Mini-reviewPro-inflammatory prostaglandins and progression of colorectal cancer
Introduction
Clinical and epidemiologic studies suggest that chronic inflammation caused by infectious or autoimmune diseases is clearly associated with increased risk of cancer, including colorectal cancer (CRC) [1] and chronic inflammation contributes to the development of approximately 15–20% of malignancies worldwide [2]. Experimental studies indicate that inflammation promotes tumor growth, in part, through stimulation of proliferation and angiogenesis as well as inhibition of apoptosis and immune surveillance. The best evidence for the link between inflammation and tumor progression come from recent epidemiologic studies and clinical trials showing that long-term use of nonsteroidal anti-inflammatory drugs (NSAIDs) reduced the relative risk of developing colorectal cancer by 40–50% [3]. NSAIDs are thought to exert their anti-inflammatory, analgesic, and anti-pyretic effects mainly by targeting cyclooxygenase (COX) enzymes [4]. The COX enzyme exists in three isoforms commonly referred to as COX-1, COX-2, and COX-3. COX-1 is constitutively expressed in a broad range of cells and tissues and its expression remains constant under most physiological or pathological conditions. COX-1 contributes to maintenance of the gastric mucosa, regulation of renal blood flow in the afferent vessels of the kidney, and regulation of platelet aggregation. By contrast, COX-2 is an immediate-early response gene normally absent from most cells but is induced mainly at sites of inflammation in response to inflammatory stimuli including pro-inflammatory cytokines such as IL-1α/β, IFN-γ, and TNF-α produced by inflammatory cells [5]. COX-2 is involved in inflammation and tumorigenesis. COX-3 is an acetaminophen-sensitive splice variant of COX-1 and its function remains unknown. Therefore, COX-2 is a pro-inflammatory mediator and NSAIDs and specific COX-2 inhibitors are currently used to treat acute pain as well as the signs and symptoms of osteoarthritis and rheumatoid arthritis [6].
The gastrointestinal mucosa forms a complex, semi-permeable barrier between the host and the largest source of foreign antigens. The mucosal immune system has the ability to mount an immune response to pathogens while maintaining tolerance to the vast array of benign luminal antigens from food and commensal bacteria. Many inflammatory processes are self-limiting, supporting the existence of endogenous anti-inflammatory mechanisms. An abnormal mucosal immune response is thought to result in chronic inflammation such as arthritis and inflammatory bowel disease (IBD). IBD in humans is a complex class of disorders that has been grouped into two major forms, ulcerative colitis (UC) and Crohn’s disease (CD). These chronic conditions of the gut ordinarily affect individuals between the age of 16 and 40 and can cause significant morbidity. Chronic IBD (especially pan-colitis) significantly increases the risk of developing colorectal cancer [7]. IBD is thought to result from inappropriate activation of immune responses and/or a deficient feedback system that normally down-regulates the mucosal response to luminal factors.
The first evidence linking COX-2 to carcinogenesis emerged from studies on CRC [8]. Several subsequent reports confirmed that elevated COX-2 expression was found in approximately 50% of adenomas and 85% of adenocarcinomas [9], [10]. Similarly, COX-2 is induced in large intestinal epithelium in active human IBD and in inflamed tissues of IL-10 deficient mice (a mouse model of IBD) [11], [12]. An increasingly large body of evidence from population-based studies and clinical trials have shown that regular use of NSAIDs, including aspirin and related drugs, over a 10–15 year period reduces the relative risk of developing colorectal cancer and adenomas by 40–50% [3]. In particularly, aspirin specifically prevents the subgroup of colon cancers in which COX-2 is most highly induced [13]. Furthermore, NSAID use leads to the regression of preexisting adenomas in patients with the hereditary colon cancer syndrome, familial adenomatous polyposis coli (FAP) [14], [15]. Direct molecular evidence that COX-2 plays a key role in colorectal carcinogenesis was obtained from studies in animal models. Genetic studies demonstrate that deletion of COX-2 gene results in decreased tumor formation in both the small intestine and colon of ApcMin mice (a mouse model of CRC) [16] as well as in ApcΔ716 mice, another Apc mutant model [17]. Although the effects of COX-2 overexpression upon colorectal carcinogenesis in transgenic mouse models have not been reported, overexpression of COX-2 in transgenic mice under a murine mammary tumor virus (MMTV) promoter induced breast carcinomas formation [18]. Moreover, transgenic mice with COX-2 expression driven by the keratin-5 promoter did not develop skin cancer spontaneously, but were much more sensitive to carcinogen-induced tumor formation [19].
The COX enzymes convert free arachidonic acid into prostanoids, including prostaglandins (PGs) and thromboxanes (TXs). The key regulatory step in this process is the enzymatic conversion of arachidonate to PGG2, which is then reduced to an unstable endoperoxide intermediate, PGH2. Specific PG synthases in turn metabolize PGH2 to at least five structurally related bioactive lipid molecules, including PGE2, PGD2, PGF2α, PGI2, and thromboxane A2 (TxA2), in a cell type-specific manner. PGs are unstable compounds that are rapidly metabolized in vivo[20]. PGE2 and PGF2α are rapidly metabolized to a stable 13,14-dihydro-15-keto-PGA2 (PGEM) and 13,14-dihydro-15-keto-PGF2αin vivo by the enzyme 15-hydroxy prostaglandin dehydrogenase (15-PGDH), respectively. PGI2 is non-enzymatically hydrated to 6-keto PGF2α, and then quickly converted to the major urinary metabolite, 2,3-dinor-6-keto PGF2α and PGD2 is also rapidly metabolized to 15-deoxy-Δ12,Δ14PGJ2 (15dPGJ2) and 11β-PGF2αin vivo. Moreover, TXA2 is rapidly hydrolyzed to TXB2 in a non-enzymatic manner. Prostaglandins exert their cellular functions by binding cell surface receptors that belong to the family of seven transmembrane G protein-coupled rhodopsin-type receptors. These cell surface receptors are designated DP for the PGD2 receptor, EP (EP1, EP2, EP3, and EP4) for the PGE2 receptors, FP for the PGF2α receptor, IP for the PGI2 receptor, and TP for the TxA2 receptor. In some cases, however, certain prostaglandins and their metabolites bind nuclear receptors such as peroxisome proliferator-activated receptors (PPARs). It has been shown that PGI2 can transactivate PPARδ[21], while 15dPGJ2 is a natural ligand for PPARγ [22]. Moreover, recent studies show that PGE2 indirectly induces PPARδ activation in certain contexts [23].
Section snippets
Prostaglandins and colorectal cancer
The prostanoids are involved in a variety of pathophysiologic processes, including modulation of the inflammatory reaction, gastrointestinal cytoprotection and ulceration, angiogenesis, cancer, hemostasis and thrombosis, renal hemodynamics, and progression of kidney disease. Multiple lines of evidence demonstrate that overexpression of COX-2 in epithelial, mesenchymal, and inflammatory cells leads to the production of multiple PGs, which in turn promote angiogenesis, protect against apoptosis,
PGE2
Recent research has indicated that PGE2 is a key mediator of acute inflammatory responses [24], stem cell differentiation [25], arthritis [26], and inflammatory bowel disease (IBD) [27]. Direct evidence came from observations that blocking either PGE2 synthases or PGE2 receptors impaired both acute and chronic inflammatory responses. Mice deficient in PGE2 synthase displayed a marked reduction in acute pain during the inflammatory response and collagen antibody-induced arthritis (an animal
TxA2
Although the role of TxA2 in atherogenesis has been established [46], few studies have delineated the biological function of TxA2 in CRC and IBD. TxA2 is the only other COX-2 derived prostaglandins implicated in oncogenesis. TxA2 has been shown to promote tumor growth and tumor-associated angiogenesis [47]. Moreover, it has been reported that TxA2 synthase inhibitor blocks colorectal carcinoma liver metastasis in an in vivo study [48]. However, disruption of TP receptor does not affect colon
PGD2
Although PGD2 have been implicated as an anti-inflammatory regulator of the IBD [50], the role of PGD2 in colon cancer is not defined. PGD2 and/or its metabolites may have tumor inhibitory effects. Recent study shows that disruption of the gene for hematopoietic PGD synthase in ApcMin/+ mice accelerates intestinal tumor growth, while ApcMin/+ mice with transgenic human hematopoietic PGD synthase exhibit fewer intestinal adenomas than controls [51]. These results suggest that PGD2 serves as
PGF2α
Although the emerging data support the role of PGF2α in acute and chronic inflammation [53], one study showed that FP is not involved in the progression of chronic inflammation in IBD [33]. Furthermore, there are no clear studies showing that PGF2α participates in IBD. Similarly, the observation that PGF2α failed to induce cell proliferation in CRC cell lines and deletion of FP receptor did not affect colon tumor formation in AOM-treated mice suggests that PGF2α is not involved in colorectal
PGI2
In normal physiological processes, COX-1-derived PGI2 is a major prostaglandin product in the gastrointestinal tract and plays a role in the cytoprotection of gastric mucosal surfaces and in maintaining normal vasculature [55]. Under pathological conditions, PGI2 serves as a mediator of acute and chronic inflammation. Loss or inhibition of IP (the prostacyclin receptor) reduces pain and inflammation in a chronic model of inflammatory arthritis [56]. In an animal model of IBD, one study showed
Conclusions
Prolonged use of high doses of NSAIDs (except for aspirin) is associated with unacceptable cardiovascular side effects [58], [59], [60]. The mechanism of the side effects of NSAIDs is unclear. A potential explanation for the cardiovascular side effects of NSAIDs is proposed based on the following observations. The synthesis of PGI2 depends principally on COX-2 activity in the vascular wall, whereas the production of TxA2 in platelets is dependent on COX-1. Since PGI2 antagonizes the biological
Acknowledgements
This work is supported, in part, from the National Institutes of Health Grants RO1DK 62112, P01-CA-77839, R37-DK47297, and P30 DK-58404 (RND). RND (R37-DK47297) is recipient of an NIH MERIT award. We also thank the National Colorectal Cancer Research Alliance (NCCRA) for generous support (RND).
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