Abstract LB 130: Omega 3 fatty acids suppress platelets associated melanoma metastasis
Venue: Tumor Biology
Year: 2019

Melanoma is the most aggressive neoplasm due to its propensity to metastasize and poor response to classical therapies. Platelets are a critical factor for metastatic dissemination. Omega 3 polyunsaturated fatty acids (n 3 PUFAs) are known to be able to modulate platelet function and have also been reported to have anti cancer effects. Whether n 3 PUFAs have a preventive effect on melanoma metastasis by altering platelet structure and function is unclear. Fat 1 transgenic mice, which express an n 3 fatty acid desaturase from Caenorhabditis elegans and are capable of converting omega 6 (n 6) PUFAs to n 3 PUFAs, is a well controlled model without dietary confounding factors for investigating the impact of n 3 PUFAs on melanoma metastasis. For in vivo experiments, melanoma B16 F10 cells (5x105) suspended in PBS were intravenously injected to fat 1 and WT mice, pulmonary tumor colonies, inflammatory indices and platelet function were analyzed 3 weeks after injection. For in vitro experiments, platelets isolated from either WT or fat 1 mice were incubated with B16 F10 cells for 24 hours, and metastatic potential was determined by epithelial mesenchymal transition (EMT) markers, invasion assay, and wound healing test. To further examine whether the n 6/n 3 ratio alters lipid metabolism in platelets and cancer cells, the lipidomic analysis was performed using GC and LC/MS MS. Fat 1 mice exhibited a marked decrease in pulmonary tumor colonies, macrophage infiltration to lungs, and serum TNF a levels compared with wild type mice. In terms of platelet structure and function, platelet granules for cytokine storage were reduced in number as observed by using transmission electron microscope; the abundance of coagulation molecules (e.g. p selectin and collagen IV) was lower in platelets of fat 1 mice. But, the platelet count was similar between WT and fat 1 mice. Intriguingly, platelets associated metastatic behavior such as mRNA levels of EMT markers (e.g. b catenin and Vimentin) and TGFb was decreased in lungs of fat 1mice, suggesting that a lower platelet n 6/n 3 ratio has a substantial impact on platelet structure and function and significantly inhibit cancer metastasis. In vitro, relative to WT mouse platelets, B16 F10 cells cultured with fat 1 mouse platelets exhibited a decreased metastatic potential as observed by a reduction of cell migration and a delay of EMT. Moreover, we used lipidomic analysis to examine the differential effects of n 6 and n 3 PUFAs on platelet lipid metabolism during tumorigenesis and found a great difference in fatty acid composition between WT and fat 1 mouse platelets. Accordingly, the fatty acid composition of cancer cells was altered; those cultured with fat 1 mouse platelets exhibited lower levels of n 6 fatty acids and their derivatives such as thromboxane A2 (TXA2) a pro thrombotic metabolite released from platelets.  Our results have demonstrated that increased tissue levels of n 3 PUFAs (or a decreased n 6/n 3 ratio) can suppress melanoma metastasis by altering platelet structure and function. Therefore, our study has revealed a new mechanism for the anti metastatic effect of n 3 PUFAs and also highlighted the importance of platelet lipid metabolism in cancer progression. Our findings also suggest that n 3 PUFA supplementation can be a potential dietary strategy for prevention of melanoma metastasis.  Chih Yu Chen, Jingchao Li, Makoto Arita, Chien Wen Su, Jeiping Li, Shanfu Xie, Jing X. Kang. Omega 3 fatty acids suppress platelets associated melanoma metastasis [abstract]  2019; 2019 Mar 29 Apr 3; Atlanta, GA. Philadelphia (PA) AACR;