Gemcitabine-releasing mesenchymal stromal cells inhibit in vitro proliferation of human pancreatic carcinoma cells
Gemcitabine-releasing mesenchymal stromal cells inhibit in vitro proliferation of human pancreatic carcinoma cells
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DOI：
10.1016/j.jcyt.2015.09.005
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发表时间：
2015-12-01
期刊：
影响因子：
4.5
通讯作者：
Pessina, Augusto
中科院分区：
文献类型：
--
作者：
Bonomi, Arianna;Sordi, Valeria;Pessina, Augusto
背景目标。胰腺癌(PCa)是一种以纤维化状态为特征的肿瘤，预后不良。间充质基质细胞(MSCs)在全身给药后向炎性微环境迁移并植入肿瘤间质，这为利用工程MSCs直接在肿瘤内运送和产生抗癌分子提供了新的治疗方法。此前，我们证明了在没有任何基因修饰的情况下，间充质干细胞能够输送抗癌药物。通过暴露于高浓度紫杉醇的骨髓间充质干细胞在体外和体内释放药物，抑制肿瘤增殖。在这些观察的基础上，我们评估了(来自骨髓和胰腺的)间充质干细胞摄取和释放吉西他滨(GCB)的能力，吉西他滨是一种广泛用于前列腺癌治疗的药物。方法：研究方法。骨髓间充质干细胞暴露于2000 ng/mLGCB中24小时。然后用对GCB敏感的胰腺癌细胞系CFPAC-1进行体外抗增殖实验，研究诱导后的MSCs的抗肿瘤作用。通过高效液相色谱分析证实了其吸收/释放能力。细胞周期研究和分泌组评估也被用来更好地了解预置的MSCs的特性。结果。释放GCB的MSCs在体外抑制人前列腺癌细胞系的生长。结论。使用间充质干细胞作为“特洛伊木马”可以开启一种新的PCA治疗方法；携带GCB的骨髓间充质干细胞整合到肿瘤肿块中可以提供比静脉注射更高浓度的药物。关键词：药物传递、吉西他滨、间充质干细胞、胰腺癌
Background aims. Pancreatic cancer (pCa) is a tumor characterized by a fibrotic state and associated with a poor prognosis. The observation that mesenchymal stromal cells (MSCs) migrate toward inflammatory micro-environments and engraft into tumor stroma after systemic administration suggested new therapeutic approaches with the use of engineered MSCs to deliver and produce anti-cancer molecules directly within the tumor. Previously, we demonstrated that without any genetic modifications, MSCs are able to deliver anti-cancer drugs. MSCs loaded with paclitaxel by exposure to high concentrations release the drug both in vitro and in vivo, inhibiting tumor proliferation. On the basis of these observations, we evaluated the ability of MSCs (from bone marrow and pancreas) to uptake and release gemcitabine (GCB), a drug widely used in pCa treatment. Methods. MSCs were primed by 24-h exposure to 2000 ng/mL of GCB. The anti-tumor potential of primed MSCs was then investigated by in vitro anti-proliferation assays with the use of CFPAC-1, a pancreatic tumor cell line sensitive to GCB. The uptake/release ability was confirmed by means of high-performance liquid chromatography analysis. A cell-cycle study and secretome evaluation were also conducted to better understand the characteristics of primed MSCs. Results. GCB-releasing MSCs inhibit the growth of a human pCa cell line in vitro. Conclusions. The use of MSCs as a "trojan horse" can open the way to a new pCa therapeutic approach; GCB-loaded MSCs that integrate into the tumor mass could deliver much higher concentrations of the drug in situ than can be achieved by intravenous injection. Key Words: drug delivery, gemcitabine, MSCs, pancreatic adenocarcinoma