Mechanisms for the Prevention of Gastrointestinal Cancer: The Role of Prostaglandin E2

Department of Cell and Developmental Biology, Vanderbilt University, Нашвилл, Michigan, United States
Oncology (Impact Factor: 2.42). 02/2005; 69 Suppl 1(Suppl 1):28-32. DOI: 10.1159/000086629
Source: PubMed


Carcinoma of the colon or rectum represents one of the most common malignancies worldwide with a higher prevalence in industrialized regions. Epidemiologic studies of individuals taking non-steroidal anti-inflammatory drugs (NSAIDs) have shown a significant reduction in colorectal cancer (CRC) mortality compared to those individuals not receiving these agents. NSAIDs inhibit the enzymatic activity of both isoforms of cyclooxygenase (COX-1 and COX-2), while COX-2-selective inhibitors have shown some efficacy in reducing polyp formation. COX-2-derived bioactive lipids, including the primary prostaglandin (PG) generated in colorectal tumors, PGE(2), are known to stimulate cell migration, proliferation and tumor-associated neovascularization while inhibiting cell death. Here we briefly review the role of NSAIDs in preventing CRC, as well as the proposed mechanism by which a COX-2-derived PG, PGE(2), promotes colon cancer.

8 Reads
  • Source
    • "Several studies have identified a tumour suppressor activity of 15-PGDH in colon, lung, bladder, gastrointestinal and breast cancer (Yan et al., 2004; Backlund et al., 2005; Ding et al., 2005; Myung et al., 2006). The critical physiological role of this enzyme is to inactivate the PGs by conversion to the corresponding 15-keto-PGs. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The pulmonary artery endothelial cells dysfunction and injury play a critical role in chronic hypoxia-induced hypertensive process. The influence of hypoxia on the endothelial cells proliferation remains to be explored in detail. In the present study, we performed immunohistochemistry and western blot analysis and observed that hypoxia increased the expression of 15-hydroxyprostaglandin dehydrogenase (15-PGDH) in pulmonary vessels which was majorly localized in the vascular intima. Since 15-PGDH is responsible for catalyzing the 15(S)-hydroxyl group of 15-hydroxyeicosatetraenoic acid to 15-keto-6Z, 8Z, 11Z, 13E-eicosatetraenoic acid (15-KETE), the role of 15-PGDH/15-KETE pathway in the processes of hypoxia-induced endothelium proliferation and migration were detected by bromodeoxyuridine incorporation, cell cycle analysis, scratch-wound and tube formation assay. We found that 15-KETE increased cells DNA sythesis and enhanced the cell-cycle transition from the G0 /G1 phase to the S phase in hypoxia. 15-PGDH inhibitor and 15-PGDH RNA interference reversed all the alterations. Meanwhile, our results indicated that ERK1/2 signaling system was activated by 15-KETE. Additionally, 15-KETE-induced cell migration and tube formation could be reversed after blocking ERK1/2 but not p38 MAPK pathway. These observations suggest that 15-PGDH/15-KETE mediates hypoxia-induced endothelium proliferation and migration via the ERK1/2 signaling, an important underlying mechanism contributing to hypoxic pulmonary vascular remodeling.
    Full-text · Article · Jan 2014 · British Journal of Pharmacology
  • Source
    • "Cox-2/PGE2 pathways have multiple effects on tumor development [50], [52], [53], [54]. Importantly, PGE2 not only promotes cell proliferation and tumor associated angiogenesis but also induces the development of MDSC [55], [56], [57]. Over expression of Cox-2 enhances whereas a defect in Cox-2 suppresses TPA induced inflammation and DMBA/TPA induced chemical carcinogenesis [25], [26]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The mechanism for inflammation associated tumor development is a central issue for tumor biology and immunology and remains to be fully elucidated. Although IL-17 is implicated in association with inflammation mediated carcinogenesis, mechanisms are largely elusive. In the current studies, we showed that IL-17 receptor-A gene deficient (IL-17R-/-) mice were resistant to chemical carcinogen-induced cutaneous carcinogenesis, a well-established inflammation associated tumor model in the skin. The deficiency in IL-17R increased the infiltration of CD8+ T cells whereas it inhibited the infiltration of CD11b+ myeloid cells and development of myeloid derived suppressor cells. Inflammation induced skin hyperplasia and production of pro-tumor inflammatory molecules were inhibited in IL-17R-/- mice. We found that pre-existing inflammation in the skin increased the susceptibility to tumor growth, which was associated with increased development of tumor specific IL-17 producing T cells. This inflammation induced susceptibility to tumor growth was abrogated in IL-17R-/- mice. Finally, neutralizing IL-17 in mice that had already developed chemical carcinogen induced skin tumors could inhibit inflammation mediated tumor progression at late stages. These results demonstrate that IL-17 mediated inflammation is an important mechanism for inflammation mediated promotion of tumor development. The study has major implications for targeting IL-17 in prevention and treatment of tumors.
    Full-text · Article · Feb 2012 · PLoS ONE
  • Source
    • "The potential anti-neoplastic properties of NSAIDs are attributed to their inhibition of cyclooxygenases (COX), enzymes that catalyze the synthesis of prostaglandins [4] [5], which contribute to carcinogenesis by promoting cellular proliferation, stimulating angiogenesis, and inhibiting apoptosis [55] [56]. Therefore, it is biologically plausible that the putative protective effects of NSAIDs are influenced by the amount or activity of COX in cells, both partially determined by specific polymorphisms. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Inflammation and non-steroidal anti-inflammatory agents (NSAIDs) may play important role in ovarian cancer. However, epidemiologic data are inconsistent, possibly reflecting inter-individual genetic differences affecting the metabolism of NSAIDs. We examined whether common polymorphisms affecting the metabolism of NSAIDs modify the association between NSAIDs and ovarian cancer risk. We genotyped 1,353 DNA samples from women who developed ovarian cancer and 1,823 samples from matched controls participating in the New England Case-Control study and the Nurses' Health Studies. Conditional logistic regression estimated odds ratios (ORs) and 95% confidence intervals (CIs) associated with regular use of NSAIDs and with relevant polymorphisms on ovarian cancer risk. Multivariable unconditional logistic regression estimated the association of NSAID use across stratum of each genotype. Regular use of NSAIDs was not associated with ovarian cancer risk. Multivariable OR (95% CI) associated with use NSAIDs was 0.85 (95% CI: 0.71-1.02). Associations between NSAID use and ovarian cancer risk did not differ significantly across strata of genotypes. None of the studied polymorphisms was associated with ovarian cancer risk. The multivariable ORs (95% CI) associated with CYP2C9 and UGT1A6 variant genotypes were 0.99 (0.90-1.08) and 0.93 (0.82-1.05), respectively. The multivariable ORs (95% CI) associated with PPAR-γ, COX-2 -765G>C, and COX-2 Ex10+837T>C polymorphisms were 1.02 (0.87-1.20), 0.87 (0.75-1.00), and 0.97 (0.87-1.09), respectively. In this relatively large study, we found no convincing evidence supporting an association between NSAIDs use and ovarian cancer risk. Furthermore, data did not suggest interaction between selected polymorphisms and use of NSAIDs in relation to ovarian cancer risk.
    Full-text · Article · Jan 2010 · International Journal of Molecular Epidemiology and Genetics
Show more