At present it is not clear whether prostaglandins other than

At present, it is not clear whether prostaglandins other than PGE-M could also serve as prognostic or predictive biomarkers for colorectal cancer. To examine this, Li et al. took blood samples from healthy individuals, as well as from patients with familial adenomatous polyposis (FAP, an inherited predisposition to colorectal tumour formation due to germline heterozygosity in the gene) and sporadic colorectal cancer. The authors then examined the levels of circulating PGE, PGD, PGFα, PGI and thromboxane A [TXA] — in most cases by measuring their stable metabolites as surrogates. Perhaps surprisingly, the authors only observed a modest increase in circulating PGE (and PGD) levels in FAP patients, but the levels of TXA (inferred by measurement of its more stable derivative TXB) were dramatically elevated in both FAP and sporadic colorectal cancer patients relative to healthy individuals. These observations were confirmed by measuring TXA levels in the urine of colorectal cancer patients (by measuring 11-dehydro-TXB) and are consistent with a previous report of increased urinary TXA in FAP patients (). The authors went on to show that the majority of patients with colorectal cancer in their study could be identified by measuring circulating TXA levels, and suggest that TXA levels may therefore have prognostic value in colorectal cancer patients. What could account for the high levels of circulating TXA in patients with colorectal cancer? Could there be a role for TXA signalling in tumour development? In an effort to understand this, Li et al. performed immunohistochemistry on patient colorectal tumour biopsies to examine the myd88 signaling of TXA synthase (TBXAS1), an important enzyme for TXA production (). Expression of TBXAS1 was upregulated in tumour tissue, as was the TXA receptor (TBXA2R), raising the possibility that they have a functional role in tumour development. In a series of in vitro experiments using colorectal cancer cells, the authors found that RNAi-mediated depletion of either TBXAS1 or TBXA2R resulted in decreased anchorage-independent growth — suggestive of reduced malignant potential. These findings are consistent with a previous study in which enforced expression of TBXAS1 accelerated tumour growth and angiogenesis in vivo (). Finally, the authors asked whether aspirin might target TXA signalling as part of its chemopreventive action. Tumour biopsies from FAP patients grouped into aspirin users and non-users revealed an association between reduced TBXAS1 and TBXA2R expression and aspirin use. In support of these data, aspirin treatment of colorectal cancer cell lines in vitro decreased the protein expression of TBXAS1 and TBXA2R. The findings of Li et al. highlight the possibility that the measurement of circulating prostaglandins might be useful in cancer screening and prevention, but naturally there are caveats (). The study used small patient numbers, so further validation will be necessary to determine the usefulness of circulating TXA as a prognostic or predictive biomarker, and the study does not address the role of confounding factors such as inflammation and infection. Furthermore, it is unclear what contribution tumour-derived vs platelet-derived TXA made to the level detected in the circulation. Does exogenous TXA (or a stable analogue) promote colorectal tumour cell growth in vitro and would this rescue the inhibitory effects of TBXAS1-depletion the authors observe on anchorage-independent growth? If so, what signal transduction pathways are activated by TXA in colorectal tumour cells? It will also be interesting to determine whether circulating TXA levels can be used to report the efficacy of NSAIDs in cancer prevention and/or an adjuvant setting. In summary, there is much to do before TXA metabolites are used as biomarkers for cancer screening, but with careful validation in larger patient populations the case for using circulating prostaglandins as biomarkers for early detection, disease progression and response to treatment is gaining momentum.