The Potential Role of Dietary Platelet-Activating Factor Inhibitors in Cancer Prevention and Treatment

ABSTRACT

Cancer is the second leading cause of mortality worldwide. The role of unresolved inflammation in cancer progression and metastasis is well established. Platelet-activating factor (PAF) is a key proinflammatory mediator in the initiation and progression of cancer. Evidence suggests that PAF is integral to suppression of the immune system and promotion of metastasis and tumor growth by altering local angiogenic and cytokine networks. Interactions between PAF and its receptor may have a role in various digestive, skin, and hormone-dependent cancers. Diet plays a critical role in the prevention of cancer and its treatment. Research indicates that the Mediterranean diet may reduce the incidence of several cancers in which dietary PAF inhibitors have a role. Dietary PAF inhibitors such as polar lipids have demonstrated inhibitory effects against the physiological actions of PAF in cancer and other chronic inflammatory conditions in vitro and in vivo. In addition, experimental models of radiotherapy and chemotherapy demonstrate that inhibition of PAF as adjuvant therapy may lead to more favorable outcomes. Although promising, there is limited evidence on the potential benefits of dietary PAF inhibitors on cancer prevention or treatment. Therefore, further extensive research is required to assess the effects of various dietary factors and PAF inhibitors and to elucidate the mechanisms in prevention of cancer progression and metastasis at a molecular level.

Introduction

Cancer is a major public health concern worldwide, although cancer death rates have decreased by 26% over the last 2 decades (1). Despite this decline, cancer remains a major cause of mortality. At least 1 in 2 people will develop a form of cancer within their lifetime in Ireland and the United Kingdom (2, 3). Cancer is not a single disease, but a collection of related diseases that act through similar but distinctive inflammatory pathways (4). It is typically considered a disease of old age, but with increasing longevity the incidence of most cancers is increasing (5). Known risk factors fail to fully explain the patterns of cancer development. Cancers arise from accumulation of genetic mutations, either inherited or acquired, that lead to dysregulation of cell division mechanisms to induce uncontrolled proliferation. Proliferation is accompanied by low-grade inflammation mediated by several bioactive molecules such as platelet-activating factor (PAF) that have an integral role in the tumor microenvironment, particularly in hormone-dependent cancers (6, 7).

Cells generally regulate growth by decreasing their production rate or apoptosis, but uncontrolled growth can lead to tumor development and, eventually, symptomatic manifestations of cancer. In general, a healthy immune system can eradicate neoplastic cells as soon as they appear. In cancer, the immune system fails to eradicate the cancer cells and proliferative growth occurs (5). Lifestyle, dietary, and environmental factors account for 95% of cancers, whereas genetic factors account for 5% (8, 9). It would seem that a large proportion of cancers are preventable by diet and lifestyle modification; however, the association between nutrition and cancer is bidirectional and exceedingly complicated (5). When cancerous cells develop, nutrition may exert significant effects on the growth and involution of a tumor (5). Several studies have reported evidence of an association between individual nutrients or foods and the risk of cancer; some foods have been known to induce or protect against mutagenic effects and improve the efficiency of the immune system (5).

Inflammation is a protective physiological process of the innate immune system that occurs in response to tissue injury (10). Inflammation can be induced by both acute and chronic infections, physicochemical agents, diet, and lifestyle, which are causative and promotive of cancer (11). In some cancers, inflammatory conditions precede the development of malignancy; in others, oncogenic changes drive a tumor-promoting inflammatory milieu. Regardless of the origin of inflammation, both processes aid in proliferation and survival of malignant cells, angiogenesis, and metastasis; subvert adaptive immunity; and alter responses to hormones and chemotherapeutic agents (12). Epidemiological studies have demonstrated that systemic inflammation predisposes individuals to various types of cancer (13). It is estimated that underlying infections and inflammatory responses are linked to 15–20% of all cancer-related deaths globally (14). Cancer development because of systemic inflammation is triggered by several factors such as autoimmune diseases [e.g., inflammatory bowel disease is associated with colon cancer (15)], microbial infections [e.g., Helicobacter pylori is associated with gastric mucosal lymphoma and gastric cancer (16)], and inflammatory condition of unknown origin [e.g., prostatitis is associated with prostate cancer (17)]. In addition, nonsteroidal anti-inflammatory treatments decrease the incidence of cancers and mortality rates (18–21).

PAF is a potent proinflammatory phospholipid mediator that is implicated in the development of cancer and other inflammatory conditions such as cardiovascular disease (22). PAF plays a major role in angiogenesis, thrombosis, carcinogenesis, and metastasis (10, 23). However, several dietary PAF inhibitors, particularly found in foods in the Mediterranean diet, have been identified that may inhibit the physiological actions of PAF (24), thus preventing the onset of inflammatory conditions such as cancer. In this review, we explore the potential role of dietary PAF inhibitors considering the most recent literature available.

Current Status of Knowledge

PAF structure, function, signaling, and metabolism

Phospholipid mediators, including prostaglandins and PAF, are present in several biological pathways of inflammatory diseases, including cardiovascular disease and cancer (25, 26). The classical PAF structure (1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine; Figure 1) is a prominent member of a family of molecules known as PAF-like lipids (27), which have semi-similar or non-similar structures with similar biological activities (22, 23, 28). PAF is synthesized by various cells including neutrophils, endothelial cells, platelets, macrophages, and monocytes (10). PAF is a potent proinflammatory mediator that affects various cells and pathological processes (10) and is implicated in angiogenesis, thrombosis, carcinogenesis, and metastasis (10, 23). PAF and its homologous lipid molecules are specific, structurally defined ligands that exclusively bind and induce their biological activities through a unique 7-transmembrane G-protein-coupled receptor known as the PAF-receptor (PAF-R) with exceptionally high affinity (29–31). Engagement of the PAF-R by PAF or PAF-like lipids triggers an assortment of intracellular signaling cascades. This initiates biochemical mechanisms and functional responses of PAF-R-bearing cells, which then initiate or amplify inflammatory processes (32). The PAF-R is expressed on the surface of various mammalian cells, including leukocytes, platelets, macrophages, and endothelial cells (33, 34). PAF-induced inflammatory processes are intensely involved in initiation and progression of various cancers (22, 23, 34, 35). Although PAF-like lipids can bind to the PAF-R and initiate downstream effects, their effects are less severe than activation by PAF itself (36).

FIGURE 1.

The structure of platelet-activating factor.

PAF can activate cells in subpicomolar concentrations (37), thus the physiological concentrations of PAF are tightly regulated by the PAF metabolic enzymes. Dysregulation of PAF metabolism leads to an increase in PAF that exacerbates the inflammatory response. PAF is inactivated and catabolized by removal of the acetyl-group at the sn-2 position of the phospholipid molecules by PAF-specific acetylhydrolase (PAF-AH, EC 3.1.1.47) to form lyso-PAF (38). Lyso-PAF lacks the activity of PAF and is cytotoxic in nature. Lyso-PAF is then reconverted into PAF or other phospholipids by introduction of an acetyl or acyl group to the sn-2 position; hence, the biological cycle of PAF is spontaneously regulated (39). The PAF-AH enzymes are a class of enzymes with the capacity to indirectly terminate PAF-induced signaling pathways by directly reducing either enzymatic or oxidative upregulation of increased PAF (23). Thus administration of recombinant PAF-AH has exhibited beneficial effects by downregulating PAF concentrations (33, 40, 41).

The primary role of PAF in physiology is to mediate cellular function and cell-cell interactions, which are critical in both physiologic and pathologic processes (42). The role of PAF is best characterized by its involvement in mediation of normal inflammatory responses and of blood circulation, blood pressure, and regulation of coagulation responses (22, 42). However, it also exerts signaling functions in glycogen degradation, reproduction, fetal implantation, exocrine gland function, lung maturation, initiation of parturition, and brain function (22). PAF is synthesized by many cells on demand, in response to specific stimuli, including cytokines, endotoxins, Ca²⁺ ionophores, and PAF itself (25). The biosynthesis of PAF is accomplished by 2 distinctive enzymatic processes: the de novo and the remodeling pathways (43–45). The first biosynthetic pathway is the remodeling pathway, whereby phospholipase A₂ converts the ether analogues of phosphatidylcholine to lyso-PAF, which is then acetylated to PAF by isoforms of acetyl-CoA and lyso-PAF acetyltransferases (Lyso-PAF ATs, EC 2.3.1.67), notably lysophosphatidylcholine acyltransferase (LPCAT)1 and LPCAT2 (46, 47). Evidence suggests that production of PAF by LPCAT2 is activated under inflammatory conditions, whereas the role of LPCAT1 is still under investigation, as it is calcium-independent and does not seem to engage in inflammatory processes (47).

The second PAF biosynthetic pathway is the de novo pathway, which initiates with acylation of 1-O-alkyl-sn-glycero-3 phosphate by 1-O-alkyl-sn-glycero-3 phosphate acetyl-CoA acyltransferase, followed by the sequential actions of a phosphohydrolase and the specific activity of dithiothreitol-insensitive CDP-choline: 1-alkyl-2-acetyl-sn-glycerol cholinephosphotransferase (PAF-CPT, EC 2.7.8.2), which incorporates CDP-choline into 1-O-alkyl-2-acetyl-glycerol to form PAF (44). PAF-CPT and lyso-PAF-acetyltransferase both catalyze the final steps in each biosynthetic pathway and exhibit a basic regulatory role in PAF production. It is hypothesized that the de novo pathway is responsible for endogenous PAF production to maintain physiological concentrations, whereas the remodeling route leads to production of PAF in response to inflammatory stimuli and is the main pathway involved in inflammatory cascades (23, 48). A simplified schematic of the remodeling pathway is presented in Figure 2. Long-term induction of PAF-CPT gradually increases systemic PAF with related consequences. Furthermore, PAF-CPT activity contributes to systemic inflammation and age-related malfunctions of the central nervous system and cancer (23, 49), whereas its inhibition has demonstrated beneficial outcomes in several chronic disorders (22, 50–52).

FIGURE 2.

The remodeling pathway of PAF and lyso-PAF biosynthesis. PAF-AH converts active PAF to the inactive lyso-PAF by the loss of an acetate group at the sn-2 position. Lyso-PAF AT converts lyso-PAF back to the active PAF by the reincorporation of an acetate back to the sn-2 position. Acetyl-CoA, acetyl coenzyme A; AT, acetyltransferase; Lyso-PAF, lyso-platelet-activating factor; PAF, platelet-activating factor; PAF-AH, platelet-activating factor acetylhydrolase.

PAF and cancer

Angiogenesis and PAF

The mechanism of angiogenesis, neoangiogenesis, and carcinogenesis is complex and not completely understood, but PAF plays a significant role (34). Established tumors can increase in diameter by 1–2 mm, before their growth is inhibited by insufficient nutrient and oxygen supply, therefore the tumor can remain dormant for several years because of the balance between proliferation and apoptosis. In this state, tumors are capable of further intrusion into proximal tissues where they can form neoplastic blood vessels driven by the hypoxic microenvironment. This process precedes metastasis and is known as neoangiogenesis, which is a promising target for cancer treatment (19–21, 53).

Angiogenesis initiates through activation of endothelial cells on pre-existing blood vessels by cancer cells. Chronic inflammatory manifestations facilitate endothelial activation and may induce cancer cells to secrete angiogenic factors such as PAF (23). These cancer cells produce growth factors and cytokines that link to their reciprocal receptors in the endothelium, which trigger membrane signaling pathways that stimulate the vessel. These cytokines can induce further production of PAF and expression of the PAF-R, which induces the production of more cytokines in a cyclic manner (23, 34). The activated endothelial cells also degrade the extracellular matrix through production of metalloproteases and serine proteases. The endothelial cells express adhesion molecules that create a microenvironment, which enhances the migration and proliferation of endothelial cells from pre-existing vessels through microtubules that join the circulatory system. These newly established microtubules create a functional tumor microenvironment that can continue to proliferate (53, 54). Adhesion molecules also cause cancer cells to attach to platelets and endothelial cells in newly synthesized blood vessels, which enables metastasis and subsequent colonization of other tissues (23, 54).

Angiogenic factors including cytokines, growth factors, and their specific receptors, are implicated in induction of tumor neoangiogenesis (55–57). However, targeting of single growth factors or their corresponding receptors has not been successful because of the ability of cancer cells to reprogram and produce other growth factors. For example, when targeting vascular endothelial growth factor (VEGF), tumors adapt by producing basic fibroblast growth factor instead of VEGF, which induces the proliferation and migration of endothelial cells (58). Therefore, bi-specific antiangiogenic inhibitors have been developed that have the ability to inhibit >1 receptor, such as SU-6668 (58) or sunitinib (59).

However, endothelium activation and the cascades induced by growth factors share common pathways, which are related to production and release of lipid mediators such as PAF and arachidonate (58). When PAF is released in the tumor microenvironment it can affect the endothelial cells in an autocrine or paracrine mode, which can also affect platelets and cancer cells (23). Increased circulating PAF initiates a rapid inflammatory response that results in increased permeability of the endothelium and other significant biological responses (23), such as: 1) increased expression of PAF-R and production of PAF by endothelial cells, platelets, and cancer cells; 2) induction of cellular proliferation; 3) prostaglandin production via cyclooxgenase-2 activation; and 4) expression of metalloproteases and serine proteases through activation of Janus tyrosine kinase signaling cascades and signal transducers and activators of transcription, leading to extracellular matrix degradation. These effects are crucial to the processes of angiogenesis and metastasis, which are discussed in the next section.

PAF, metastasis, and cancer

Several studies have indicated that PAF may be produced and PAF-R may be expressed on cell membranes of activated endothelium and/or cancer cells in the tumor microenvironment (22, 34, 49, 60–62). Cytokines and growth factors such as VEGF, fibroblast growth factor, and TNF-α induce PAF production (54, 63). PAF produced by these cytokines further stimulates production of inflammatory cytokines, which promotes metastasis through activation of the NF-κB pathway via toll-like receptors (64–66). The NF-κB pathway controls expression of proinflammatory cytokines (TNF-α, fibroblast growth factor, IL-1, IL-2, and IL-6), chemokines (IL-8, macrophage inflammatory protein-1α, and monocyte chemoattractant protein-1), adhesion molecules (intercellular adhesion molecule, vascular cell adhesion molecule, and E-selectin), acute-phase proteins, immune receptors, growth factors, and inducible enzymes (VEGF, cyclooxygenase-2, matrix metalloproteinases, inducible nitric oxide synthase), which are all implicated in inflammation, angiogenesis, or in tumor cell or endothelial cell proliferation, adhesion, migration, and invasion (67). It has been reported that PAF induces NF-κB activation in intestinal epithelial cells by enhancing IκBα (nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha) phosphorylation (68). Furthermore, reactive oxygen species activate protein kinase CK2 (formally known as casein kinase II) via p38, which in turn induces NF-κB activation. Subsequently, PAF, LPS, and TNF-α increase pulmonary tumor metastasis through induction of a reactive oxygen species/p38/CK2/NF-κB pathway (66). The interactions and relations between many of these inflammatory molecules and their effects in relation to PAF and cancer are presented in Figure 3.

FIGURE 3.

A schematic of the key biological events surrounding PAF-induced inflammation in the tumor microenvironment, angiogenesis, and metastasis. These biological events are inextricably linked and exacerbate in inflammatory conditions. aFGF, acidic fibroblast growth factor; bFGF, basic fibroblast growth factor; COX-2, cyclooxygenase-2; HGF, hepatocyte growth factor; ICAM-1, intercellular adhesion molecule-1; IGF-1, insulin-like growth factor 1; iNOS, inducible nitric oxide synthase; MCP-1, monocyte chemoattractant protein-1; MIP-1α, macrophage inflammatory protein; MMPs, matrix metalloproteinases; PAF, platelet-activating factor; PAF-R, platelet-activating factor-receptor; PDGE, platelet-derived growth factor; ROS, reactive oxygen species; RNS, reactive nitrogen species; VCAM, vascular cell adhesion molecule; VEGF, vascular endothelial growth factor.

PAF overexpression correlates with malignancy of various tumors (34, 54). Elevated levels of PAF and PAF-R transcripts 1 and 2 are evident in hepatocellular carcinoma specimens in comparison to noncarcinoma specimens (69). In breast cancer, cells that express a higher ability to synthesize and release PAF are more malignant with a higher capability to metastasize, and also express more PAF-R on their membranes (54). PAF may be involved in breast cancer initiation as well as promotion by enhancing the migratory ability of cancer cells mediated via phosphoinositide 3-kinase and/or the Jun N-terminal kinase pathway, and is independent of the mitogen-activated protein kinase pathway (26). PAF also induces the transformation of nontumorigenic cells (26). PAF overexpression in pancreatic cancer leads to cell proliferation and tumorigenesis. It has also been shown that PAF ectopic activation of the phospholipid-regulating mitogen-activated protein kinase signaling pathway via activation of the late endosomes/lysosomal adaptor, MAPK and mammalian target of rapamycin activator 3 complex pathway, caused neoplasia in pancreatic cancer. Thus, PAF may be a biomarker for targeted therapy in pancreatic cancer (70).

PAF seems to be heavily implicated in digestive cancers. Concentrations of PAF-AH and phospholipase A₂ are elevated in patients with colon cancer (71), and elevated PAF has been observed in metastatic colon cancer (72, 73). Likewise, PAF-R is strongly expressed in esophageal squamous cell carcinoma, PAF-R levels are positively correlated with malignancy in esophageal squamous cell carcinoma (74), and lysophosphatidylcholine acyltransferase 1 overexpression promotes oral squamous cell carcinoma progression via enhanced biosynthesis of PAF (75). Interestingly, PAF-R expression is also increased in patients with gastric adenocarcinoma, which is associated with organ metastasis. However, increased PAF-R expression was also significantly associated with higher tumor differentiation, smaller tumor size, absence of lymph nodes, and low tumor histopathological stage in adenocarcinoma patients who had significantly longer survival times compared to those with low PAF-R expression (76). These occurrences seem contradictory considering that increased PAF-R expression is correlated with malignancy in esophageal squamous cell carcinoma but smaller tumor size in gastric adenocarcinoma. However, the morphological features such as, for example, smaller tumor size, that correlate with high PAF-R expression are characteristic features of gastric cancer. These features are the reason that gastric cancer is considered slow and progressive (77), thus leading to longer patient survival (78); however, it is important to note that gastric cancer is still malignant and the third leading cause of cancer-related death worldwide (77). It may also be the case that the high expression of PAF-R is a characteristic of gastric cancer, because high expression of the PAF-R may induce apoptosis (79), thus explaining why gastric cancers are slow to develop and grow, but are still lethal as they can metastasize to other organs (77). Therefore, expression of the PAF-R in gastric cancer may have some prognostic value, but the role of PAF and the PAF-R in digestive cancers is complex and further extensive research is necessary.

PAF is present in human meningiomas where it is believed to act on tumor growth by altering the local angiogenic and/or cytokine networks as previously seen in human breast cancer and colorectal cancer (80). A recent study has indicated that PAF can alter the permeability of the blood-brain barrier (81), this may prove important for central nervous system inflammatory disorders, including cancer. PAF and PAF-R may also have a major role in prostate cancer (82).

UV radiation is the primary cause of nonmelanoma skin cancer and UV exposure is implicated in the induction of melanoma, the most severe form of skin cancer. As well as being carcinogenic, UV light is immunosuppressive (83). PAF and PAF-like lipids are produced by epidermal keratinocytes in response to UVB radiation (84, 85) and are linked to systemic immune suppression (35, 86), which is a major risk factor for skin cancer development (87). Although PAF-like lipids are produced and involved in the inflammatory milieu, they possess only 10% of the potency of native PAF (36). Dermal mast cell migration from the skin to the draining lymph nodes plays a crucial role in activating immune suppression. PAF produced by UV-induced keratinocytes upregulates the expression of C-X-C chemokine receptor type 4 on the surface of mast cells (88). In addition, PAF upregulates CXCR4 ligand expression on lymph node cells, therefore directing mast cell migration from the skin to the draining lymph node, where mast cells secrete IL-10 and suppress the immune response (89). PAF synthesis by keratinocytes in response to UVB radiation is enhanced by overexpression of the PAF-R and is inhibited by PAF-R antagonists such as WEB 2086 (90). In addition, in B16F10 murine melanoma PAF-R antagonists were shown to decrease lung metastasis (91). Therefore, inhibition of the actions of PAF by the action of PAF-R antagonists could be a therapeutic target for prevention of some cancers.

It was previously reported that PAF may not have a role in some human lung cancers (92). However, murine models have revealed that PAF-R antagonists can augment tumor growth and lung cancer metastasis in a PAF-R-dependent manner (93). Although PAF is critical in some cancers, it seems that there is no conclusive evidence to suggest PAF is implicated in all cancers, such as thyroid cancer (94). However, there is limited research regarding the role of PAF in various other cancers. Evidence for the role of PAF in several cancers is presented in Table 1.

TABLE 1.

Role of PAF in various cancers¹

Cancer type	Role of PAF and PAF-R	Reference
Breast cancer cells	Increased PAF production and PAF-R expression promotes migration, proliferation of tumor cells, and neoangiogenesis	(26, 54)
Colon cancer	PAF-AH and PLA2 are elevated in patients. Metastatic colon cancer cells exhibit elevated PAF	(71–73)
ESCC	PAF-R is overexpressed in ESCC and correlated with malignancy. Lysophosphatidylcholine acyltransferase 1 overexpression promotes ESCC progression via enhanced biosynthesis of PAF	(74, 75)
Gastric cancer	PAF-R expression is increased in patients with gastric adenocarcinoma and is associated with higher tumor differentiation, smaller tumor size, absence of lymph node and organ metastasis, and low tumor histopathological stage. Patients with elevated PAF-R expression have significantly longer survival times compared to those with low PAF-R expression	(76)
HCC	Elevated PAF and PAF-R involved in the angiogenic response in HCC	(69)
Lung cancer	The role of PAF in lung cancer is not clear; PAF-R antagonists can augment tumor growth and lung cancer metastasis in a PAF-R-dependent manner in murine models. In a double-blind study, nutritional status and inflammatory markers were improved in 40 patients with stage III non-small cell lung cancer during multimodality treatment who had taken ω3 PUFA supplements. ω3 PUFA supplementation may possess anticachectic effects and reduce inflammatory markers during chemotherapy treatment of advanced inoperable non-small cell lung cancer	(93, 95, 96)
Pancreatic cancer	PAF overexpression in pancreatic cancer leads to cell proliferation and tumorigenesis through mitogen-activated protein kinase signaling	(70)
RCC	CD154-induced PAF production and PAF-R expression stimulate cell proliferation motility, growth, and dissemination of RCC	(97)
Skin cancers—melanoma and nonmelanoma	PAF and PAF-like lipids are produced by epidermal keratinocytes in response to UVB radiation and are linked to UVB-induced systemic immune suppression. PAF synthesis is enhanced by overexpression of the PAF-R	(35, 84–86, 90)

¹ESCC, esophageal squamous cell carcinoma; HCC, hepatocellular carcinoma; PAF, platelet-activating factor; PAF-AH, platelet-activating factor acetylhydrolase; PAF-R, platelet-activating factor-receptor; PLA₂, phospholipase A₂; PUFA, polyunsaturated fatty acids; RCC, renal cell carcinoma.

Notably, PAF may exhibit beneficial effects on some cancer cells. For example, it was shown that loss of the PAF-R in mice augmented PMA-induced inflammation and chemically induced carcinogenesis, indicating that the PAF-R may suppress PMA-induced inflammation and neoplastic development in response to chemically induced carcinogenesis (98). Furthermore, elevated expression of the PAF-R can enhance cell apoptosis through activation of NF-κB (79, 99), and through the dual action of the NF-κB pathway in malignancy and apoptosis via the immune response (100), as extensively reviewed by Tsoupras et al. (23).

Several conclusions can be drawn from the relation between PAF, PAF-R, and cancer. It is unknown how PAF becomes present in the tumor environment initially. It is proposed that activated endothelial cells, leukocytes, and/or platelets may synthesize PAF, which can activate other cells to produce more PAF in an autocrine, paracrine, or juxtacrine way (23). Cancer cells themselves synthesize PAF, which may induce neighboring cells to synthesize PAF in a similar fashion (23). Therefore, as cancer cells have the autonomy to produce PAF and express PAF-R on their membrane, PAF plays an integral role in cancer malignancy (34). Although PAF is not the only mediator of inflammation involved in the complex inflammatory mechanisms of cancer, it is one yet to be fully explored or elucidated and deserves further attention for the development of therapeutic measures.

Types of PAF inhibitors and cancer

Several molecules, both of synthetic (101, 102) and natural (10) origins, have been described that demonstrate inhibitory effects against PAF-induced biological activities. These molecules act directly through antagonistic/competitive displacement of PAF in the PAF-R or through other indirect mechanisms. These indirect mechanisms have not yet been fully elucidated; however, it is proposed that changes in the lipid rafts and membrane microenvironment of the PAF-R and/or the antioxidant capacity of these molecules may be responsible (10, 23). In addition, some PAF inhibitors such as dietary polar lipids demonstrate beneficial effects against PAF metabolism by downregulating PAF synthesis and upregulating PAF catabolism (22, 103, 104).

Many studies have focused on synthetic PAF inhibitors that modulate PAF metabolism (52), such as rupatadine, which is used in treatment of inflammatory conditions such as allergies (105–107) or cisplatin for cancer treatment (108). In addition, natural PAF-R antagonists have been described; the most well-known being ginkgolides A and B (109). Ginkgolides are a family of molecules derived from Ginkgo biloba tree (109), which can modulate PAF metabolism in chronic diseases (50). In cancer, ginkgolide B has exhibited beneficial effects through inhibiting tumorigenesis and angiogenesis in azoxymethane/dextran sulfate sodium-induced colitis-associated cancer in mice (110), in which tumor number and load was reduced, whereas serum PAF-AH activity and thus PAF catabolism was increased and VEGF expression and microvessel density decreased after treatment with ginkgolide B. The effects of various PAF-R antagonists including BN-50730 and WEB-2170, which exhibit anticancer effects through their anti-PAF activities (23, 52, 111, 112) were reviewed by Tsoupras et al. (23).

Conventional cancer treatment and PAF-R antagonists

Traditional cancer treatment involves chemotherapy and radiation treatments. To date there are no PAF- or PAF-R-related cancer treatments available. Many in vitro and in vivo studies indicate that co-treatment with PAF-R antagonists and chemotherapeutic drugs may have better antineoplastic effects. It has been shown that PAF-R-dependent pathways are activated during experimental tumor growth, altering the tumor microenvironment, and cause polarization of macrophages, which favors tumor growth; combination therapy including a PAF-R antagonist (WEB-2170) and a chemotherapeutic drug (dacarbazine) reduced tumor volume in mice, and the survival of tumor-bearing animals improved when both treatments were used in combination in a murine model of melanoma (113). Another study treated a SKmel37 human melanoma cell line with cisplatin, which led to increased expression of PAF-R and its accumulation. In the presence of exogenous PAF, melanoma cells were significantly more resistant to cisplatin-induced cell death. However, use of a PAF-R antagonist, WEB-2086, demonstrated inhibition of PAF-R-dependent signaling pathways and exhibited chemosensitization of melanoma cells in vitro. In the same study, nude mice that were inoculated with SKmel37 cells and treated with cisplatin and WEB-2086 showed significant decreases in tumor growth compared to mice with only 1 treatment agent and controls. These results suggest that activation of the PAF-R pathways may support tumor survival and tumor repopulation in melanomas (114). Similarly, an in vivo study demonstrated that cisplatin induced an increase of PAF-R expression in SKOV-3 and CAOV-3 human ovarian cancer cell lines. The upregulation of PAF-R by cisplatin correlated with a time-dependent accumulation of hypoxia-inducible factor 1-alpha and NF-κB in the nucleus. Inhibition of PAF-R by ginkgolide B sensitized the ovarian cells to cisplatin treatment through blockade of the extracellular signal-regulated kinase and PI3K pathways downstream of activated PAF-R. Furthermore combined treatment of ovarian cancer cells with ginkgolide B and cisplatin reduced tumor growth (115). PAF-R antagonists may also treat intestinal mucositis as demonstrated in murine models, which is a common side effect of cancer chemotherapy (116).

Radiotherapy is important for treatment of many cancers. Ionizing radiation is used to selectively kill tumor cells and spare normal tissue. Ionizing radiation causes significant damage to a wide variety of targets in tumor cells but it mainly causes disruption to DNA and/or DNA replication or repair mechanisms, which are key to radiation-induced cell death (117). However, ionizing radiation can also cause generation of reactive oxygen species (118). Pro-oxidative stressors can suppress host immunity through their ability to generate oxidized lipids and PAF-R agonists. Sahu et al. have shown in radiation exposure of multiple tumor cell lines in vitro and in vivo, along with human subjects undergoing radiation therapy for skin tumors, that all generate PAF-R agonists, which can induce several proinflammatory signaling pathways. Their structural analysis revealed that radiation therapy leads to nonenzymatic production of multiple oxidized glycerophosphocholines, which are PAF-R agonists, and PAF itself (119). In a murine melanoma tumor model, irradiation of 1 tumor led to alterations in nontreated tumors in a PAF-R-dependent process that could be blocked by cyclooxygenase-2 inhibitor. Therefore, the occurrence of PAF-R agonists as a byproduct of radiation therapy could result in treatment failure. Similar results were observed in a recent study which demonstrated that PAF-like molecules with agonistic properties are generated by radiotherapy, and that their action on tumor cells protects them from radiation-induced cell death by acting on macrophages. Such PAF-like molecules stimulate tumor growth through immunosuppression. Therefore, the association of radiotherapy with the PAF-R antagonists represents a promising strategy for improving the efficacy of radiotherapy (120).

In a series of experiments by da Silva-Junior et al. (121), cervical cancer patients who underwent radiotherapy had a significantly higher expression of PAF-R. In addition, cervical cancer-derived cell lines (C33, SiHa, and HeLa) and squamous carcinoma cell lines (SCC90 and SCC78) express higher levels of PAF-R mRNA and protein than immortalized keratinocytes. γ-Radiation also increased PAF-R expression and induced PAF-R ligands and prostaglandin E₂ in these tumor cells. Inhibition of PAF-R activities with the antagonist CV3938 before irradiation inhibited prostaglandin E₂ and increased tumor cell death. Similarly, human carcinoma cells transfected with PAF-R were more resistant to radiation compared to those lacking the receptor. Prostaglandin E₂ production by irradiated cells transfected with PAF-R was also inhibited by CV3988. These results show that irradiation of carcinoma cells generates PAF-R ligands and higher PAF-R expression that protects tumor cells from death, and suggest that a combination of radiotherapy with PAF-R antagonists could be a promising strategy for cancer treatment.

Nutrition and Cancer

Links between diet and cancer have been substantiated in several epidemiological studies (122). The World Cancer Research Fund International/American Institute for Cancer Research has collated and summarized published research on the relations among cancer prevention and survivorship and diet, nutrition, and physical activity. Its Second Expert Report was published in 2007 (123) and the World Cancer Research Fund International/American Institute for Cancer Research have since been publishing cancer prevention research from around the world. It is clear from these reports that a healthy diet could be key in prevention of cancer. In fact, they have estimated that for the 13 most common cancers, at least 29% of cases in the United States and the United Kingdom could be prevented by adhering to a healthy diet and lifestyle (124), if the research can be translated to preventive interventions, and the literature cited is valid (125).

Nutrition and cancer prevention: inhibiting inflammation

Carcinogenesis is a multimechanism process consisting of initiation, promotion, and progression phases. Diet can affect any of these phases, but an efficacious strategy for dietary chemoprevention would be intervention during the promotion phase because of the associations with inflammation. The tumor-promotion process requires sustained exposure to agents that stimulate growth and inhibition of apoptosis of initiated cells in the absence of antipromoters (126).

A maladaptive diet and lifestyle are key modifiable risk factors for prevention of systemic inflammation (127). The majority of tumor-promoting conditions and agents, reversibly, inhibit cell-cell communication. However, antioxidants and anti-inflammatory agents are capable of ameliorating the effects of tumor promotors on cell-cell communication (126). Inflammatory mediators such as PAF are key molecules in cell-cell communication (10). Research demonstrates that many nutrients can modulate the immune response to act against cancerous cells, but not against adjacent cells (126, 128, 129). Certain dietary components have been proposed as possible PAF-R antagonists that may ameliorate PAF-related neoplastic mechanisms (23). However, lifestyle factors are also important. For example, smoking directly affects metastatic disease via inhibition of PAF-AH, resulting in accumulation of PAF-like agonists and an increase in cell motility in breast cancer cells (130)

PUFA and polar lipids in PAF-related cancer prevention

Many nutrients seem to possess antioxidant, antiproliferative, and antiangiogenic properties that prevent the spread of cancer (23, 131). Several foods and supplements contain antioxidants that exhibit antineoplastic activities that function far beyond antioxidant activity alone, but also operate through direct inhibition of PAF activity and downregulation of PAF levels (23). Long-chain ω3 PUFA possess multiple anti-inflammatory properties including reduction in the synthesis of proinflammatory eicosanoids, reduction of leukocyte and platelet-adhesive endothelial interactions, inhibition of inflammatory gene expression, and stimulation of glutathione production, which can decrease oxidative injury (132, 133). Immunonutritional support in cancer treatment may modulate the immune response and improve cancer patient outcomes (133); in a double-blind study, nutritional status and inflammatory markers were improved in 40 patients with stage III non-small cell lung cancer during multimodality treatment who had taken ω3 PUFA supplements (95). Evidence suggests that ω3 PUFA supplementation may be useful in anticachectic therapy, and may reduce the amounts of C-reactive protein and IL-6 during chemotherapy treatment of lung cancer (96). In a similar study, pancreatic cancer patients were supplemented with low doses of ω3 PUFA fish oil or marine phospholipids for 6 wk. Both supplements resulted in significant weight stabilization at very low doses (300 mg/d), an improved appetite, and quality of life. The phospholipid-based supplement was better tolerated than the fish oil supplement. Furthermore, both supplements increased the patient's ω3 concentration of plasma triglycerides and phospholipids (134).

Similar outcomes were observed in patients with various tumors, who suffered tumor-associated weight loss (135). It has been concluded that ω3 PUFA supplementation during chemotherapy improves patient outcomes related to tolerability, regardless of the chemotherapy used (136). The mechanisms by which ω3 PUFA improves patient chemotherapy tolerability are unclear (136). Positive outcomes in patients’ health may result from the anti-inflammatory properties of the marine phospholipids and ω3 PUFA, which have both demonstrated anti-PAF activities and the effects of which have recently been reviewed (10). The benefits of marine PUFA supplements as an adjuvant to chemotherapy have been comprehensively reviewed (136, 137).

Systemic inflammation is implicated in atherosclerosis (22, 127) and glomerulosclerosis (138). Because atherosclerosis and glomerulosclerosis share common features with cancer angiogenesis and metastasis, several molecules with pleiotropic activities such as antiatherogenic and antithrombotic molecules including warfarin, statins, vitamin D analogues, and nonsteroidal anti-inflammatory molecules such as cyclooxgenase-2 inhibitors have demonstrated beneficial effects against cancer (139, 140). Several of these treatments exhibit inhibitory effects against the bioactivities of PAF and its biosynthetic enzymes (52). Polar lipids (phospholipids, sphingolipids, glycolipids, and phenolic lipids) that are widely distributed in foods have the capacity to inhibit the biological actions of PAF (10). These lipids are structurally specific and bind to the PAF-R directly or indirectly (10). Polar lipid extracts from marine and dairy sources (10, 103, 127, 141) have demonstrated the ability to inhibit PAF-induced platelet aggregation in animal and human platelets in cardiovascular-related studies. These studies investigate the potential of various food lipids to inhibit the binding of PAF to the PAF-R through direct antagonistic or competitive binding. Observing the inhibition of PAF-induced platelet aggregation by dietary polar lipids allows for identification of PAF-R antagonists. These studies identified phosphatidylcholine and phosphatidylethanolamine derivatives as the biologically active polar lipids against the actions of PAF (10, 142), which also had the ability to modulate PAF metabolism, with beneficial outcomes against atherosclerosis (10, 51, 104, 143).

Therefore, it is logical to propose that molecules that can inhibit the binding of PAF to PAF-R and its subsequent signaling pathways, may possess the same beneficial biological activities in cancer. Certainly in vitro and in vivo studies indicate that polar lipid compounds can affect PAF metabolism (104) and have antiproliferative effects against human ovary and colon cancer cells (144), although not all of the mechanisms are fully elucidated. In particular, phosphatidylcholine may induce apoptosis (145) and inhibit DNA synthesis in colon cancer (146). Furthermore, polar lipids and phenolic compounds in red and white wine have also demonstrated antiproliferative effects in prostate cancer cells (147). These effects were attributed to their antioxidant effects, as the PAF pathway was not assessed.

Dairy products are consumed in moderation in most dietary patterns. Polar lipids isolated from bovine, ovine, and caprine dairy products have exhibited potent inhibition of PAF-induced platelet aggregation in vitro (148–151). Interestingly, caprine and ovine milk lipids seem to possess greater anti-PAF activity in contrast to bovine milk lipids, and fermented products may exhibit greater bioactivity (152). This is attributed to the structural differences between these polar lipids.

Studies directly investigating dietary polar lipids with anticancer activities are limited. However, a food grade extract rich in polar lipids from the milk fat globule membrane of buttermilk was strongly antiproliferative against human ovary and colon cancer cells (OVCAR-3 and HT29) (144). Similarly, buttermilk polar lipids inhibited the growth of SW480 colon cancer cells in a dose-dependent manner. This study determined that a sphingolipid fraction mainly composed of lactosylceramide downregulated growth-signaling pathways mediated by β-catenin, extracellular signal-regulated kinase 1/2, phosphorylated serine/threonine-specific protein kinase, and c-myc (153). Extensive study of sphingomyelin and related compounds confirms that they are central to control of cell growth, differentiation, migration, and apoptosis, and may have therapeutic value (154, 155). Specifically, dairy-derived sphingomyelin is reported to decrease the number of aberrant foci crypts and to protect against colon cancer by inhibiting tumorigenesis and increasing alk-sphingomyelinase in mice fed a concentration of 0.5 g/kg over 22 wk ad libitum (156), and supplementation of 0.005 g/100 g sphingomyelin in the diet of CF1 mice transformed malignant adenocarcinomas to benign adenomas (157).

Other murine models have shown that dietary supplementation of dairy-derived sphingomyelin may also be chemopreventative when administered before tumor induction (156, 158–161). These effects are attributed to ceramide and sphingosine phosphate, which induce apoptosis by modification of expression of regulator genes in cancer (162, 163). The literature suggests that sphingomyelin may be the most active polar lipid against cancer (158). Furthermore, these anticancer phospholipids seem to share similar compositions to those that demonstrated inhibition of PAF-induced platelet aggregation and thus the PAF inflammatory pathway (150). In particular, it has been confirmed that dairy-derived sphingolipids inhibit the binding of PAF to the PAF-R in PAF platelet aggregation studies (148–150). Therefore, it is possible that these molecules may also inhibit PAF-related mechanisms in cancer, as was previously postulated (23).

Polar lipids from other sources have exhibited similar effects on various cancer cell lines. For instance it has been shown that microalgae polar lipids may induce antiproliferative effects in MCF-7 breast cancer cells (164); however, a similar study of dairy polar lipids did not observe the same effects (144). This may be because of differences in polar lipid composition or isolation techniques (158). The same microalgae study also demonstrated a 50% decrease in growth of hepatic cancer cells (Hep-G2) (164). In a similar in vitro study of hepatic cell lines (Alexander cell, Hep-3b, Hep-G2, and HuH-7), phosphatidylcholine isolated from egg yolk inhibited cancer cell growth. A study of the same cells in Sprague-Dawley rats administered the same polar lipid concentrates (0.05 g/100 g of diet) in an intragastric manner over 14 wk, reported similar inhibition of growth of cells (165, 166). Similarly, polar lipids may be beneficial in treatment and prevention of pancreatic cancer (167).

Phosphatidylcholine, phosphatidylethanolamine, and sphingomyelin have displayed positive effects against metastasis in gastric cancer cells by decreasing migration and adhesion (168). Although not dietary, synthetic phosphatidylethanolamine has demonstrated various antiproliferative, antiangiogenic, and antimetastatic effects in murine renal cell carcinoma and human umbilical vein endothelial cells. Furthermore, in vivo results show that phosphatidylethanolamine potentially inhibits lung metastasis in nude mice, with a superior efficacy when compared to sunitinib (169). Although not specified in these studies, it is likely that inhibition of the PAF pathway could be involved. Considering these findings, further research should address the possible role of dietary phospholipids for prevention of neoangiogenesis, cell proliferation, and metastasis through the PAF pathways.

Other nutrients including phenolic lipids, such as resveratrol, yuccaols, and epigallocatechin-3-gallate, found in various foods also exhibit beneficial effects against the PAF inflammatory pathways (52, 112, 170). However, there is a lack of substantial mechanistic evidence to explain their observed effects.

The Mediterranean diet and cancer

The traditional Mediterranean diet and cancer prevention

Several studies have linked the Mediterranean diet to lower risk of cardiovascular disease (171). Evidence suggests that this may extend to lower incidences of other chronic diseases mediated by inflammation including diabetes (172), cerebrovascular disease (173), cancers of the digestive system (174–177), breast cancer (178), overall types of cancer (179, 180), and premature mortality in general (181). The traditional Mediterranean diet is broadly characterized by high fruit, vegetable, legume, bread, cereal foods composed of wheat, tree nuts, and olive oil consumption, including moderate helpings of milk and dairy products, and low intake of red meat (24). Wine is also consumed within moderation in non-Islamic regions. Coffee is considered the hot beverage of choice and is generally consumed with sugar (123). The compounds and nutrients found in the Mediterranean diet seem to exhibit bioactivities against PAF-related inflammation, cancer development, and metastasis. Detopoulou et al. (182) examined the effects of nutrition, lifestyle, and biochemical variables of 106 subjects. Dietary patterns and food constituents containing bioactive molecules were inversely related to PAF levels or its biosynthetic enzymes. It is uncertain whether this association is facilitated by attenuation of subclinical inflammation induced by an antioxidant-rich diet or is a direct action of antioxidants on PAF metabolism. Nevertheless, this association illustrates a potential mechanism of the diet-disease hypothesis.

It has been proposed that the Mediterranean diet may in part exert some of the observed beneficial effects through dietary PAF antagonists such as polar lipids, which reduce PAF-related cascades implicated in platelet activation, aggregation, and inflammation (10, 24, 150, 183, 184) as many foods of the Mediterranean diet are rich in compounds with anti-PAF biological activities (Table 2). A clinical study has demonstrated that meals high in PAF antagonists improved the platelet response of patients with type 2 diabetes and healthy humans against inflammatory and prothrombotic factors (185). A similar study demonstrated that the traditional Greek Mediterranean diet can reduce platelet activity in patients with type 2 diabetes and healthy volunteers through the effects of PAF antagonists on PAF- and ADP-induced platelet aggregation (183). Although the molecular mechanisms have not yet been fully elucidated, diets that contain high amounts of PAF antagonists may help to inhibit the biological actions mediated by PAF, thus potentially lowering the risk of cancer. Indeed, other similar healthy dietary patterns such as the Nordic diet may also exert beneficial effects against cancer in part via dietary PAF inhibitors and related anti-inflammatory mechanisms (186). Furthermore, it is not clear whether the presence of other health conditions (e.g., cardiovascular diseases, obesity, etc.) in patients with cancer may compromise or improve the efficacy of dietary PAF inhibitors against PAF, and subsequently cancer; thus, further research is warranted. Some of the foods and compounds of the Mediterranean diet that exhibit these effects are summarized in Table 2.

TABLE 2.

Studies examining the anti-PAF activities of whole foods and polar lipid extracts in the Mediterranean diet¹

Studied food and components	Study type	Results
PL of fish (cod, coley, haddock, mackerel, salmon, sardines, seabass, and seabream)	In vitro studies in WRP, hPRP, and HMCs Ex vivo studies in hPRP In vivo studies in hyperlipidemic rabbits	Inhibition of PAF-PA Modulation of PAF metabolism towards reduced PAF and reduction of atherosclerotic lesions in hypercholesterolemic rabbits (51, 142, 192–197)
PL of olive oil and olive pomace	In vitro studies in WRP and HMCs In vivo studies in hyperlipidemic rabbits	Inhibition of PAF-PA Modulation of PAF metabolism towards reduced PAF and reduction of atherosclerotic lesions in hypercholesterolemic rabbits and regression of existing lesions (198, 199)
PL of dairy products	In vitro studies in WRP and hPRP	Inhibition of PAF-PA (148–150)
PL of goat and sheep meat	In vitro studies in hPRP	Inhibition of PAF-PA (200)
PL of seed oils (corn, sesame oil, sunflower oil)	In vitro studies in WRP	Inhibition of PAF-PA (201)
PL of hen eggs	In vitro studies in WRP	Inhibition of PAF-PA (202)
PL of red and white wine, musts, grape skins, and yeast	In vitro studies in WRP and U937 macrophages Postprandial dietary intervention studies in humans Ex vivo studies in hPRP	Inhibition of PAF-PA Modulation of PAF metabolism towards reduced PAF (103, 104, 203–206)
PL of honey	In vitro studies in WRP	Inhibition of PAF-PA (207)
EOE of garlic and onion	In vitro studies in WRP	Inhibition of PAF-PA (208, 209)
Wild plants of the Mediterranean diet (Reichardia picroides, Cynara cardunculus, Urospermum picroides, and Chrysanthemum coronarium)	In vitro studies in WRP Postprandial dietary intervention studies in humans	Reduced postprandial platelet hyperaggregability of metabolic syndrome patients Inhibition of PAF-PA ex vivo Inhibition of PAF-PA in vitro (210)
Compounds of the Mediterranean diet found in oils, herbs, spices, tea, wine, etc. (PL, hesperidin, luteolin, naringin, oleic acid, oleuropein, proanthocyanidins, quercetin, resveratrol, tyrosol)	In vitro studies in WRP and hPRP In vitro and in vivo studies on various cells Ex vivo studies in hPRP Postprandial dietary intervention studies in humans	Inhibition of PAF-PA (211, 212) Modulation of PAF metabolism towards reduced PAF (170, 213, 214)

¹EOE, essential oil extract; HMCs, human mesangial cells; hPRP, human platelet-rich plasma; PA, platelet aggregation; PAF, platelet-activating factor; PL, polar lipids; WRP, washed rabbit platelets.

Cancer incidence and the Mediterranean diet

A recent meta-analysis of 83 studies assessed adherence to the Mediterranean diet on the risk of overall cancer mortality and the risk of various cancers in a total of 2,130,753 subjects. It was found that the highest adherence score to a Mediterranean diet was inversely associated with a lower risk of cancer mortality, head and neck cancer, breast cancer, gastric cancer, liver cancer, colorectal cancer, and prostate cancer. However, the association between adherence to the highest Mediterranean diet category and the risk of cancer mortality and cancer recurrence in survivors was not statistically significant. Furthermore, it was demonstrated that these protective effects were associated with high fruit, vegetable, and wholegrain intake (187). Other studies have demonstrated similar results with varying statistical strength for overall cancer and specific cancers (174, 177, 188–190). In particular in southern Europe, adherence to the Mediterranean diet was associated with a 6% reduction in cancer mortality (179). It is clear that adherence to the Mediterranean diet is associated with a reduction in mortality and morbidity, which results from the types of foods consumed and the nutrients within the diet and their anti-inflammatory bioactivities (191). Hence, the presence of nutrients with the capacity to inhibit PAF and related inflammatory pathways may be significant in inflammation and cancer. While PAF plays a central role in several key mechanisms of cancer development and progression, and there are a plethora of inflammatory pathways interlinked in an exceedingly complex process, it is important to note that blocking 1 inflammatory mediator is not a panacea. Dietary PAF inhibitors may have the potential to prevent the physiological actions of PAF in cancer, but it must be acknowledged that this is only 1 of many mechanisms. The adherence to healthy dietary patterns rich in microconstituents with anti-inflammatory bioactivities such as those of the Mediterranean diet, may in part aid in impeding multiple proinflammatory mechanisms.

However, concern has been raised that the traditional Mediterranean dietary patterns are gradually becoming less common as the food supplies of the countries of the Mediterranean littoral become increasingly ‘Western’ (123). The Western diet is associated with high intake of processed food, which may make up anything between 25% and 50% of total daily energy intake, which is synonymous with the United States (215). A recent perspective cohort study found that a 10% increase in the proportion of ultraprocessed foods in the diet was associated with a significant increase of >10% in risks of overall cancer and breast cancer (216). Furthermore, there is evidence of a higher risk for colorectal cancer in Western societies where there is higher consumption of processed meat and red meat, although there are concerns that red meat itself unprocessed may not be negatively associated with colorectal cancer risk (217). This is in contrast to those who adhere to the Mediterranean diet, who benefit from lower overall cancer mortality (218). A recent study demonstrated that adherence to a Western-style diet was related to an increased risk of breast cancer, especially in premenopausal women; whereas, the Mediterranean diet was related to a lower risk. These observations were again attributed to a diet high in fruits, vegetables, and oily fish (177). Therefore, it is clear that the modern Mediterranean regions should adhere to their traditional dietary patterns, as Westernization may lead to an increase of chronic diseases including cancers.

Future Research Perspectives

PAF plays a central role in digestive, skin, breast, and reproductive cancers, but may not be involved in other cancers and has demonstrated attenuating effects in some cancers. Many studies have demonstrated that PAF-R antagonists may inhibit cancer growth and affect PAF metabolism in several cancers. In addition, PAF antagonists may be useful as an adjuvant therapy for current chemotherapy and radiation treatments. Certainly, the PAF pathway is a novel target for developing cancer treatments and recently PAF was proposed as a biomarker of cancer. In light of these findings, several dietary PAF inhibitors such as polar lipids present in various components of the Mediterranean diet may affect cancer occurrence and development. Furthermore, the Mediterranean diet is associated with a lower incidence of various cancers. Many compounds of the Mediterranean diet exhibit anti-PAF activities, which may be partly responsible for some of these beneficial observations. However, these anti-inflammatory mechanisms have yet to be fully elucidated and further molecular studies are required to decipher the precise mechanisms that govern PAF-induced inflammation, angiogenesis, and metastasis. Although the PAF pathway may be an attractive therapeutic target for various inflammatory diseases, it is not yet certain whether this would be advantageous to inhibit PAF in human cancer. Therefore, randomized controlled trials are required to assess use of PAF-R antagonists as an adjuvant mode of treatment in cancer.

Notes

The authors reported no funding received for this study.

Author disclosures: RL, AT, and IZ no conflicts of interest.

Abbreviations used: LPCAT, lysophosphatidylcholine acyltransferase; PAF, platelet-activating factor; PAF-AH, platelet-activating factor-acetylhydrolase; PAF-CPT, 1-alkyl-2-acetyl-sn-glycerol cholinephosphotransferase; PAF-R, platelet-activating factor-receptor; VEGF, vascular endothelial growth factor.