by cigarette smoke exposure, meanwhile the increase of epithelial cell proliferation was also normalized to the control level. Removal of salivary glands, the main source of EGF in the body, from the animals, induced similar effects on the gastric mucosa as with cigarette smoke exposure. Conclusion: Cigarette smoking decreased gastric blood flow and potentiated gastric epithelial cell apoptosis which was linked with an increase in epithelial cell proliferation. Reduction of EGF level in serum was, at least partially, involved in these effects by cigarette smoking. This project was supported in part from a grant from Hong Kong Research Grant Council. G2622 DESCRIBING THE DISTRIBUTION OF PROLIFERATING CELLS IN COLORECTAL CRYPTS BY A SINGLE CHARACTERISTIC VALUE: UTILITY FOR INTERVENTION TRIALS. FA Macrae, D Kilias, H Smith, K Sharpe, L Schlipalius. Dept of Gastroenterology, Royal Melbourne Hospital, Depts of Medicine and Statistics, University of Melbourne, Betateue Ltd. Vic. Australia. Persons at above risk for colorectal cancer have profiles of mucosal crypt proliferation with mitoses towards the luminal aspect. Compartmental analyses reflect this distribution change but are complex to analyse. A single
Transcript of p27KIPI Expression inversely correlates with microsatellite instability and TGF-β receptor type II...
A636 AGA ABSTRACTS
• G2618 THE ASSOCIATION OF LIFESTYLE AND DIETARY FACTORS WITH THE DEVELOPMENT OF PRECANCEROUS LESIONS IN H. PYLORI-INFECTED SUBJECTS IN CHINA. SR Lin*. JY Sung, ALM Yu, JYL Ching, LY Zhou*, CCH Lam, RT Wang*, WK Leung, JWY Lau, EKW Ng, W Chao, SCS Chung. Beijing Medical University* and Chinese University of Hong Kong.
Epidemiological studies suggest that the risk of gastric cancer is increased with high intake of salty food, lack of fresh vegetable and fruit, consumption of tobacco and alcohol. AIM To assess the association of lifestyle and dietary habits and the risk of developing precancerous gastric lesions in H. pylori-infected subjects. METHOD A population-based endoscopy screening study for gastric cancer was conducted in a high cancer prevalent area in Yantai county of China. Healthy volunteer subjects with H. pylori infection were identified by biopsy urease test and histology. They were interviewed individually using a structured questionnaire on diet and other lifestyle factors. These factors were correlated to the risk of developing intestinal metaplasia and gastric atrophy. RESULTS Among 514 subjects interviewed (mean age: 52_+8.4 year, M:F=I:I.6), histological examination showed superficial gastritis in 11 (2.1%), chronic active gastritis in 201 (39.1%), intestinal metaplasia in 193 (37.5%) and gastric atrophy in 109 (21.2%) subjects. The consumption of salty fish, dry fish, pickle vegetable, fresh fruit, milk, raw meat and water supply from community well showed no correlation with the development of intestinal metaplasia and gastric atrophy. Smoking was associated with an increased risk of developing intestinal metaplasia (OR: 1,59, 95%CI 1.03-2.44 P=0.032) and gastric atrophy (OR:1.69, 95%CI 1.03-2.79, P=0.036). Alcohol consumption was associated with a significant increased risk of developing intestinal metaplasia (OR: 1.74, 95%CI 1.12-2.69, P=0.013) but an insignificant increase in gastric atrophy (OR: 1.62, 95%CI 0.97-2.70 P=0.067). CONCLUSION With the exception of tobacco and alcohol consumption, the importance of the aforementioned dietary and lifestyle factors in the development of precancerous gastric lesions in the 1t. pylori-infected population was not confirmed.
• G2619 p27 KIPI EXPRESSION INVERSELY CORRELATES WITH MICROSATELLITE INSTABILITY AND TGF-13 RECEPTOR TYPE II MUTATIONS IN SPORADIC COLON CANCER. Done Fene Liu. William M Grady, Ashwani Rajput, Sanford Markowitz, Joseph Willis. University Hospitals of Cleveland and Case Western Reserve University, Cleveland, OH.
Background: TGF-[3 is a potent inhibitor of colon epithelial cell growth, and mutations that inactivate the type II TGF-I3 receptor (Rll) have been identified in 80 - 90% of colon cancers that have microsatellite instability (MSI). p27 is a nuclear cyclin dependent kinase, which inhibits cell cycle progression and has in some cell types been shown to be induced by TGF-13 and also in part moderate TGF-13 stimulated grade inhibition. Decreased p27 expression has also been shown to characterize colon cancer with poor prognosis. Purpose: The purpose of this study was to determine if absent p27 expression in colon cancer reflects mutations in TGF-13 receptors by examining p27 expression in tumors with documented RII mutations as well as with MSI and hence presumed RII mutations. Materials and Methods: Twenty-six colon cancers from patients with nonfamilial cancer were obtained. The specimens were routinely processed for pathologic diagnosis. The cancers were microdissected from formalin, fixed paraffin-embedded sections for MSI and TGF-13 RII mutation analysis using PCR based techniques. MSI was identified if at least 2/5 loci studied showed instability. Expression of p27 was determined by performing immunostaining. Results: p27 expression was demonstrated in 19/26 cases (73%). p27 expression was detected in 93% (n=13/14) of cases without MSI and in 50% (n=6/12) of cases with MSI (p<0.05). A subset of these cases were analyzed for TGF-I3 RII mutations, p27 expression was shown in 75% (n=12/16) of cases with wild type TGF-13 RII but in only 50% (n=3/6) of cases with TGF-I 3 RII mutations. Conclusions: MSI and TGF-13 RII mutations are associated with an increased liklihood of absence of p27 expression in colon cancer suggesting that in vivo growth inhibitory signals from TGF-~ may be important in the regulation of the cell cycle inhibitor p27.
G2620 CELLULAR MITOGENESIS IS INHIBITED BY SELECTIVE CYCLOOXYGENASE-2 (COX-2) INHIBITOR-S. W, Longo; B. Erickson; J. Mazuski; N. Panesar; Y. Deshpande; D. Kaminski, St. Louis, MO.
Background: Various studies indicate that non-steroidal, antiinflammatory drugs alter the incidence of colorectal cancer, a process which may be mediated by alterations in cyclooxygenase (COX), a key enzyme in arachidonic acid metabolism. The COX enzymes are well recognized. COX-I is generally constitutive and cytoprotective, and COX-2 is inducible in response to various stimuli. Aim: The present study was undertaken to
GASTROENTEROLOGY Vol. 114, No. 4
determine the effects of specific COX-1 and COX-2 inhibitors on epithelial proliferation of intestinal cells. Methods: A continuously proliferating rat intestinal cell line (IEC-18) and a rat colon cancer cell line (WB 2054) which expresses COX-2 constitutively, were used for these experiments. The cells were seeded onto microwells in serum-containing medium at 1,000 cells per well. After 24 hours, the cells were exposed for 48 hours to either the COX-1 inhibitor valerylsalicylicacid (VSA), the COX-2 inhibitor SC-58125, Indomethacin (Indo), or a serum-free environment. Cells were allowed to incorporate 3H thymidine for the final six hours, and the amount of isotope incorporated into the cells was determined. Results are expressed as the counts per minute (cpm) 3H thymidine incorporated. Serum PGE2 levels were measured using an RIA. Statistical significance was set at p<0.05. Results are from five different experiments.
IEC-18 Control VSA SC-58125 Indo Serum (50uM) (50 ug/mi) (100 uM) Free
cpm 8200 6956 3631 7321 3225 Std 11342 1100 887 1254 590 p-value !0.20 0.01 0.74 0.02
WB Control !VSA SC-58125 lndo Serum 2054 (50uM) (50 ug/ml) (100 uM) Free cpm 66,554 58,561 22,424 53,523 19,775 Std 23,421 31,200 13,844 24,490 3500 p-value 0.44 0.01 0.66 0.02
Results: SC-58125, but not VSA or Indo inhibited the proliferation of both intestinal epithelial ceils and malignant cells. This effect was similar to that seen when the cells were placed into serum-free medium. SC-58125 and Indo but not VSA significantly inhibited PGE 2 levels in proliferating IEC-18 but not WB 2054 cells. Conclusions: A differential effect on intestinal cell mitogenesis was seen with different COX inhibitors. COX-2 inhibition, as compared to the COX-1 inhibitor appeared to significantly inhibit both epithelial cell restitution and carcinogenesis. COX-2 inhibitors may be specific inhibitors of epithelial cell mitogenesis.
G2621 CIGARETTE SMOKING AND GASTRIC EPITHELIAL CELL APOPTOSIS: ROLE OF EPIDERMAL GROWTH FACTOR. L. Ma, J.Y.C. Chow, H. Y. Wang and C.H. Cho. Department of Pharmacology, Faculty of Medicine, The University of Hong Kong, Hong Kong, China
Previous studies have shown that cigarette smoking potentiated lesion formation by challenge with 70% of ethanol and also delayed acetic acid- induced ulcer healing in rats by either augmenting the aggressive factors or/and depressing the protective mechanisms. However, effects of cigarette smoke exposure alone on gastric mucosa are still undefined. Aim: To study the effects of cigarette smoking on the basal condition of gastric mucosa in rats. Methods: Male Sprague-Dawley rats (180-200 g) were exposed to different concentrations of cigarette smoke (0, 2 or 4%) for 1-hr period given once daily for 3 or 6 days. During these periods, gastric blood flow, serum and gastric mucosal EGF levels were assessed. In addition, gastric epithelial cell proliferation and apoptosis were also determined by immuno- histochemical method for the incorporation of 5-bromo-2'-deoxyuridine (BrdU) and TdT-mediated dUTP-biotin nick end labeling (TUNEL), respectively, in the formalin fixed- and paraffin-embedded sections. Results: Cigarette smoke exposure decreased serum EGF level which was accompanied with a reduction of basal gastric blood flow. It also increased gastric epithelial cell apoptosis together with an increase in epithelial cell proliferation. Intravenous administration of EGF (20 /ag/kg) before each cigarette smoke exposure reversed the reduced gastric blood flow and increased epithelial cell apoptosis induced by cigarette smoke exposure, meanwhile the increase of epithelial cell proliferation was also normalized to the control level. Removal of salivary glands, the main source of EGF in the body, from the animals, induced similar effects on the gastric mucosa as with cigarette smoke exposure. Conclusion: Cigarette smoking decreased gastric blood flow and potentiated gastric epithelial cell apoptosis which was linked with an increase in epithelial cell proliferation. Reduction of EGF level in serum was, at least partially, involved in these effects by cigarette smoking. This project was supported in part from a grant from Hong Kong Research Grant Council.
G2622 DESCRIBING THE DISTRIBUTION OF PROLIFERATING CELLS IN COLORECTAL CRYPTS BY A SINGLE CHARACTERISTIC VALUE: UTILITY FOR INTERVENTION TRIALS. FA Macrae, D Kilias, H Smith, K Sharpe, L Schlipalius. Dept of Gastroenterology, Royal Melbourne Hospital, Depts of Medicine and Statistics, University of Melbourne, Betateue Ltd. Vic. Australia.
Persons at above risk for colorectal cancer have profiles of mucosal crypt proliferation with mitoses towards the luminal aspect. Compartmental analyses reflect this distribution change but are complex to analyse. A single
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