Advanced imaging and technology in gastrointestinal neoplasia: summary of the AGA-NCI Symposium October 4-5, 2004

Imaging and other advanced technologies for detection of gastrointestinal cancers are undergoing a major revolution on several fronts. This is facilitated by convergence of key technologies including advanced endoscopic-detection systems, more specific contrast agents, rapid and high-resolution cross-sectional imaging, and miniaturization of construction systems for making all imaging equipment smaller and less invasive. This convergence is occurring along traditional translational research pathways (clinical medicine-molecular biology) as well as nontraditional lines (clinical medicine-optical physics/engineering and molecular biology-optical physics/engineering). These new efforts are producing a wide array of technologies aimed at improving detection, classification, and monitoring of gastrointestinal neoplasia, especially for colorectal and esophageal cancer because of easier accessibility. A critical goal is to detect lesions at their premalignant stages, thereby permitting meaningful intervention. Inspired by these advances, the American Gastroenterological Association and the National Cancer Institute sponsored a symposium held in Bethesda, MD, from October 4-5, 2004, bringing together leading investigators with diverse backgrounds in imaging technology. The aims of this symposium were to summarize the state of the art and priorities for research in the coming decade in the field of imaging and advanced technology for gastrointestinal neoplasia. In this overview, we summarize the salient results of that symposium. The initial sections discuss the major technologies in each area of endoluminal imaging and molecular imaging followed by applications to specific diseases such as Barrett's esophagus and colon neoplasia. Each section focuses on the current state of the art then lists major priorities for research in the field.     

Rimonabant inhibits human colon cancer cell growth and reduces the formation of precancerous lesions in the mouse colon

The selective CB1 receptor antagonist rimonabant (SR141716) was shown to perform a number of biological effects in several pathological conditions. Emerging findings demonstrate that rimonabant exerts antitumor action in thyroid tumors and breast cancer cells. In our study, human colorectal cancer cells (DLD‐1, CaCo‐2 and SW620) were treated with rimonabant and analyzed for markers of cell proliferation, cell viability and cell cycle progression. Rimonabant significantly reduced cell growth and induced cell death. In addition, rimonabant was able to alter cell cycle distribution in all the cell lines tested. Particularly, rimonabant produced a G2/M cell cycle arrest in DLD‐1 cells without inducing apoptosis or necrosis. The G2/M phase arrest was characterized by a parallel enhancement of the number of mitoses associated to elevated DNA double strand breaks and chromosome misjoining events, hallmarks of mitotic catastrophe. Protein expression analyses of Cyclin B1, PARP‐1, Aurora B and phosphorylated p38/MAPK and Chk1 demonstrated that rimonabant‐induced mitotic catastrophe is mediated by interfering with the spindle assembly checkpoint and the DNA damage checkpoint. Moreover, in the mouse model of azoxymethane‐induced colon carcinogenesis, rimonabant significantly decreased aberrant crypt foci (ACF) formation, which precedes colorectal cancer. Our findings suggest that rimonabant is able to inhibit colorectal cancer cell growth at different stages of colon cancer pathogenesis inducing mitotic catastrophe in vitro. © 2009 UICC.     

Effect of complex polyphenols on colon carcinogenesis

Summary Background: Complex polyphenols and tannins from wine (WCPT) are being considered increasingly as potential cancer chemopreventive agents, since epidemiological studies suggest that populations consuming a high amount of polyphenols in the diet may have a lower incidence of some types of cancer. Aim of the study: We studied the effect of WCPT on a series of parameters related to colon carcinogenesis in rats. Methods: WCPT were administered to F344 rats at a dose of 14 or 57 mg/kg/d, mixed with the diet. The higher dose is about ten times the exposure to polyphenols of a moderate drinker of red wine. In rats treated with WCPT, we measured fecal bile acids and long chain fatty acids, colon mucosa cell proliferation, apoptosis and, after administration of colon carcinogens, the number and size of aberrant crypt foci (ACF) and nuclear aberrations. Results: Colon mucosa proliferation was not varied by chronic administration (90 d) of WCPT (14 or 57 mg/kg/d). The highest dose of WCPT decreased the number of cells in the colon crypts, but did not increase apoptosis. WCPT (57 mg/kg) administered before or after the administration of azoxymethane (AOM) did not vary the number or multiplicity of ACF in the colon. The number of nuclear aberrations (NA) in colon mucosa was studied after administration of 1,2-dimethylhydrazine (DMH) and 2-amino-3-methylimidazo (4,5-f)quinoline (IQ), colon-specific carcinogens which require metabolic activation. The effect of DMH and IQ was not varied by pre-feeding WCPT (57 mg/kg) for 10 d. Similarly, the levels of total, secondary bile acids and long chain fatty acids did not varied significantly in animals fed WCPT for 90 d. Conclusions: WCPT administration does not influence parameters related to colon carcinogenesis in the rat. Received: 18 January 1999, Accepted: 18 May 1999     

Four-dimensional elastic light-scattering fingerprints as preneoplastic markers in the rat model of colon carcinogenesis

BACKGROUND & AIMS: Identification of preneoplastic changes in histologically normal epithelium (the "field effect") could provide a powerful screening tool for colorectal cancer. However, to date, reliable detection has not been possible. We have recently developed a new generation of optical technology, 4-dimensional elastic light-scattering fingerprinting (4D-ELF), which enables us to probe the nanoscale/microscale architecture of living cells. We therefore investigated whether 4D-ELF would be able to identify preneoplastic changes in the colonocytes of the azoxymethane (AOM)-treated rat model of colon carcinogenesis. METHODS: Forty-eight Fisher 344 rats were randomized to either 2 weekly injections of AOM or saline. Animals were killed 2-20 weeks after the second injection of AOM. Colons were removed and subjected to 4D-ELF analysis, with a subset undergoing assessment of aberrant crypt foci (ACF). All AOM-treated animals were compared with age-matched saline-treated controls. RESULTS: AOM-induced ACF became apparent at approximately 4-6 weeks and continued to increase over time. ACF were predominantly located in the distal colon. At 2 weeks (before development of ACF), there were marked changes in a number of 4D-ELF signatures. The relevance to carcinogenesis of these 4D-ELF-detected microarchitectural abnormalities is supported by their spatial and temporal correlation with subsequent development of ACF. All changes reported were highly statistically significant. CONCLUSIONS: We show that probing the nanoscale cellular architecture with 4D-ELF provided an unprecedented tool for detecting the earliest stages of colon carcinogenesis. Future studies are necessary to explore the clinical applicability of this technology and elucidate the biological determinants of these microarchitectural changes.     

Wound-peritoneal shunts: part of the complex management of anterior dural lacerations in patients with ossification of the posterior longitudinal ligament

Background

The complex management of dural lacerations occurring after the resection of multilevel ossification of the posterior longitudinal ligament (OPLL) requires further clarification.

Methods

Both preoperative MR and CT studies documented multilevel ventral cord compression attributed to OPLL with kyphosis in 82 patients requiring multilevel anterior corpectomy/fusion (ACF) (average, 2.6 levels) followed by posterior fusion (PF) (average, 6.6 levels) under the same anesthetic. The 5 patients who developed intraoperative dural lacerations/penetration demonstrated the single-layer sign (2 patients: large central mass) or the double-layer sign (3 patients: hyperdense/hypodense/hyperdense layers) on preoperative 2-dimensional CT studies. All 5 patients were managed with complex dural repair (sheep pericardial grafts, fibrin sealant, microfibrillar collagen) and had shunts placed (wound-peritoneal and lumboperitoneal).

Results

After complex dural repair/shunting, all 5 intraoperative dural lacerations (DLs) resolved. The application of low-pressure wound-peritoneal shunts was unique to this study (Uni-Shunts, Codman, Johnson and Johnson, Dorchester, Mass). The proximal end is placed lateral/parallel to the fibula strut graft/plate complex, whereas the distal catheter is tunneled into the peritoneum in the right upper quadrant (always prepared and draped in anticipation of the need for a shunt).

Conclusions

Of 82 patients undergoing multilevel anterior corpectomy for OPLL/kyphosis, 5 developed intraoperative DLs successfully managed with a complex dural repair, wound-peritoneal, and lumboperitoneal shunting procedures.     

Combination of curcumin and green tea catechins prevents dimethylhydrazine-induced colon carcinogenesis

The chemopreventive effects of curcumin and green tea catechins individually and in combination on 1,2-dimethylhydrazine (DMH)-induced colon carcinogenesis were studied in male Wister rats following 32 weeks of dietary treatment. The incidence, number and size of colorectal cancer were measured. Colorectal aberrant crypt foci (ACF) were analyzed by methylene blue staining. Proliferation indices and apoptotic indices were determined by PCNA immunostaining and TUNEL assay, respectively. The results showed that dietary curcumin, catechins and combination administration significantly inhibited the total number of ACF per rat. The combination treatment displayed the most potent inhibitory effect, while there was no difference of inhibition between curcumin and catechins-treated groups. The incidence of colorectal cancer in the treated groups was significantly lower than that of positive control group. Compared with the positive control group, the proliferation index was significantly decreased and the apoptotic index was significantly increased in all treatment groups, while the effect of the combination was the greatest among the treated groups. Our findings suggest that the combination of curcumin and catechins may produce a synergistic colon cancer-preventative effect that would be more potent than each of the compounds alone.     

Diet supplemented with citrus unshiu segment membrane suppresses chemically induced colonic preneoplastic lesions and fatty liver in male db/db mice

The modulatory effects of dietary citrus unshiu segment membrane (CUSM) on the occurrence of aberrant crypt foci (ACF) and beta-catenin accumulated crypts (BCACs) were determined in male C57BL/KsJ-db/db (db/db) mice initiated with azoxymethane (AOM). Male db/db, db/+ and +/+ mice were given 5 weekly subcutaneous injections of AOM (15 mg/kg body weight), and then they were fed the diet containing 0.02%, 0.1% or 0.5% CUSM for 7 weeks. At Week 12, a significant increase in the numbers of ACF and BCAC was noted in the db/db mice in comparison with the db/+ and +/+ mice. Feeding with CUSM caused reduction in the frequency of ACF in all genotypes of mice and the potency was high in order of the db/db mice, db/+ mice and +/+ mice. The number of BCACs was also reduced by feeding with CUSM, thus resulting in a 28-61% reduction in the db/db mice, possibly due to suppression of cell proliferation activity in the lesions by feeding with CUSM-containing diet. Clinical chemistry revealed a low serum level of triglyceride in mice fed CUSM. In addition, CUSM feeding inhibited fatty metamorphosis and fibrosis in the liver of db/db mice. Our findings show that CUSM in the diet has a chemopreventive ability against the early phase of AOM-induced colon carcinogenesis in the db/db as well as db/+ and +/+ mice, indicating potential use of CUSM in cancer chemoprevention in obese people.     

Nonsteroidal anti-inflammatory drug-activated gene-1 over expression in transgenic mice suppresses intestinal neoplasia

BACKGROUND & AIMS: The nonsteroidal anti-inflammatory drug-activated gene (NAG-1) was identified as a proapoptotic, antitumorigenic protein in vitro, induced by many antitumorigenic and chemopreventive drugs including cyclooxygenase inhibitors. However, its antitumorigenic activity has not been elucidated in vivo. METHODS: Transgenic mice were generated that ubiquitously overexpress human NAG-1 under the control of a chicken beta-actin promoter (CAG). The NAG-1 transgenic mice (NAG-(Tg+)) were characterized, and then the antitumorigenic activity was evaluated with 2 colorectal carcinogenesis models: chemical induction with azoxymethane and genetic induction using the Apc(Min+) mutation. RESULTS: NAG-(Tg+) showed no apparent phenotype other than a reduction in body weight, particularly in males. To examine whether NAG-1 expression would suppress intestinal tumorigenesis, the NAG-(Tg+) mice were treated with the colorectal carcinogen azoxymethane. NAG-(Tg+) mice developed 50% fewer aberrant crypt foci and no tumors, in comparison with nontransgenic littermates. This result demonstrates that expression of this human protein in vivo can suppress chemically induced carcinogenesis in the colon. The NAG-(Tg+) mice were also crossed with Apc(Min+) mice to determine the effect of the transgene on intestinal polyp formation. NAG-(Tg+) mice heterozygous for the Apc(Min+) mutation had a significantly reduced polyp load (60%) compared with nontransgenic Apc(Min+) littermates. CONCLUSIONS: Our results support NAG-1 as an important regulator of intestinal adenoma growth in vivo and suggest that NAG-1 may act as a tumor suppressor gene.