Abstract LB-130: Omega-3 fatty acids suppress platelets-associated melanoma metastasis
Authors: Chen Chih-Yu , Li Jingchao , Arita Makoto , Su Chien-Wen , Li Jeiping , Xie Shanfu , Kang Jing X. 
Published: August 2019

Background: 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.

Methods: 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.

Results: Fat-1 mice exhibited a marked decrease in pulmonary tumor colonies, macrophage infiltration to lungs, and serum TNF-α 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. β-catenin and Vimentin) and TGFβ 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.

Conclusions: 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.

Citation Format: 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]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-130.