thromboxane-a2 and Colorectal-Neoplasms

Platelets play a central role in inflammation through their direct interaction with other cell types, such as leucocytes and endothelial cells, and by the release of many factors, that is, lipids [such as thromboxane (TX)A2 ] and proteins (a wide number of angiogenic and growth factors) stored in α-granules, and adenosine diphosphate (ADP), stored in dense granules. These platelet actions trigger autocrine and paracrine activation processes that lead to leucocyte recruitment into different tissues and phenotypic changes in stromal cells which contribute to the development of different disease states, such as atherosclerosis and atherothrombosis, intestinal inflammation and cancer. The signals induced by platelets may cause pro-inflammatory and malignant phenotypes in other cells through the persistent induction of aberrant expression of cyclooxygenase (COX)-2 and increased generation of prostanoids, mainly prostaglandin (PG)E2 . In addition to cardiovascular disease, enhanced platelet activation has been detected in inflammatory disease and intestinal tumourigenesis. Moreover, the results of clinical studies have shown that the antiplatelet drug aspirin reduces the incidence of vascular events and colorectal cancer. All these pieces of evidence support the notion that colorectal cancer and atherothrombosis may share a common mechanism of disease, that is, platelet activation in response to epithelial (in tumourigenesis) and endothelial (in tumourigenesis and atherothrombosis) injury. Extensive translational medicine research is necessary to obtain a definitive mechanistic demonstration of the platelet-mediated hypothesis of colon tumourigenesis. The results of these studies will be fundamental to support the clinical decision to recommend the use of low-dose aspirin, and possibly other antiplatelet agents, in primary prevention, that is, even for individuals at low cardiovascular risk.

Topics: Animals; Aspirin; Blood Platelets; Cardiovascular Diseases; Colorectal Neoplasms; Cyclooxygenase 2; Disease Models, Animal; Endothelial Cells; Humans; Inflammation; Leukocytes; Neoplasms; Platelet Activation; Platelet Aggregation Inhibitors; Stromal Cells; Thromboxane A2; Up-Regulation

Topics: Anti-Inflammatory Agents, Non-Steroidal; Anticarcinogenic Agents; Aspirin; Blood Platelets; Cardiovascular Diseases; Celecoxib; Colorectal Neoplasms; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Depression, Chemical; Dinoprostone; Epoprostenol; Gastric Mucosa; Gastrointestinal Hemorrhage; Humans; Incidence; Intestinal Mucosa; Isoenzymes; Lactones; Membrane Proteins; Peptic Ulcer; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Pyrazoles; Randomized Controlled Trials as Topic; Substrate Specificity; Sulfonamides; Sulfones; Thromboembolism; Thromboxane A2; Treatment Outcome

Tumor cell-induced platelet aggregation represents a critical process both for successful metastatic spread of the tumor and for the development of thrombotic complications in cancer patients. To get further insights into this process, we investigated and compared the molecular mechanisms of platelet aggregation induced by two different breast cancer cell lines (MDA-MB-231 and MCF7) and a colorectal cancer cell line (Caco-2). All the three types of cancer cells were able to induce comparable platelet aggregation, which, however, was observed exclusively in the presence of CaCl

Topics: Amino Acid Chloromethyl Ketones; Aspirin; Blood Platelets; Breast Neoplasms; Caco-2 Cells; Calcium Chloride; Colorectal Neoplasms; Female; Fibrin; Fibrinogen; Humans; Integrin alpha2; MCF-7 Cells; Platelet Activation; Platelet Aggregation; Thromboxane A2; Type C Phospholipases

Tumor growth of colorectal cancers accompanies upregulation of cyclooxygenase-2, which catalyzes a conversion step from arachidonic acid to prostaglandin H(2) (PGH(2)). Here, we compared the expression levels of thromboxane synthase (TXS), which catalyzes the conversion of PGH(2) to thromboxane A(2) (TXA(2)), between human colorectal cancer tissue and its accompanying normal mucosa. It was found that TXS protein was consistently upregulated in the cancer tissues from different patients. TXS was also highly expressed in human colonic cancer cell lines. Depletion of TXS protein by the antisense oligonucleotide inhibited proliferation of the cancer cells. This inhibition was rescued by the direct addition of a stable analogue of TXA(2). The present results suggest that overexpression of TXS and subsequent excess production of TXA(2) in the cancer cells may be involved in the tumor growth of human colorectum.

Topics: Blotting, Western; Cell Line, Tumor; Cell Proliferation; Colorectal Neoplasms; Humans; Immunohistochemistry; Oligonucleotides; Thromboxane A2; Thromboxane-A Synthase; Up-Regulation