Abstract
Platelet-activating factor-receptor (PAF-R) agonists are pleiotropic lipid factors that influence multiple biological processes, including the induction and resolution of inflammation as well as immunosuppression. PAF-R agonists have been shown to modulate tumorigenesis and/or tumor growth in various skin cancer models by suppressing either cutaneous inflammation and/or anti-tumoral adaptive immunity. We have previously shown that a chronic systemic PAF-R agonist administration of mice enhances the growth of subcutaneously implanted melanoma tumors. Conversely, chronic topical applications of a PAF-R agonist suppressed non-melanoma skin cancer (NMSC) in a topical chemical carcinogenesis model (dimethylbenz[a]anthracene/phorbol 12-myristate 13-acetate (DMBA/PMA)) in-part via anti-inflammatory effects. These results indicate that the context of PAF-R agonist exposure via either chronic cutaneous or systemic administration, result in seemingly disparate effects on tumor promotion. To further dissect the contextual role of PAF-R agonism on tumorigenesis, we chronically administered systemic PAF-R agonist, carbamoyl-PAF (CPAF) to mice under a cutaneous chemical carcinogenesis protocol, recently characterized to initiate both NMSC and melanocytic nevus formation that can progress to malignant melanoma. Our results showed that while systemic CPAF did not modulate melanocytic nevus formation, it enhanced the growth of NMSC tumors.
Highlights
Platelet-activating factor-receptor (PAF-R) is a widely expressed seven-transmembrane-spanning G protein-coupled receptor, which binds with varying affinities to platelet-activating factor (PAF, 1-0-alkyl-2-acetyl-sn-glycero-3-phosphocholine) or glycerophosphocholines that have been oxidatively modified on the sn-2 polyunsaturated fatty acid [1,2]
The stability of PAF-R agonists is regulated by PAF metabolizing enzymes, PAF-acetyl hydrolases (PAF-AH), which are found in multiple cell types and lipoproteins [3,4]
Our previous studies have shown that intraperitoneal injections of PAF-R agonist, CPAF, augment the growth of subcutaneously implanted murine melanoma tumors via mechanisms involving interleukin 10 (IL-10) and Tregs [7]
Summary
Platelet-activating factor-receptor (PAF-R) is a widely expressed seven-transmembrane-spanning G protein-coupled receptor, which binds with varying affinities to platelet-activating factor (PAF, 1-0-alkyl-2-acetyl-sn-glycero-3-phosphocholine) or glycerophosphocholines that have been oxidatively modified on the sn-2 polyunsaturated fatty acid (oxGPCs) [1,2]. Using PAF-R-expressing and -deficient cells or mouse models with a C57BL/6 background, we have shown that administration of systemic CPAF augments the growth of subcutaneously-implanted melanoma tumors [7]. 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. 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. The ability of the PAF-R agonist via topical [19] and systemic (current study) applications seems to exert both tumor suppressive and tumor promoting activities on NMSC, respectively
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