Cytological and molecular analysis of malignant mesothelioma cells and identification of its cancer stem cells

恶性间皮瘤是一种浆膜表面的侵袭性肿瘤，对目前的治疗方案是难治的。我们分析了间皮瘤细胞的细胞学和分子特征，以确定启动其肿瘤发生的干细胞。我们首先分析了临床上用于治疗急性早幼粒细胞白血病的三氧化二砷(As_2O_3)诱导间皮瘤细胞凋亡的作用。我们发现As_2O_3对间皮瘤细胞系NCI-H2052的细胞活力有抑制作用。As_2O_3诱导NCI-H2052细胞凋亡，并伴随着JNK1/2、ERK1/2和caspase-3的激活。As_2O_3主要通过激活JNK1/2诱导NCI-H2052细胞的凋亡，JNK1/2失活时ERK1/2参与了As_2O_3诱导的细胞凋亡。另一方面，我们发现选择性SFK抑制剂PP2通过caspase-8途径诱导对As_2O_3耐药的NCI-H28细胞发生凋亡。Fyn缺失是SFK抑制剂诱导间皮瘤细胞caspase-8依赖性凋亡的先决条件。在寻找肿瘤干细胞的过程中，我们发现间皮瘤细胞表达CD318，CD318在间皮瘤中起作用。

Malignant mesothelioma is an aggressive tumor of serosal surfaces which is refractory to current treatment options. We analyzed cytological and molecular characteristics of mesothelioma cells to identify the stem cells that initiate its tumorogenesis. We first analyzed the apoptosis of mesothelioma cells induced by arsenic trioxide (As_2O_3), which is used clinically to treat acute promyelocytic leukemia. We found that As_2O_3 inhibited cell viability of a mesothelioma cell line, NCI-H2052. As_2O_3 induced apoptosis of NCI-H2052 cells, which was accompanied by activation of JNK1/2, ERK1/2 and caspase-3. As_2O_3 induced apoptosis of NCI-H2052 cells mainly through JNK1/2 activation, and ERK1/2 was involved in As_2O_3-induced apoptosis when JNK1/2 was inactivated. On the other hands, we found that PP2, a selective SFK inhibitor, induced apoptosis through a caspase-8 pathway in NCI-H28 cells which are resistant to As_2O_3. Fyn-deficiency is prerequisite for caspase-8-dependent apoptosis induced by SFK inhibitors in mesothelioma cells. In our search for cancer stem cells, we found that mesothelioma cells expressed CD318, which play a role in mesotheiloma.