Abstract
BackgroundThe pathogenesis for colorectal cancer remains unresolved. A growing body of evidence suggests a direct correlation between cyclooxygenase enzyme expression, prostaglandin E2 metabolism and neoplastic development. Thus further understanding of the regulation of epithelial functions by prostaglandin E2 is needed. We hypothesized that patients with colonic neoplasia have altered colonic epithelial ion transport and express functionally different prostanoid receptor levels in this respect.MethodsPatients referred for colonoscopy were included and grouped into patients with and without colorectal neoplasia. Patients without endoscopic findings of neoplasia served as controls. Biopsy specimens were obtained from normally appearing mucosa in the sigmoid part of colon. Biopsies were mounted in miniaturized modified Ussing air-suction chambers. Indomethacin (10 μM), various stimulators and inhibitors of prostanoid receptors and ion transport were subsequently added to the chamber solutions. Electrogenic ion transport parameters (short circuit current and slope conductance) were recorded. Tissue pathology and tissue damage before and after experiments was assessed by histology.ResultsBaseline short circuit current and slope conductance did not differ between the two groups. Patients with neoplasia were significantly more sensitive to indomethacin with a decrease in short circuit current of 15.1 ± 2.6 μA·cm-2 compared to controls, who showed a decrease of 10.5 ± 2.1 μA·cm-2 (p = 0.027). Stimulation or inhibition with theophylline, ouabain, bumetanide, forskolin or the EP receptor agonists prostaglandin E2, butaprost, sulprostone and prostaglandin E1 (OH) did not differ significantly between the two groups. Histology was with normal findings in both groups.ConclusionsEpithelial electrogenic transport is more sensitive to indomethacin in normal colonic mucosa from patients with previous or present colorectal neoplasia compared to colonic mucosa from control patients. Stimulated epithelial electrogenic transport through individual prostanoid subtype receptors EP1, EP2, EP3, and EP4 is not significantly different between neoplasia diseased patients and controls. This indicates that increased indomethacin-sensitive mechanisms in colonic mucosa from neoplasia diseased patients are not related to differences in functional expression of EP receptor subtypes.
Highlights
The pathogenesis for colorectal cancer remains unresolved
Our findings indicate that normally appearing colon in colorectal neoplasia (CRN) patients, including Colorectal cancer (CRC) patients, express higher cyclooxygenase enzyme (COX) enzyme activity than in control patients but with no difference in the functional expression of the four EP receptor subtypes with respect to transepithelial ion transport
Patients agreeing were pooled into the neoplasia group (i.e. N-patients) if they presented a history of CRN or if CRN was macroscopically detected during colonoscopy
Summary
The pathogenesis for colorectal cancer remains unresolved. A growing body of evidence suggests a direct correlation between cyclooxygenase enzyme expression, prostaglandin E2 metabolism and neoplastic development. There is a need for additional medical therapy and prevention of CRC, which necessitates By their inhibitory action on the cyclooxygenase enzyme (COX), non-steroidal anti-inflammatory drugs (NSAIDs) are partly chemopreventive against CRC, an effect maybe due to attenuation of the enzyme isoform 2 (COX-2) [3,4,5,6]. This protection is believed to be mediated, at least in part, through reduction of prostaglandin E2 (PGE2) levels [7,8], as PGE2 promotes cell growth, migration and angiogenesis and reduce apoptosis [4]. With respect to PGE2 receptors, CRC cells and their neighboring cells have augmented expression of receptors EP2 and EP4, while initially the EP3 receptor expression often is lowered [4,8,12,13,14,15], Figure 1
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
