Bone marrow stromal-derived soluble factors and direct cell contact contribute to de novo drug resistance of myeloma cells by distinct mechanisms
Bone marrow stromal-derived soluble factors and direct cell contact contribute to de novo drug resistance of myeloma cells by distinct mechanisms
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DOI：
10.1038/sj.leu.2402924
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发表时间：
2003-06-01
期刊：
影响因子：
11.4
通讯作者：
Dalton, WS
中科院分区：
文献类型：
--
作者：
Nefedova, Y;Landowski, TH;Dalton, WS
肿瘤微环境在决定肿瘤细胞的命运中起着关键作用。我们以前曾报道，粘附的人骨髓瘤和白血病细胞系的细胞外基质蛋白，纤连蛋白，赋予多药耐药表型。与这种细胞粘附介导的耐药性相关的机制是药物类型特异性的。在本研究中，我们研究了骨髓基质细胞（BMSCs）对骨髓瘤细胞对拓扑异构酶II抑制剂米托蒽醌反应的影响。与悬浮培养的骨髓瘤细胞相比，粘附于骨髓基质细胞的细胞凋亡抑制率超过50%。为了研究骨髓瘤细胞与BMSCs接触时产生耐药性的机制，我们在四种不同的条件下检查了BMSCs的保护作用：（1）直接细胞接触;（2）BMSCs条件培养基;（3）骨髓瘤细胞与BMSCs直接接触共培养的条件培养基;（4）骨髓瘤细胞与BMSCs无直接物理接触共培养的条件培养基。条件培养基从骨髓间充质干细胞单独是不足以保护骨髓瘤细胞从药物诱导的细胞凋亡，然而，可溶性因子产生的骨髓瘤-骨髓间充质干细胞相互作用过程中降低了骨髓瘤细胞的敏感性米托蒽醌，表明骨髓瘤细胞和骨髓间充质干细胞之间的动态相互作用。我们还发现，骨髓瘤细胞与骨髓间充质干细胞直接接触发生生长停滞，而骨髓瘤细胞BMSCs共孵育产生的可溶性因子刺激骨髓瘤细胞的增殖。这些数据表明，骨髓间充质干细胞与骨髓瘤细胞的细胞-细胞粘附以及这种细胞-细胞相互作用诱导的可溶性因子都参与了骨髓瘤细胞对米托蒽醌诱导的凋亡的保护;然而，导致耐药性的机制是不同的。
The tumor microenvironment plays a critical role in determining the fate of tumor cells. We have previously reported that adhesion of human myeloma and leukemia cell lines to the extracellular matrix protein, fibronectin, confers a multidrug-resistant phenotype. Mechanisms associated with this cell adhesion-mediated drug resistance are drug-type specific. In the present study, we examined the influence of bone marrow stromal cells (BMSCs) on myeloma cell response to the topoisomerase II inhibitor, mitoxantrone. Apoptosis was inhibited by more than 50% when cells were adhered to BMSCs as compared to myeloma cells maintained in suspension. To investigate the mechanisms contributing to the resistance of myeloma cells in contact with BMSCs, we examined the protective effects of BMSCs under four separate conditions: ( 1) direct cell contact; ( 2) BMSCs conditioned medium; ( 3) medium conditioned by coculturing myeloma cells in direct contact with BMSCs; and ( 4) medium conditioned by coculturing myeloma cells and BMSCs without direct physical contact. Conditioned medium from BMSCs alone was not sufficient to protect myeloma cells from drug-induced apoptosis; however, soluble factors produced during the myeloma-BMSCs interaction decreased the sensitivity of myeloma cells to mitoxantrone, suggesting a dynamic interaction between myeloma cells and BMSCs. We also found that myeloma cells in direct contact with BMSCs underwent growth arrest, whereas soluble factors produced by myeloma cells-BMSCs coincubation stimulated the proliferation of myeloma cells. These data show that both cell - cell adhesion of BMSCs with myeloma cells and soluble factors induced by this cell - cell interaction are involved in the protection of myeloma cells from mitoxantrone-induced apoptosis; however, the mechanisms contributing to the drug resistance are different.