The Implication of Platelet Activating Factor in Cancer Growth and Metastasis: Potent Beneficial Role of PAF-Inhibitors and Antioxidants

Abstract

Cancer is one of the leading causes of death in Europe and United States. New blood vessel formation penetrating into solid tumors seems to be required for their growth and metastasis. Several protein growth factors can induce endothelial cell proliferation and angiogenesis, through signal transduction cascades that result in the production of several inflammatory mediators and lipid second messengers such as prostaglandins and Platelet Activating Factor (PAF). PAF is a potent mediator of inflammation that is implicated in several inflammatory pathological conditions such as atherosclerosis, cardiovascular and renal diseases, allergy, AIDS, cancer etc. It exerts its biological activities through G-protein-coupled receptors. The presence of PAF in the microenvironment of tumors may be due to its synthesis from circulating and / or cancer cells. Moreover, cancer cells and activated endothelial cells expose PAF-receptor on their membrane surface. PAF binding on its receptor induces several pathways that result in the onset and development of tumor induced angiogenesis and metastasis. PAF-receptor antagonists have exhibited promising results in vitro and in vivo as anti-angiogenic molecules in several cancer cells and tumors. A dietary profile reach in antioxidants and PAF-inhibitors (such as the Mediterranean Diet) may provide beneficial preventive and protective effects against development, growth and metastatic manifestations of cancer cells, through either their inhibition of PAF activity and / or its biosynthesis. The clarification of factors that may down regulate pathologically increased PAF-levels in a tumor microenvironment may also contribute to the planning of a potent nontoxic preventive and therapeutic approach against cancer.

Platelets in the immune response: Revisiting platelet-activating factor in anaphylaxis

“…16 Circulating levels of PAF are controlled by the activity of PAF-AH, 31,48 which is an important determinant of PAF's short half-life. 9,10,31 Patients with the lowest PAF-AH levels were at highest risk of severe anaphylaxis, whereby PAF-AH activity correlated inversely with PAF levels. 21,31,42 Several studies have independently confirmed that PAF-AH deficiency predisposes to severe anaphylaxis, and more rapid rates of inactivation of PAF result in milder allergic manifestations.…”

Effects of Highly Active Antiretroviral Therapy on Platelet Activating Factor Metabolism in Naïve HIV-Infected Patients: II) Study of the Abacavir/Lamivudine/Efavirenz Haart Regimen

“…However, its basic enzyme, PAF-CPT, seems to be implicated in systemic inflammatory manifestations such as cancer (7), central nervous system failure (8) and AIDS (9). On the other hand, although it is well established that the remodeling pathway is activated mainly during acute inflammatory disorders, it has also been found to be activated in systemic ones (7,9,10). Its main enzyme lyso-PAF-AT under resting conditions contributes to membrane glycerophospholipids production and membrane biogenesis, while upon acute inflammatory stimulation leads to PAF production (10).…”

Paf-Metabolic Enzymes and Paf-like Activity inL. InfantumandL. MajorPromastigotes

“…In mammals for example, the de novo pathway contributes to PAF synthesis for maintaining its basal levels under physiological conditions, while the remodeling pathway is activated under inflammatory situations. However, the de novo pathway, especially PAF-CPT, may contribute to systemic disorders such as cancer (25), central nervous system failure (26), and AIDS (27). As far as we know there has been no previous study to give sufficient data regarding the contribution of these two distinct basic PAF biosynthetic enzymes in any protozoa.…”