Department of Pharmaceutical Sciences, College of Pharmacy, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States of America.
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States of America.
PLoS One. 2024 Aug 27;19(8):e0309125. doi: 10.1371/journal.pone.0309125. eCollection 2024.
Increasing evidence is implicating roles for platelets in the development and progression of ovarian cancer, a highly lethal disease that can arise from the fallopian tubes, and has no current method of early detection or prevention. Thrombosis is a major cause of mortality of ovarian cancer patients suggesting that the cancer alters platelet behavior. The objective of this study was to develop a cell culture model of the pathological interactions of human platelets and ovarian cancer cells, using normal FT epithelial cells as a healthy control, and to test effects of the anti-platelet dihomo-gamma-linolenic acid (DGLA) in the model. Both healthy and cancer cells caused platelet aggregation, however platelets only affected spheroid formation by cancer cells and had no effect on healthy cell spheroid formation. When naturally-formed spheroids of epithelial cells were exposed to platelets in transwell inserts that did not allow direct interactions of the two cell types, platelets caused increased size of the spheroids formed by cancer cells, but not healthy cells. When cancer cell spheroids formed using magnetic nanoshuttle technology were put in direct physical contact with platelets, the platelets caused spheroid condensation. In ovarian cancer cells, DGLA promoted epithelial-to-mesenchymal (EMT) transition at doses as low as 100 μM, and inhibited metabolic viability and induced apoptosis at doses ≥150 μM. DGLA doses ≤150 μM used to avoid direct DGLA effects on cancer cells, had no effect on the pathological interactions of platelets and ovarian cancer cells in our models. These results demonstrate that the pathological interactions of platelets with ovarian cancer cells can be modeled in cell culture, and that DGLA has no effect on these interactions, suggesting that targeting platelets is a rational approach for reducing cancer aggressiveness and thrombosis risk in ovarian cancer patients, however DGLA is not an appropriate candidate for this strategy.
越来越多的证据表明血小板在卵巢癌的发生和发展中起作用,卵巢癌是一种高度致命的疾病,可能起源于输卵管,目前尚无早期检测或预防方法。血栓形成是卵巢癌患者死亡的主要原因,这表明癌症改变了血小板的行为。本研究的目的是建立一个人血小板与卵巢癌细胞病理相互作用的细胞培养模型,以正常 FT 上皮细胞作为健康对照,并在模型中测试抗血小板二高-γ-亚麻酸(DGLA)的作用。健康细胞和癌细胞都能引起血小板聚集,但血小板仅能影响癌细胞的球体形成,而对健康细胞球体形成没有影响。当天然形成的上皮细胞球体在不能使两种细胞类型直接相互作用的 Transwell 插入物中暴露于血小板时,血小板会导致癌细胞形成的球体增大,但不会导致健康细胞形成的球体增大。当使用磁性纳米穿梭技术使癌细胞球体直接与血小板接触时,血小板会导致球体凝结。在卵巢癌细胞中,DGLA 以低至 100 μM 的剂量促进上皮细胞向间充质(EMT)转化,以 150 μM 以上的剂量抑制代谢活力并诱导细胞凋亡。用于避免 DGLA 对癌细胞的直接影响的≤150 μM 的 DGLA 剂量,对我们模型中血小板与卵巢癌细胞的病理相互作用没有影响。这些结果表明,血小板与卵巢癌细胞的病理相互作用可以在细胞培养中建模,并且 DGLA 对这些相互作用没有影响,这表明靶向血小板是降低卵巢癌患者癌症侵袭性和血栓形成风险的合理方法,然而 DGLA 不是这种策略的合适候选药物。