Hepatocellular Carcinoma Cells and Their Fibrotic Microenvironment Modulate Bone Marrow-Derived Mesenchymal Stromal Cell Migration in Vitro and in Vivo
Hepatocellular Carcinoma Cells and Their Fibrotic Microenvironment Modulate Bone Marrow-Derived Mesenchymal Stromal Cell Migration in Vitro and in Vivo
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DOI：
10.1021/mp200137c
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发表时间：
2011-09-01
影响因子：
4.9
通讯作者：
Mazzolini, Guillermo
中科院分区：
文献类型：
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作者：
Garcia, Mariana G.;Bayo, Juan;Mazzolini, Guillermo
肝细胞癌（HCC）是第五大常见癌症，也是癌症相关死亡的第三大原因。纤维化是一个活跃的过程，其特征在于产生几种促炎细胞因子、趋化因子和生长因子。它涉及肝星状细胞（HSC）的活化，肝星状细胞在损伤部位积聚并且是细胞外基质沉积的主要来源。对于晚期HCC没有治愈性治疗，因此迫切需要新的治疗方法。间充质基质细胞（MSC）有能力迁移到损伤部位或重塑组织后，在体内管理;然而，在几种癌症模型中，他们表现出有限的疗效，部分由于移植不良，以消除实验肿瘤。因此，这项工作的目的是分析人MSC（hMSC）迁移和锚到HCC肿瘤的能力。我们观察到，HCC和HSC，而不是非肿瘤间质，在体外产生诱导hMSC迁移的因子。发现从已建立的HCC细胞系产生的条件培养基（CM）比来自新鲜患者肿瘤样品的CM诱导更高水平的hMSC迁移。此外，暴露于来自HCC细胞或HSC的CM后，hMSCs表现出对内皮细胞、IV型胶原和纤维蛋白原的粘附和侵袭能力。一致地，发现这些细胞增加金属蛋白酶-2活性。皮下和原位HCC模型的体内研究表明，静脉输注的hMSCs迁移到肺，脾和肝。hMSC输注后7天，细胞也位于两种模型中的肿瘤中，但原位模型中的信号强度显著高于皮下模型。有趣的是，当原位HCC肿瘤在非增生性或增生性肝脏中建立时，与健康动物相比，位于肝脏中的hMSC的量更高。在肺和脾中发现了非常低的信号，表明肝脏肿瘤能够以高效率招募它们。总之，我们的研究结果表明，HCC和HSC细胞产生的因子，有效地诱导hMSC迁移到肿瘤微环境在体外和体内，并使MSC的候选人为基于细胞的治疗策略，肝细胞癌相关的纤维化。
Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third cause of cancer-related death. Fibrogenesis is an active process characterized by the production of several proinflammatory cytokines, chemokines and growth factors. It involves the activation of hepatic stellate cells (HSCs) which accumulate at the site of injury and are the main source of the extracellular matrix deposits. There are no curative treatments for advanced HCC, thus, new therapies are urgently needed. Mesenchymal stromal cells (MSCs) have the ability to migrate to sites of injury or to remodeling tissues after in vivo administration; however, in several cancer models they demonstrated limited efficacy to eradicate experimental tumors partially due to poor engraftment. Thus, the aim of this work was to analyze the capacity of human MSCs (hMSCs) to migrate and anchor to HCC tumors. We observed that HCC and HSCs, but not nontumoral stroma, produce factors that induce hMSC migration in vitro. Conditioned media (CM) generated from established HCC cell lines were found to induce higher levels of hMSC migration than CM derived from fresh patient tumor samples. In addition, after exposure to CM from HCC cells or HSCs, hMSCs demonstrated adhesion and invasion capability to endothelial cells, type IV collagen and fibrinogen. Consistently, these cells were found to increase metalloproteinase-2 activity. In vivo studies with subcutaneous and orthotopic HCC models indicated that intravenously infused hMSCs migrated to lungs, spleen and liver. Seven days post-hMSC infusion cells were located also in the tumor in both models, but the signal intensity was significantly higher in orthotopic than in subcutaneous model. Interestingly, when orthotopic HCC tumors where established in noncirrhotic or cirrhotic livers, the amount of hMSCs localized in the liver was higher in comparison with healthy animals. A very low signal was found in lungs and spleens, indicating that liver tumors are able to recruit them at high efficiency. Taken together our results indicate that HCC and HSC cells produce factors that efficiently induce hMSC migration toward tumor microenvironment in vitro and in vivo and make MSCs candidates for cell-based therapeutic strategies to hepatocellular carcinoma associated with fibrosis.