PubMed · 12646143
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Mariann Bienz. 2003-03-18. APC.. https://doi.org/10.1016/s0960-9822(03)00152-0
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In humans, mutations in BMPR1A, SMAD4 and PTEN are responsible for juvenile polyposis syndrome, juvenile intestinal polyposis and Cowden disease, respectively. The development of polyposis is a common feature of these diseases, suggesting that there is an association between BMP and PTEN pathways. The mechanistic link between BMP and PTEN pathways and the related etiology of juvenile polyposis is unresolved. Here we show that conditional inactivation of Bmpr1a in mice disturbs homeostasis of intestinal epithelial regeneration with an expansion of the stem and progenitor cell populations, eventually leading to intestinal polyposis resembling human juvenile polyposis syndrome. We show that BMP signaling suppresses Wnt signaling to ensure a balanced control of stem cell self-renewal. Mechanistically, PTEN, through phosphatidylinosital-3 kinase-Akt, mediates the convergence of the BMP and Wnt pathways on control of beta-catenin. Thus, BMP signaling may control the duplication of intestinal stem cells, thereby preventing crypt fission and the subsequent increase in crypt number.
Cyclooxygenase 2 (COX-2), also called prostaglandin endoperoxide synthase 2, is involved in colorectal tumor development. This review deals with particular questions raised in this field such as the mechanisms of COX-2 related tumor promotion, the role of the different types of cells (epithelial and interstitial) expressing COX-2, the factors that trigger COX-2 induction, and the clinical potential of selective COX-2 inhibitors to treat or prevent colorectal tumors. Several mechanisms of COX-2 related tumor promotion have been identified. Some are dependent on prostaglandin E(2) production (such as induction of cell proliferation, angiogenenis or local immunosuppression, inhibition of apoptosis, increase in cell motility) and others are not (such as carcinogen activation or malondialdehyde production). COX-2 expression has been demonstrated in epithelial cells of colorectal cancers and adenomas and also in interstitial cells. These cells correspond to macrophages and/or fibroblasts and endothelial cells. COX-2 expression in these interstitial cells participates in tumor development. Factors or events that trigger COX-2 expression include oncogene activation, antioncogene inactivation, cytokines, growth factors, some fatty acids, bile salts, and mucins. Finally, selective COX-2 inhibitors may be effective in preventing or treating colorectal adenomas or carcinomas. However, their real efficiency and the cost/benefit balance are currently evaluated, and no definite conclusion can be made at the moment.
Cyclooxygenase-2 (COX-2), an inducible prostaglandin G/H synthase, is overexpressed in pre-neoplastic tissues and several human cancers including colorectal cancer. Evidence linking COX-2 activity to carcinogenesis was derived from epidemiologic studies and animal models with defect adenomatous polyposis coli (APC) gene. PGE2 induced by COX-2 exerts several biological properties that may be advantageous for tumorigenesis: 1) Promoting angiogenesis (increased VEGF, bFGF, and PDGF production), 2) Anti-apoptosis mechanism (via increased bcl-2 and Akt activity), 3) Stimulating tumor metastasis (by increasing matrix metalloproteinases) and 4) Decreased immune surveillance (decreased cytokine production and NK activity). In addition, COX-2 reaction can cause DNA oxidation and induce mutations. Chemoprevention of colorectal cancer has attracted great attention in recent years. Epidemiologic data showed that chronic intake of traditional nonsteroidal anti-inflammatory drugs (NSAIDs) could reduce the incidence of colorectal cancer. Recent clinical trial studies showed that celecoxib, a selective COX-2 inhibitor, is equally effective in reducing colorectal adenomas in animal models and patients with familial adenomatous polyposis (FAP), yet with superior GI safety. Two COX-2 inhibitors (celecoxib and refocoxib) have been approved by FDA as adjuncts to usual care in FPA patients, and are currently being studied in patients with sporadic adenomas and other types of cancers. These studies are expected to generate evidence in favor of targeting COX-2 and its gene products as chemopreventive strategies, which may provide an alternative in current approach to reducing the morbidity and mortality of this disease.