The thromboxane A2 pathway and its components are implicated in the regulation of tumor cell angiogenesis, migration, invasion, metastasis and apoptosis. Scientific studies report cyclooxygenase-2 is up-regulated in many different types of cancer including breast, cervix, colon, esophagus, glioma, head and neck, lung, melanoma, pancreas, prostate, stomach and thyroid. Levels of urinary 11-dehydrothromboxane B2 reflect activity of components of the thromboxane A2 pathway impacting thromboxane A2 generation. Test results may be of use to the healthcare provider in the diagnosis, prognosis and therapeutic management of patients with cancer.

Effects of celecoxib on prostanoid biosynthesis and circulating angiogenesis proteins in familial adenomatous polyposis2

"There is increasing appreciation of the role of platelets in tumor growth and metastatic dissemination (Gay and Felding-Habermann, 2011). Platelet activiation can lead to the release of growth and angiogenesis factors present in a-granules into the tumor microenvironment. (Italiano et al., 2008).  Moreover, platelets and the factors they release can up-regulate cyclooxygenase (COX)-2 which is considered an early event of cell transformation (Patrono et al., 2001). In colorectal cancer, COX-2 expression is induced early in stromal cells and subsequently at high levels in epithelial cells (Prescott, 2000), where it correlates with advanced tumor invasion and poor clinical outcomes (Sheehan et al., 1999)."

"Intestinal tumorigenesis was associated with enhanced urinary TX-M levels, but unaffected by celecoxib, suggesting the involvement of a COX-1-dependent pathway, presumably from platelets."

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Epigenetic deregulation of the COX pathway in cancer

"Inflammation is a major cause of cancer and may condition its progression.  The deregulation of the cyclooxygenase (COX) pathway is implicated in several pathophysiological processes, including inflammation and cancer.  Although, its targeting with nonsteroidal antiinflammatory drugs (NSAIDs) and COX-2 selective inhibitors has been investigated for years with promising results at both preventive and and therapeutic levels, undesirable side effects and the limited understanding of the regulation and functionalities of the COX pathway compromise a more extensive application of these drugs.  Epigenetics is bringing additional levels of complexity to the understanding of basic biological and pathological processes.  The deregulation of signaling and biosynthetic pathways by epigenetic mechanisms may account for new molecular targets in cancer therapeutics.  Genes of the COX pathway are seldom mutated in neoplastic cells, but a large proportion of them show aberrant expression in different types of cancer.  A growing body of evidence indicates that epignetic alterations play a critical role in the deregulation of the genes of the COX pathway.  This review summarizes the current knowledge on the contribution of epignetic processes to the deregulation of the COX pathway in cancer, getting insights into how these alterations may be relevant for the clinical management of patients."

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The thromboxane synthase and receptor signaling pathway in cancer: an emerging paradigm in cancer progression and metastasis

“Increased cyclooxygenase (COX)-2 expression has been described in a variety of human cancers, which has focused attention on TXA2 as a downstream metabolite of the COX-2-derived PGH2.”

“It is a great importance to further determine whether and how prostanoids, such as TXA2, mediate the effects of COX-2 in cancer, potentially leading to a more targeted approach for cancer prevention and treatment."

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Cigarette smoking, cyclooxygenase-2 pathway and cancer

Cigarette smoking is a major cause of mortality and morbidity worldwide.  Cyclooxygenase (COX and its derived prostanoids, mainly including prostaglandin E2 (PGE2), thromboxane A2 (TXA2) and prostacyclin (PGI2), have well-known roles in cardiovascular disease and cancer, both of which are associated with cigarette smoking.  This article is focused on the role of the COX-2 pathway in smoke-related pathologies and cancer."

"Cigarette smoke exposure can induce COX-2 expression and activity, increase PGE2 and TxA2 release, and lead to an imbalance in PGI2 and TxA2 production in favor of the latter."

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Examination of thromboxane synthase as a prognostic factor and therapeutic target in non-small cell lung cancer

"Thromboxane synthase (TXS) metabolizes prostaglandin H2 into thromboxanes, which are biologically active on cancer cells. TXS over-expression has been reported in a range of cancers, and associated with a poor prognosis. TXS inhibition induces cell death in-vitro, providing a rationale for therapeutic intervention.  We aimed to determine the expression profile of TXS in NSCLC and if it is prognostic and/or a survival factor in the disease."

“Measurement of TXB2 levels in human plasma would be indicative of circulating levels in the blood. Thromboxane B2 levels were found to be significantly (p<0.01) higher in plasma samples taken from patients with NSCLC, relative to age-matched controls (3307 ± 189 pg/mL versus 2201 ± 317 pg/mL); n= 49 NSCLC patients, 19 cancer-free controls."

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The Role of Cyclooxygenase-2 in Cell Proliferation and Cell Death in Human Malignancies

"It is well admitted that the link between chronic inflammation and cancer ionvolves cytokines and mediators of inflammatory pathways, which act during the different steps of tumorigenesis.  The cyclooxygenases (COXs) are a family of enzymes, which catalyze the rate-limiting step of prostaglandin biosynthesis.  This family contains three members:  ubiquitously expressed COX-1, which is involved in homeostasis; the inducible COX-2 isoform, which is upregulated during both inflammation and cancer; and COX-3, expressed in brain and spinal cord, whose functions remain to be elucidated."

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Activation of the Thromboxane A2 Pathway in Human Prostate Cancer Correlates with Tumor Gleason Score and Pathologic Stage

"We investigated the potential involvement of the thromboxane A2 (TXA2) pathway in human prostate cancer (PCa). Expression of cyclooxygenase-2 (COX-2), TXA2 synthase (TXS), and TXA2 receptors (TPRs), the main actors of the TXA2 pathway, was analyzed on serial tissue sections from 46 human PCa specimens.

"The expression levels of COX-2, TXS, and TPRs were significantly higher in malignant than in corresponding nontumoral prostatic epithelial cells.  Increased immunoreactivity for these antigens was also observed in high-grade prostate intraepithelial neoplasia (HGPIN) glands.  COX-2, TXS, and TPR proteins usually displayed a coordinated overexpression pattern in PCa lesions, as assessed in serial tissue sections.  Increased levels of these proteins in the tumors were all significantly associated with higher Gleason scores and pathologic stages"

"Proteins specifically involved in the TXA2 pathway are upregulated in human PCa and their level of expression is associated with tumor extraprostatic extension and loss of differentiation.  Our study is the first to examine simultaneously all key proteins involved in the pathway including TXA2 receptors and results suggest that the TXA2 pathway may be a potential target for PCa prevention/therapy."

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Platelet activation in patients with colorectal cancer

“Enhanced platelet activation occurs in colorectal cancer patients. Permanent inactivation of platelet COX-1 by low dose aspirin might restore anti tumor reactivity.”

"Thus we aimed to address whether enhanced platelet activation, as assessed by the measurement of the urinary excretion of 11-dehydro-TXB(2) (a major enzymatic metabolite of TXB(2), occurs in patients with colorectal cancer.  In 10 patients with colorectal cancer, the urinary excretion of 11-dehydro-TXB(2) was significantly higher than in 10 controls, matched for sex, age and cardiovascular risk factors"

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Role of thromboxane A2 in the induction of apoptosis of immature thymocytes by lipopolysaccharide

"Lipopolysaccharide (LPS) causes apoptotic deletion of CD4+ CD8* thymocytes, a phenomenon that has been linked to immune dysfunction and poor survival during sepsis.  Given the abundance of thromboxane-prostanoid (TP) receptors in CD4+ CD8* thymocytes and in vitro evidence that thromboxane A2 (TXA2) causes apoptosis of these cells, we tested whether enhanced generation of TXA2 plays a role in LPS-induced thymocyte apoptosis."

"These studies indicate that TXA(2) mediates a portion of apoptotic thymocyte death caused by LPS."

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Inhibition of the arachidonic acid metabolism blocks endothelial cell migration and induces apoptosis 2

"In highly migratory subpopulations of human glioma cells differential mRNA display identified human thromboxane synthase as a strongly overexpressed motility associated gene.  Subsequently, we demonstrated that this enzyme is expressed in gliomas in vitro and in vivo and that specific thromboxane synthase inhibitors block migration, which is paralleled by a decrease of thromboxane B2 formation.  These data implicate thromboxane synthase as an important regulator of glioma motility.  Interestingly, following thromboxane synthase inhibitor treatment the decrease of motillity rates is paralleled by increased caspase activity followed by intracellular DNA fragmentation and subsequent apoptotic cell death.  Prostanoid synthesis in general appears to be important in pathogenesis and progression of cancer because these metabolites influence cellular behaviour in several ways such as mitotic activity, cellular adhesion, invasion, angiogenesis and apoptosis."

"These data suggest that inhibitors of thromboxane synthase influence migration and apoptosis in both human glioma cells and human endothelial cells. An anti-invasive treatment strategy using this class of compounds may therefore not only sensitize glioma cells to conventional treatments inducing apoptosis but may also be supported by an anti-angiogenic effect.”

“We demonstrated that this enzyme is expressed in gliomas in vitro and in vivo and that specific thromboxane synthase inhibitors block migration, which is paralleled by a decrease of thromboxane B2."

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