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BACKGROUND: Recent studies have demonstrated that heparin-binding epidermal growth factor-like growth factor (HB-EGF) plays a role in carcinogenesis and carcinoma progression. In this study we investigated the expression of HB-EGF in human colonic non-neoplastic and neoplastic tissues. MATERIALS AND METHODS: We performed immunohistochemistry using a polyclonal antibody against HB-EGF for normal colon hyperplastic polyps, adenomas and adenocarcinomas. RESULTS: Normal human colon and hyperplastic polyps did not express HB-EGF. In adenomas with moderate or severe dysplasia, HB-EGF was positive in 92% of the cases, whereas only 14.6% of those with mild dysplasia, expressed HB-EGF (p < 0.0001). HB-EGF expression was observed in 75% of carcinoma-in-adenoma cases. In adenocarcinomas, the incidence of HB-EGF expression significantly decreased as compared to adenomas with moderate or severe dysplasia (p < 0.0001) and CIA (p = 0.0005), with only 27.5% of the cases being classified as positive. In adenocarcinomas, HB-EGF expression was inversely linked to carcinoma differentiation (p = 0.0003) and lymph node metastasis (p = 0.0358). CONCLUSION: Our results demonstrated the bimodal expression of HB-EGF in colonic neoplasms and suggested that HB-EGF may play a role in colonic carcinogenesis and at an early phase of the progression of colonic adenocarcinoma.
The Birt-Hogg-Dubé syndrome, a genodermatosis characterized by benign tumors of the hair follicle, has been associated with renal and colonic neoplasms and spontaneous pneumothorax, but the risk of developing these disorders is unknown. We identified risk factors for renal tumors and spontaneous pneumothorax in 98 patients affected with the Birt-Hogg-Dubé syndrome, in 13 Birt-Hogg-Dubé haplotype carriers, and in 112 unaffected family members. Development of renal tumors was strongly associated with the Birt-Hogg-Dubé syndrome and age. The odds ratio for renal tumor in BHD-affected family members adjusted for age was 6.9 (95% confidence interval, 1.5-31.6) and approximately 9.0 for the other risk factors considered. Chromophobe renal carcinoma, an uncommon type of renal cancer, was the predominant type of renal cancer found. Spontaneous pneumothorax was also strongly associated with the Birt-Hogg-Dubé syndrome and age. The odds ratio for pneumothorax in BHD-affected individuals, adjusted for age, was 50.3 (95% confidence interval, 6.4-392), and about 32 times higher adjusting for the other risk variables. Colon cancer and colon polyps were not related to the Birt-Hogg-Dubé syndrome. The Birt-Hogg-Dubé syndrome confers an increased risk for the development of renal tumors and spontaneous pneumothorax. We found no increase in risk for the development of colon polyps or colon carcinomas.
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BACKGROUND: Investigation of transcription regulators in carcinoma can contribute greatly to clarifying the biological character of the carcinoma. In this study, we examined the expression of ets-1 and ets-2, prominent transcription regulators belonging to the ets family, in various colonic tissues. MATERIALS AND METHODS: We investigated the expression of ets-1 and ets-2 in normal colon, hyperplastic polyps, adenomas, carcinoma-in-adenoma and colonic adenocarcinomas by means of immunohistochemistry. RESULTS: Expression of ets-1 and ets-2 was not observed in normal colon and hyperplastic polyp. The ets-1 labeling index significantly increased with the successive events of colonic carcinogenesis. A similar tendency was observed for ets-2 expression in colonic neoplasms. In adenocarcinoma, ets-1 and ets-2 expression was directly linked to lymph node metastasis. CONCLUSION: These results suggest that ets-1 and ets-2 may act as transcription regulators of the genes related to colonic carcinogenesis and the progression of colonic adenocarcinoma.
To study the effects of intestinal bacteria on the development of colonic neoplasm, we have established gnotobiotic mice with a single species of intestinal bacteria. In the previous study, the incidence of colonic adenoma induced with 1,2-dimethylhydrazine (DMH) in the gnotobiotic mice with Lactobacillus acidophilus, gnotobiotic mice with Escherichia coli and germ-free mice were 30, 50 and 74%, respectively. In this study, 7-week-old mice in each group were sacrificed without the administration of DMH to examine the constituents of immuno-competent cells in various mouse organs using flow cytometry. In the gnotobiotic mice, CD3 intermediate interleukin (IL)-2Rbeta positive cells were observed predominantly in the liver. In the gnotobiotic mice with L. acidophilus, Mac-1 positive Gr-1 positive cells were observed predominantly in the colonic lamina propria. The activation of extrathymic T cells in the liver and granulocytes in the colonic mucosa may be related to anti-neoplastic effects of L. acidophilus in this experimental model.
Tenascin, a novel six-armed extracellular matrix glycoprotein, was immunohistochemically examined in the human normal adult colon, and colonic neoplasms such as tubular adenomas, primary and metastatic adenocarcinomas. In contrast to previous reports, tenascin was hardly detectable in the normal adult colons, being predominantly localised in the fibrous stroma surrounding the glandular epithelia of the neoplastic lesions. The neoplastic cells themselves were totally negative for tenascin expression. Both the tubular adenoma tissues and the superficial layer of well-differentiated adenocarcinomas in general were intensely reactive to tenascin antibody, and the staining intensity increased as the adenoma became more atypical in cases of tubular adenomas. By pretreatment of the paraffin-embedded tissue sections with pepsin, the distribution of tenascin was often intensified considerably and distinct localisation was more clearly demonstrated in the colonic tumour tissues. Tenascin was also biochemically purified from human invasive colonic carcinomas, and this cancerous tissue tenascin was compared with that extracted from a human umbilical cord fibroblast cell line in terms of molecular heterogeneity. Two major isoforms of the purified tenascin from colonic cancer tissues were found to have relative molecular masses of 250 kD and 190 kD, which were almost identical to those of human foetal fibroblast tenascin glycoproteins. In addition, several lower molecular weight isoforms were frequently detectable in the cancerous tissues, which might represent immuno-reactive tenascin isoforms proteolytically digested in human colonic carcinomas in vivo.
Endoscopy is commonly accepted as the gold standard in the evaluation of neoplastic colonic disease. The procedure is used to confirm or exclude lesions detected on barium enemas, with the assumption that the endoscopist was successful in reaching the appropriate segment of the colon. We collected 18 cases, all with proved colonic neoplasm 2-8 cm in diameter that were detected by barium enema but overlooked on initial endoscopy. All of the lesions were relatively flat with little intraluminal protuberance. Histologic examination showed malignant foci in six of 11 tumors that were resected. In two of the other seven patients, unresected lesions progressed to advanced carcinomas. This experience suggests that a repeat barium enema is indicated when endoscopy fails to detect a colonic tumor suspected on barium enema examination.
BACKGROUND: Glucagon-like peptide 2 (GLP-2) is an intestinotrophic mediator with therapeutic potential in conditions with compromised intestinal capacity. However, growth stimulation of the intestinal system may accelerate the growth of existing neoplasms in the intestine. AIMS: In the present study, the effects of GLP-2 treatment on the growth of chemically induced colonic neoplasms were investigated. METHODS: In 210 female C57bl mice, colonic tumours were initially induced with the methylating carcinogen 1,2-dimethylhydrazine (DMH) and mice were then treated with GLP-2. Two months after discontinuation of the carcinogen treatment, 135 of the mice were allocated to one of six groups which were treated twice daily with 25 microg GLP-2, 25 microg Gly2-GLP-2 (stable analogue), or phosphate buffered saline for a short (10 days) or long (one month) period. The remaining 75 mice had a treatment free period of three months and were then allocated to groups subjected to long term treatment, as above. RESULTS: Colonic polyps developed in 100% of the mice, regardless of treatment. Survival data revealed no statistical significant differences among the different groups but histopathological analysis demonstrated a clear and significant increase in tumour load of mice treated with Gly2-GLP-2. The tumour promoting effect of native GLP-2 was less pronounced but the number of small sized polyps increased following long term treatment. CONCLUSIONS: The present results clearly indicate that GLP-2 promotes the growth of mucosal neoplasms. Our findings highlight the need for future investigations on the effects of GLP-2 in conditions needing long time treatment or with increased gastrointestinal cancer susceptibility.
A case of gaseous gangrene by Clostridium septicum associated with colorectal cancer is presented. The patient evolved rapidly towards septic shock and death. Autopsy showed occult neoplasm and pelvic and retroperitoneal myonecrosis. An exceptional finding was that of myocarditis in which thick gram-positive bacilli were identified. A review of the literature was carried out regarding the pathogenesis and clinical manifestations of this disease. The association of colonic neoplasm and Clostridium septicum may be related with the sensitivity of the cells of this neoplasm to the toxins of the microorganisms. The usefulness of this cytotoxicity is being tested in the therapeutic reduction of tumoral mass. With respect to clinical attitude, all the authors agree on the need for clinical suspicion as to the possible existence of occult colon neoplasm in individuals with septic shock by gaseous gangrene with no obvious entry site. Diagnosis is performed by imaging techniques with barium enema and if this is normal colonoscopy is carried out. Emergency treatment consists in laparotomy with resection of the neoplasm and debridement of the area accompanied by hyperbaric oxygen and antibiotics.
Estrogen receptor protein was found in 24% of colonic neoplasms. Presence of estrogen receptor activity was independent of age or sex of the patient, state of differentiation or spread of the tumor, and concentration of carcinoembryonic antigen in the tumor. Estrogen receptor activity in colon tumors probably reflects novel protein synthesis resulting from dedifferentiation. Measurement of tumor estrogen receptor protein and carcinoembryonic antigen may have discriminatory value in the patient with metastatic adenocarcinoma and an unknown primary neoplasm.
Sodium-potassium-stimulated adenosine triphosphatase and carbonic anhydrase isozymes I and II were localized immunocytochemically in adenomas, adenocarcinomas, and normal epithelium of human colon harboring non-neoplastic lesions. Non-neoplastic control colon showed carbonic anhydrase I and II in the cytoplasm of the columnar cells lining the upper half of the crypts. Antiserum to sodium-potassium-stimulated adenosine triphosphatase bound to the basolateral but not the apical plasmalemma of columnar epithelial cells. Staining was most intense in the superficial cells, which also contained carbonic anhydrase, but was also evident to a lesser degree in cells deep in the crypts. Adenomas and adenocarcinomas failed to stain for content of carbonic anhydrase but retained basolateral sodium-potassium adenosine triphosphatase positivity. The staining characteristics of colonic neoplasms for the two enzymes involved in the transport function of colonic epithelium thus resembled those of the less mature cells lining the base of normal crypts.
A highly effective but reduced injection schedule for the induction of the colon cancer in CF1 female mice is reported using 6 subcutaneous inoculations of 1,2-dimethylhydrazine at a dose level of 20 mg/kg body weight. Between the 20th and 45th week of the experiment, 83% of the animals were tumor-bearing with a frequency of 2.1 colonic neoplasms macroscopically visible per mouse. Tumors were isolated in nature and primarily located in the distal large bowel. Some degree of carpeting of the colonic mucosa and uncountable numbers fo tumors occurred in 30% of mice and these areas of confluent neoplasms also occurred predominantly in the distal colon. This spectrum of distribution of tumors closely parallels that seen in man thus enhancing the value of this time conserving colon tumor model.
Colonoscopic examination was performed daily on 18 normal guinea pigs for 7 weeks and on 27 guinea pigs after 24-35 weeks of biweekly intrarectal instillation of the chemical carcinogen methylnitrosourea. Four normal guinea pigs died during the first 2 weeks of the study, two from colonic perforations and two from cecal bloating due to excessive air insufflation. The other 14 normal animals remained clinically healthy and had no gross abnormalities at the end of the 7-week study. Colonic tumors were detected by colonoscopy in five of seven treated guinea pigs that had grossly visible nodular tumors on the mucosal surface of surgically resected colonic tissue. In another treated guinea pig, a tumor was detected by colonoscopy which was not confirmed grossly. In an additional two treated guinea pigs, tumors were visualized by colonoscopy which could not be demonstrated in surgically resected tissue because of their inaccessible location within the pelvic canal. At necropsy, these latter two guinea pigs had nodular, mucosal growths in the pelvic portion of the colon as indicated by colonoscopy. Microscopically, an additional 13 cases of colonic neoplasms were identified in the resected colonic tissue without gross or colonoscopic evidence of intralumenal nodular growth.