thromboxane-a2 and Neoplasm-Metastasis

Thromboxane A(2) (TXA(2)) is a biologically active metabolite of arachidonic acid formed by the action of the terminal synthase, thromboxane A(2) synthase (TXA(2)S), on prostaglandin endoperoxide (PGH(2)). TXA(2) is responsible for multiple biological processes through its cell surface receptor, the T-prostanoid (TP) receptor. Thromboxane A(2) synthase and TP are the two necessary components for the functioning of this potent bioactive lipid. Thromboxane A(2) is widely implicated in a range of cardiovascular diseases, owing to its acute and chronic effects in promoting platelet aggregation, vasoconstriction, and proliferation. In recent years, additional functional roles for both TXA(2)S and TP in cancer progression have been indicated. Increased cyclooxygenase (COX)-2 expression has been described in a variety of human cancers, which has focused attention on TXA(2) as a downstream metabolite of the COX-2-derived PGH(2). Several studies suggest potential involvement of TXA(2)S and TP in tumor progression, especially tumor cell proliferation, migration, and invasion that are key steps in cancer progression. In addition, the regulation of neovascularization by TP has been identified as a potent source of control during oncogenesis. There have been several recent reviews of TXA(2)S and TP but thus far none have discussed its role in cancer progression and metastasis in depth. This review will focus on some of the more recent findings and advances with a significant emphasis on understanding the functional role of TXA(2)S and TP in cancer progression and metastasis.

Topics: Amino Acid Sequence; Animals; Cell Movement; Disease Progression; Humans; Molecular Sequence Data; Neoplasm Metastasis; Neoplasms; Neovascularization, Pathologic; Receptors, Thromboxane; Signal Transduction; Thromboxane A2; Thromboxane-A Synthase

Eicosanoids and the enzymes responsible for their generation in living systems are involved in the mediation of multiple physiological and pathophysiological responses. These bioactive metabolites are part of complex cascades that initiate and perpetuate several disease processes such as atherosclerosis, arthritis, neurodegenerative conditions, and cancer. The intricate role played by each of these metabolites in the initiation, progression, and metastasis of solid tumors has been a subject of intense research in the scientific community. This review summarizes some of the key aspects of eicasonoids and the associated enzymes, and the pathways they mediate in promoting tumor progression and metastasis.

Topics: Animals; Arachidonic Acids; Blood Platelets; Dinoprostone; Disease Progression; Eicosanoids; Epoprostenol; Humans; Lipoxygenase; Metabolic Networks and Pathways; Neoplasm Metastasis; Neoplasms; Prostaglandin-Endoperoxide Synthases; Thromboxane A2

Topics: Animals; Arachidonic Acids; Blood Coagulation Disorders; Fibrinolysis; Hemostasis; Humans; Mice; Neoplasm Metastasis; Neoplasms; Neoplasms, Experimental; Neoplastic Cells, Circulating; Platelet Aggregation; Thrombocytopenia; Thromboxane A2

Topics: Animals; Arachidonic Acid; Arachidonic Acids; Blood Platelets; Cathepsin B; Cathepsins; Cell Line; Cell Membrane; Epoprostenol; Humans; Mice; Neoplasm Metastasis; Neoplasms; Neoplasms, Experimental; Neoplastic Cells, Circulating; Platelet Aggregation; Prostaglandins; Pyrazoles; Pyrazolones; Rats; Serotonin; Thromboxane A2

Topics: Animals; Benzo(a)pyrene; Benzopyrenes; Carcinogens; Cell Differentiation; Cell Division; Cell Transformation, Neoplastic; Cyclooxygenase Inhibitors; DNA; Epoprostenol; Female; Hematopoietic Stem Cells; Humans; Kidney; Male; Mutagens; Neoplasm Metastasis; Neoplasms; Oxidation-Reduction; Prostaglandins; Prostaglandins D; Prostaglandins E; Prostaglandins F; Skin; Tetradecanoylphorbol Acetate; Thromboxane A2

Clinical evidence recently suggests that the regular use of aspirin is associated with a lower risk of breast cancer metastasis, but mechanisms remain unclear. Resistance to anoikis has been implicated in malignant transformation and metastasis. Here, we investigated whether aspirin might prevent breast cancer metastasis to lung by targeting anoikis resistance. Aspirin sensitized breast cancer cells to anoikis in vitro and lowered the circulating tumor cells as well as distant metastasis in vivo. Mechanistically, thromboxane A2 (TXA2) pathway was identified as the relevant molecular target for aspirin in anoikis sensitization. Upon detachment, both thromboxane A2 receptor (TP) and thromboxane A2 synthase 1 (TBXAS1) were up-regulated in metastatic breast cancer cells, conferred anoikis resistance through persistent activation of Akt, thereby facilitated breast cancer metastasis to lung. Consistently, either knockdown of TP in cancer cells or genetic deletion of TP in mice protected against lung metastasis in vivo. Collectively, TXA2 pathway plays a critical role in anoikis resistance and might serve as potential target for chemoprevention of breast cancer metastasis.

Topics: Animals; Anoikis; Aspirin; Breast Neoplasms; Cell Line, Tumor; Female; Humans; Lung; Lung Neoplasms; Mice; Neoplasm Metastasis; Neoplasms, Second Primary; Signal Transduction; Thromboxane A2

Because metastasis is associated with the majority of cancer-related deaths, its prevention is a clinical aspiration. Prostanoids are a large family of bioactive lipids derived from the activity of cyclooxygenase-1 (COX-1) and COX-2. Aspirin impairs the biosynthesis of all prostanoids through the irreversible inhibition of both COX isoforms. Long-term administration of aspirin leads to reduced distant metastases in murine models and clinical trials, but the COX isoform, downstream prostanoid, and cell compartment responsible for this effect are yet to be determined. Here, we have shown that aspirin dramatically reduced lung metastasis through inhibition of COX-1 while the cancer cells remained intravascular and that inhibition of platelet COX-1 alone was sufficient to impair metastasis. Thromboxane A2 (TXA2) was the prostanoid product of COX-1 responsible for this antimetastatic effect. Inhibition of the COX-1/TXA2 pathway in platelets decreased aggregation of platelets on tumor cells, endothelial activation, tumor cell adhesion to the endothelium, and recruitment of metastasis-promoting monocytes/macrophages, and diminished the formation of a premetastatic niche. Thus, platelet-derived TXA2 orchestrates the generation of a favorable intravascular metastatic niche that promotes tumor cell seeding and identifies COX-1/TXA2 signaling as a target for the prevention of metastasis.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Blood Platelets; Cell Line, Tumor; Cyclooxygenase Inhibitors; Female; Humans; Lung Neoplasms; Macrophages; Melanoma, Experimental; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Monocytes; Neoplasm Metastasis; Neoplasm Transplantation; Platelet Aggregation; Platelet Aggregation Inhibitors; Prostaglandins; Protein Isoforms; Thrombosis; Thromboxane A2

Liqi, an herbal preparation used in traditional Chinese medicine, has been used to treat cancer in China for centuries. We investigated the anti-tumor effects of liqi and their mechanisms in mice that had been xenografted with tumors.. Sarcoma 180 tumor, Lewis lung carcinoma, and SGC-7901 cells were implanted in BALB/c mice, C57BL/6 mice, and BALB/c nude mice, respectively. Liqi was administered to subgroups of these mice. The tumor weight and size were measured. Cell cycle analysis and T lymphocyte subsets were determined by flow cytometry. The activity of NK cells and TNF was tested using cytotoxicity assay on YAC-1 cells and L929 cells, respectively, and the activity of IL-2 was tested with an IL-2-dependent CTLL-2 cell proliferation assay. Platelet aggregation was monitored by measuring electric impedance, and the levels of thromboxane A2 (TXA2) and prostacyclin (PGI2) in blood were measured by 125I-TXB2 and 125I-Keto-PGF1alpha radioimmunoassay.. The results showed that liqi inhibited tumor growth in tumor-implanted mice and arrested the cell proliferation in the G0/G1 phase and reduced the portion of cells in S and G2/M phase for SGC-7901 cells. Liqi increased the activity of NK cells and TNF-alpha, stimulated IL-2 production and activity, and regulated T lymphocyte subpopulations. Liqi inhibited the Lewis lung carcinoma metastasis by inhibiting platelet aggregation and normalizing the balance between TXA2 and PGI2.. All these findings demonstrated that liqi has an anti-tumor effect in vivo. The mechanism may be related to immune regulation and anticoagulation effects.

Topics: Animals; Antineoplastic Agents, Phytogenic; Carcinoma, Lewis Lung; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Drugs, Chinese Herbal; Epoprostenol; Female; Interleukin-2; Killer Cells, Natural; Lung Neoplasms; Magnoliopsida; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Metastasis; Phytotherapy; Platelet Aggregation; Sarcoma, Experimental; T-Lymphocyte Subsets; Thromboxane A2; Tumor Necrosis Factor-alpha

Prostaglandin endoperoxide H synthases and their arachidonate products have been implicated in modulating angiogenesis during tumor growth and chronic inflammation. Here we report the involvement of thromboxane A(2), a downstream metabolite of prostaglandin H synthase, in angiogenesis. A TXA(2) mimetic, U46619, stimulated endothelial cell migration. Angiogenic basic fibroblast growth factor (bFGF) or vascular endothelial growth factor (VEGF) increased TXA(2) synthesis in endothelial cells three- to fivefold. Inhibition of TXA(2) synthesis with furegrelate or CI reduced HUVEC migration stimulated by VEGF or bFGF. A TXA(2) receptor antagonist, SQ29,548, inhibited VEGF- or bFGF-stimulated endothelial cell migration. In vivo, CI inhibited bFGF-induced angiogenesis. Finally, development of lung metastasis in C57Bl/6J mice intravenously injected with Lewis lung carcinoma or B16a cells was significantly inhibited by thromboxane synthase inhibitors, CI or furegrelate sodium. Our data demonstrate the involvement of TXA(2) in angiogenesis and development of tumor metastasis.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Benzofurans; Bridged Bicyclo Compounds, Heterocyclic; Chemotaxis; Dinoprost; Dinoprostone; Endothelial Growth Factors; Endothelium, Vascular; Enzyme Inhibitors; Epoprostenol; Fatty Acids, Unsaturated; Fibroblast Growth Factor 2; Humans; Hydrazines; Lung Neoplasms; Lymphokines; Male; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Neoplasm Metastasis; Neovascularization, Pathologic; Rats; Receptors, Thromboxane; Thromboxane A2; Thromboxane-A Synthase; Umbilical Veins; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

Topics: Breast Neoplasms; Humans; Neoplasm Metastasis; Thromboxane A2; Thromboxane-A Synthase

For suppression of primary tumor growth and metastatic spread, aspirin and theophylline, either alone or combined, were given daily to inbred female BN rats after sc implantation of a syngeneic nonimmunogenic tumor. Treatment with 200 mg aspirin/kg (body wt) resulted in a statistically significant regression of tumor growth as well as of the number of metastases in the lungs. Aspirin given in a lower dose (20 mg/kg) did not show significant difference from the vehicle group. Theophylline (75 mg/kg) significantly increased primary tumor growth as well as lung metastases. Inhibition of in vitro platelet aggregation, determined in whole blood taken from non-tumor-bearing animals treated with the same therapeutic regimen, was most pronounced in those groups in which tumor growth and spread were significantly retarded. However, this positive correlation between inhibition of tumor spread and platelet aggregation was not associated with a favorable balance of prostacyclin and thromboxane A2 in these animals.

Topics: Animals; Aspirin; Epoprostenol; Female; Fibrosarcoma; Neoplasm Metastasis; Neoplasm Transplantation; Platelet Aggregation; Prostaglandins; Rats; Rats, Inbred BN; Theophylline; Thromboxane A2