Cancer Letters

Cancer Letters

Volume 215, Issue 1, 8 November 2004, Pages 1-20
Cancer Letters

Mini-review
Cyclooxygenases in cancer: progress and perspective

https://doi.org/10.1016/j.canlet.2004.06.014Get rights and content

Abstract

Aspirin has been used to control pain and inflammation for over a century. Epidemiological studies first associated a decreased incidence of colorectal cancer with the long-term use of aspirin in the early 1980s. Near the same time the first reports showing regression of colorectal adenomas in response to the non-steroidal anti-inflammatory drug (NSAID) sulindac were reported. In subsequent years, the use of other NSAIDs, which inhibit cyclooxygenase (COX) enzymes, was linked to reduced cancer risk in multiple tissues including those of the breast, prostate, and lung. Together these studies resulted in the identification of a new cancer preventive and/or therapeutic target-COX enzymes, especially COX-2. Meanwhile, the overexpression of COX-2, and less consistently, the upstream and downstream enzymes of the prostaglandin synthesis pathway, was demonstrated in multiple cancer types and some pre-neoplastic lesions. Direct interactions of prostaglandins with their receptors through autocrine or paracrine pathways to enhance cellular survival or stimulate angiogenesis have been proposed as the molecular mechanisms underlying the pro-carcinogenic functions of COX-2. The rapid development of safe and effective inhibitors targeting individual COX enzymes not only dramatically improved our understanding of the function of COX-2, but also resulted in discovery of COX independent functions of NSAIDs, providing important hints for future drug design. Here we review the fundamental features of COX enzymes, especially as related to carcinogenesis, their expression and function in both animal tumor models and clinical cancers and the proposed mechanisms behind their roles in cancer.

Introduction

Aspirin was introduced as an anti-pyretic, anti-inflammatory and analgesic drug at the end of nineteenth century. Soon after, a family of drugs with similar properties were discovered and collectively termed non-steroidal anti-inflammatory drugs (NSAIDs). In the late 1960s work from Samuelsson and Bergstrom revealed the prostaglandin synthesis pathways [1], [2], [3] and a few years later, J.R. Vane and his colleagues identified the therapeutic target of NSAIDs as the cyclooxygenase (COX) enzyme [4]. The Noble Prize for Physiology or Medicine was awarded to Drs. Vane, Samuelsson and Bergstrom in 1982 ‘for their discoveries concerning prostaglandins and related biologically active substances’ [5]. Both epidemiological and randomized clinical trials have indicated efficacy, albeit not uniformly, in the ability of aspirin and/or NSAIDs to decrease colorectal cancer [6], [7], [8], [9].

A number of epidemiological studies have indicated that long term aspirin/NSAID use is associated with 30–50% reduction in risk of colorectal cancer or adenomatous polyps or death from colorectal cancer [10]. In addition, these studies suggest that the duration and the consistency of NSAID use are more important than the dosage. Other epidemiologic studies also found associations between NSAID use and a lower death rate from cancers of the esophagus, stomach, breast, lung, prostate, urinary bladder and ovary [11], [12].

Meanwhile, Dr. William Waddell reported the regression of rectal polyps in a small number of familial adenomatous polyposis (FAP) patients in response to the NSAID sulindac [13], [14]. This work has been extended by a number of epidemiological studies as well as clinical trials. The results from the completed randomized double-blind placebo controlled trial on FAP patients suggest that sulindac and celecoxib cause adenoma regression in some polyposis patients, and in some cases, a complete regression is seen [15], [16], [17], [18], [19]. Clinical trials on other high risk populations have generally shown a beneficial reduction in adenoma number and/or size, although the effects are inconsistent [9], [20], [21], [22], [23], [24]. In young FAP patients who were entered into a randomized clinical trial prior to the development of colorectal adenomas, there was no significant effect of sulindac on preventing de novo adenoma formation [25]. In a large scale randomized clinical trial to determine the ability of aspirin to prevent myocardial infarction, there was no reduction in colorectal cancer in the patients receiving aspirin in a secondary analysis [26]. Taken together, despite the early very promising results, currently there is not sufficient evidence to recommend wide-spread use of any of these agents for primary prevention of colon cancer. More clinical trials are ongoing with aspirin, sulindac, celecoxib and refocoxib and we await the results of these trials to provide a more complete estimate of the chemo-preventative value of NSAIDs.

Section snippets

Cyclooxygenase genes and enzymes

In 1988, three different groups cloned a gene encoding cyclooxygenase, which later turned out to be the constitutive isoform—COX-1 [27], [28], [29]. Subsequently, the inducible isoform of COX was discovered and named—COX-2 [30], [31], [32], [33]. The human gene encoding the COX-1 enzyme (PTGS1) is located on chromosome 9 (9q32–9q33.3), contains 11 exons and spreads across 40 kb; its mRNA is approximately 2.8 kb [34]. The gene encoding COX-2 (PTGS2) is located on chromosome 1 (1q25.2–25.3),

Functions of cyclooxygenases

Prostaglandins were first discovered in semen or in the extract of prostate as lipid soluble compounds with potent vasodepressor and smooth muscle-stimulating activity. They were named based on the fact that they were believed to be derived from the prostate [45], [46]. Now it is clear that the normal human prostate itself is not the major source of prostaglandins. The large amounts of prostaglandins in the semen are derived from the nearby seminal vesicles, which are one of the most abundant

Structure of cyclooxygenases

COX-1 and COX-2 share the same substrates, generate the same products, and catalyze the same reaction using identical catalytic mechanisms. When the X-ray crystal structures of these two enzymes were solved, both human and murine COX-2 could be largely superimposed on that of COX-1, with the amino acids serving as the substrate binding pocket and catalytic site being nearly identical to each other. One exception with profound implications is that the isoleucine 590 around the substrate channel

Genetic evidence for an association between COX-2 and cancer

The studies from a murine model of FAP (mice carrying APCΔ716) provided the first genetic evidence for a link between COX-2 and carcinogenesis. When APCΔ716 mice were crossed with mice containing targeted mutations that inactivate the Pgst2 gene (homozygous or heterozygous), the size and number of small intestinal and colonic polyps, especially the number of large polyps were reduced in a dose-dependent manner in comparison with the Pgst2 wide-type littermates [59]. Deletion of the gene (Pla2g4

Role of COX-2 in angiogenesis

The ability to induce angiogenesis is essential for most solid tumors to grow beyond 2–3 mm in diameter. Angiogenesis may also provide an important path for metastasis. Tumor angiogenesis, as with other neovascular formations, includes destabilization of pre-existent blood vessels, proliferation of vascular endothelial cells, invasion by endothelial cells into the extracellular matrix (ECM) and finally the migration and positioning of endothelial cells. One of the earliest observations regarding

Expression in normal tissues

Although COX-2 protein is undetectable by immunohistochemistry in many human tissues under normal physiological conditions, there are several known exceptions. The seminal vesicles are known to have the high levels of constitutive expression of COX-2. PGE2 and its 19-hydroxy metabolites are the major components of primate semen [97]. COX-2 is also constitutively expressed in the kidney with positive staining in glomeruli and small blood vessels. The limited evidence on human subjects suggests

Other unresolved issues and opportunities in NSAID mechanisms of action

The fact that chronic or acute inflammation is commonly associated with cancer also complicates the interpretation of COX-2 expression in cancer. On one hand, the tissue disruption and cell death in cancer recruit pro-inflammatory cells and lead to inflammation. On the other hand, some types of infections or chronic inflammation are causative for the initiation of certain cancers, such as chronic hepatitis, chronic gastritis and chronic ulcerative colitis. Prostaglandins generated as a result

Summary

More than a century after the introduction into the market, aspirin is still a somewhat ‘magical’ drug that can not only prevent inflammation, and reduce pain, but can also prevent cancer. In the past 10 years, our understandings of the molecular biology of COX enzymes, from structure to catalytic mechanisms, have begun to provide evidence from multiple angles to support the pro-carcinogenic role of COX enzymes. One of the most important major issues that remain relates to the expression

Note added in proof

A recent study (Y.G. Crawford, M.L. Gauthier, A. Joubel, K. Mantei, K. Kozakiewicz, C.A. Afshari, T.D. Tlsty, Histologically normal human mammary epithelia with silenced P16INK4a over express COX-2, promoting a premalignant program, Cancer Cell 5 (2004) 263–273.) provides new evidence for a role of COX-2 in breast carcinogenesis.

Acknowledgements

Funded by Public Health Services NIH/NCI #R01CA084997, NIH/#R01CA70196 and NIH/NCI Specialized Program in Research Excellence (SPORE) in Prostate Cancer #P50CA58236.

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