Systemic platelet‐activating factor‐receptor activation augments experimental lung cancer growth and metastasis (LB496)

Abstract

Pro‐oxidative stressors including cigarette smoke (CS) generate novel lipids with Platelet‐activated Factor‐receptor (PAF‐R) agonistic activity and mediate systemic immunosuppression, one of the most recognized events in promoting carcinogenesis. Our previous studies have demonstrated that PAF‐R agonists mediated systemic immunosuppression augments the growth of experimental murine B16F10 melanoma tumors in a PAF‐R dependent manner. As CS generates PAF‐R agonists, the current studies sought to determine the impact of PAF‐R‐agonists on lung cancer growth and metastasis using an established experimental murine lewis lung carcinoma (LLC) model. We show that systemic PAF‐R agonist, CPAF augments the growth of subcutaneously implanted LLC tumors in a PAF‐R dependent manner as this effect was not observed in PAF‐R deficient (PAFR‐KO) mice. We next determined the ability of CPAF‐mediated PAF‐R dependent enhanced LLC tumor growth on lung metastasis. We observed increase number of lung mets only in CPAF‐treated WT and not in PAF‐R‐KO mice. In order to investigate the role of tumor or host cell PAF‐R in these effect, we first determined the expression of the PAF‐R in LLC tumor cells. Our results demonstrate that LLC tumor cells lack functional PAF‐R expression as measured by qRT‐PCR and functional Ca2+ mobilization assay and compared with arrays of PAF‐R sufficient and deficient cells. In addition, CPAF treatment failed to induce increase proliferation of LLC cells, indicating the role of host rather tumor cell PAF‐R in these events. This finding has clinical implications as it provides insight into a mechanism through which lung cancer cells evade immune surveillance. Grant Funding Source: NIH R01 HL062996, AICR 09A062, ACSIRG 4185607, Showlater Research Trust Fund 4485602