Topical Application of a Platelet Activating Factor Receptor Agonist Suppresses Phorbol Ester-Induced Acute and Chronic Inflammation and Has Cancer Chemopreventive Activity in Mouse Skin

Abstract

Platelet activating factor (PAF) has long been associated with acute edema and inflammatory responses. PAF acts by binding to a specific G-protein coupled receptor (PAF-R, Ptafr). However, the role of chronic PAF-R activation on sustained inflammatory responses has been largely ignored. We recently demonstrated that mice lacking the PAF-R (Ptafr-/- mice) exhibit increased cutaneous tumorigenesis in response to a two-stage chemical carcinogenesis protocol. Ptafr-/- mice also exhibited increased chronic inflammation in response to phorbol ester application. In this present study, we demonstrate that topical application of the non-hydrolysable PAF mimetic (carbamoyl-PAF (CPAF)), exerts a potent, dose-dependent, and short-lived edema response in WT mice, but not Ptafr -/- mice or mice deficient in c-Kit (c-Kit W-sh/W-sh mice). Using an ear inflammation model, co-administration of topical CPAF treatment resulted in a paradoxical decrease in both acute ear thickness changes associated with a single PMA application, as well as the sustained inflammation associated with chronic repetitive PMA applications. Moreover, mice treated topically with CPAF also exhibited a significant reduction in chemical carcinogenesis. The ability of CPAF to suppress acute and chronic inflammatory changes in response to PMA application(s) was PAF-R dependent, as CPAF had no effect on basal or PMA-induced inflammation in Ptafr-/- mice. Moreover, c-Kit appears to be necessary for the anti-inflammatory effects of CPAF, as CPAF had no observable effect in c-Kit W-sh/W-sh mice. These data provide additional evidence that PAF-R activation exerts complex immunomodulatory effects in a model of chronic inflammation that is relevant to neoplastic development.

Antiplatelet agents for cancer treatment: a real perspective or just an echo from the past?

“…The PAR1/PAFR/MUC18 pathway regulates melanoma cell adhesion to microvascular ECs and transendothelial migration, and finally enhances metastatic seeding in the lungs [ 217 ]. Upregulation of PAFR and its agonists in this context may also impact immune functions against cancer [ 218 – 222 ].…”

Systemic Platelet-Activating Factor-Receptor Agonism Enhances Non-Melanoma Skin Cancer Growth

“…Studies, including ours, have shown that enzymatic (i.e., PAF) or non-enzymatically (e.g., ultraviolet B (UVB), cigarette smoke, jet fuel, and tumor promoters, such as PMA) generated PAF-R agonists mediate various pathophysiological effects, including enhanced growth of tumors in experimental models [ 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 ]. In particular, tumor growth promoting effects can be mimicked by the administration of a non-metabolizable form of PAF (1-hexadecyl-2- N -methyl carbamoyl glycerophosphocholine (CPAF)) [ 7 , 19 ].…”

“…However, the topical applications of CPAF suppress dimethylbenz[a]anthracene/phorbol 12-myristate 13-acetate (DMBA/PMA))-induced cutaneous non-melanoma skin cancer (NMSC) growth. The DMBA/PMA protocol is a dual chemical carcinogenesis model that induces papillomas and squamous cell carcinoma [ 7 , 19 ]. These divergent findings suggest that systemic PAF-R agonists may promote cutaneous tumors, while their topical applications may suppress them.…”

“…Nevertheless, the effects of systemic PAF-R agonists on a cutaneous carcinogenesis model has not been tested. Notably, chronic systemic PAF-R agonist exposure is a physiologically and clinically relevant concern as the increase in systemic PAF-R agonists is associated with pathophysiological states including chronic infection, and xenobiotic exposure [ 9 , 10 , 11 , 19 , 20 , 21 , 22 , 23 ].…”

“…Given the intriguing roles of PAF-R agonists in modulating the growth of experimental melanoma and NMSC in response to diverse stimuli [ 7 , 15 , 19 , 23 , 24 , 25 , 26 ], the current study was designed to determine if systemic PAF-R agonist exposure modulates DMBA/PMA-induced cutaneous carcinogenesis. Our study took advantage of a recent report by Nasti et al, which characterized a DMBA/PMA cutaneous carcinogenesis model [ 27 ] in C3H/HeN mice that induces both NMSC and melanocytic nevi, which in turn can be transformed into malignant melanoma [ 28 ].…”