prostaglandin-d2 and Adenoma

Cyclooxygenase (COX)-derived prostaglandin E. We quantified oxylipins in healthy colon tissue and colorectal adenoma tissue procured during routine colonoscopy examinations. Lipid metabolite profiles were analyzed by liquid chromatography-tandem mass spectrometry.. Adenoma tissue showed a distinct prostaglandin profile as compared to normal colon mucosa. Interestingly, PGE. The human data presented here show specific changes of oxylipin profiles in colon adenoma tissue with decreased prostaglandin D

Topics: Adenoma; Aged; Arachidonate 5-Lipoxygenase; Case-Control Studies; Colon; Colonic Neoplasms; Cyclooxygenase 2; Female; Humans; Male; Oxylipins; Pilot Projects; Prostaglandin D2; Prostaglandins D

Our earlier work showed that knockout of hematopoietic prostaglandin D synthase (HPGDS, an enzyme that produces prostaglandin D2) caused more adenomas in Apc(Min/+) mice. Conversely, highly expressed transgenic HPGDS allowed fewer tumors. Prostaglandin D2 (PGD2) binds to the prostaglandin D2 receptor known as PTGDR (or DP1). PGD2 metabolites bind to peroxisome proliferator-activated receptor γ (PPARG). We hypothesized that Ptgdr or Pparg knockouts may raise numbers of tumors, if these receptors take part in tumor suppression by PGD2. To assess, we produced Apc(Min/+) mice with and without Ptgdr knockouts (147 mice). In separate experiments, we produced Apc(Min/+) mice expressing transgenic lipocalin-type prostaglandin D synthase (PTGDS), with and without heterozygous Pparg knockouts (104 mice). Homozygous Ptgdr knockouts raised total numbers of tumors by 30-40% at 6 and 14 weeks. Colon tumors were not affected. Heterozygous Pparg knockouts alone did not affect tumor numbers in Apc(Min/+) mice. As mentioned above, our Pparg knockout assessment also included mice with highly expressed PTGDS transgenes. Apc(Min/+) mice with transgenic PTGDS had fewer large adenomas (63% of control) and lower levels of v-myc avian myelocytomatosis viral oncogene homolog (MYC) mRNA in the colon. Heterozygous Pparg knockouts appeared to blunt the tumor-suppressing effect of transgenic PTGDS. However, tumor suppression by PGD2 was more clearly mediated by receptor PTGDR in our experiments. The suppression mechanism did not appear to involve changes in microvessel density or slower proliferation of tumor cells. The data support a role for PGD2 signals acting through PTGDR in suppression of intestinal tumors.

Topics: Adenoma; Adenomatous Polyposis Coli Protein; Animals; Female; Gene Expression; Humans; Intestinal Neoplasms; Intramolecular Oxidoreductases; Isomerases; Male; Mice, Inbred C57BL; Mice, Knockout; PPAR gamma; Prostaglandin D2; Prostaglandin-Endoperoxide Synthases; Receptors, Immunologic; Receptors, Prostaglandin; Tumor Burden; Tumor Suppressor Proteins

The expression and function of prostaglandin (PG) D2 DP receptors during colorectal carcinogenesis has not been elucidated. Therefore, we studied expression of DP1 and DP2 receptors by reverse transcription-polymerase chain reaction analysis of receptor mRNA levels in five human colorectal cancer cell lines (HT-29, HCA-7, HCT116, SW480 and SW48) and VACO-235 human colorectal adenoma cells. DP1 receptor transcripts were present only in HT-29 cells. In addition, none of the human colorectal epithelial cell lines tested expressed DP2 receptor mRNA. Therefore, PGD2 is unlikely to have direct activity on neoplastic colorectal epithelial cells via cell surface DP receptors.

Topics: Adenoma; Colorectal Neoplasms; DNA Primers; HT29 Cells; Humans; Prostaglandin D2; Receptors, Immunologic; Receptors, Prostaglandin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; RNA, Neoplasm; Tumor Cells, Cultured

Recent studies indicate that nonsteroidal anti-inflammatory drugs have a chemopreventive effect against colorectal neoplasia. Nonsteroidal anti-inflammatory drugs inhibit cyclooxygenases, principal enzymes that mediate the formation of prostanoids. To determine whether prostanoids are involved in the pathogenesis of colorectal adenomas, we compared the levels of five major stable metabolic products of the cyclooxygenase pathway in the normal-appearing mucosa and in adenomas of patients with familial adenomatosis polyposis. Of 12 patients tested, 6 had elevated levels of at least one prostanoid in the adenomas. More importantly, the relative levels of three prostanoids [prostaglandin (PG)D2, PGE2, and 6-keto-PGF1alpha] were elevated in adenomas compared to normal-appearing mucosa from the same patients, and the resulting ratios were correlated with the size of the adenoma. These results suggest a role for prostanoids in progression of colorectal polyposis in familial adenomatosis polyposis patients.

Topics: 6-Ketoprostaglandin F1 alpha; Adenoma; Adenomatous Polyposis Coli; Adult; Dinoprost; Dinoprostone; Female; Humans; Intestinal Mucosa; Male; Oxytocics; Prostaglandin D2; Prostaglandins; Thromboxane B2