Induction of hypoxia and necrosis in multicellular tumor spheroids is associated with resistance to chemotherapy treatment.
Induction of hypoxia and necrosis in multicellular tumor spheroids is associated with resistance to chemotherapy treatment.
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DOI：
10.18632/oncotarget.13857
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发表时间：
2017-01-03
期刊：
影响因子：
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通讯作者：
Muraro MG
中科院分区：
文献类型：
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作者：
Däster S;Amatruda N;Calabrese D;Ivanek R;Turrini E;Droeser RA;Zajac P;Fimognari C;Spagnoli GC;Iezzi G;Mele V;Muraro MG
在标准单层条件下培养癌细胞不能很好地反映在不同组织学来源的大多数癌症中通常观察到的三维结构中的生长。开发多细胞肿瘤球体（MCTS）培养模型来模拟这些特征。然而，体内肿瘤生长的特征还在于存在由氧合梯度和对营养物的差异获取产生的缺血和坏死区域。缺氧和坏死在肿瘤进展和治疗抵抗中起关键作用。为了提供在高度受控和标准化条件下重现这些事件的体外模型，我们产生了不同大小的结直肠癌（CRC）细胞球体，并分析了它们的基因表达谱和对目前用于治疗方案的5FU治疗的敏感性。在这里，我们确定了三个MCTS阶段，对应于定义的球体大小，其特点是常氧，缺氧，缺氧加上坏死，分别。重要的是，我们发现MCTS包括缺氧和坏死区域最接近地模拟体内发展肿瘤的基因表达谱，并显示出对5FU的最高抗性。总之，我们的数据表明，MCTS可以模仿在高度标准化和控制条件下的缺血和坏死区域的体外生成，从而有资格作为药物筛选目的的相关模型。
Culture of cancerous cells in standard monolayer conditions poorly mirrors growth in three-dimensional architectures typically observed in a wide majority of cancers of different histological origin. Multicellular tumor spheroid (MCTS) culture models were developed to mimic these features. However, in vivo tumor growth is also characterized by the presence of ischemic and necrotic areas generated by oxygenation gradients and differential access to nutrients. Hypoxia and necrosis play key roles in tumor progression and resistance to treatment. To provide in vitro models recapitulating these events in highly controlled and standardized conditions, we have generated colorectal cancer (CRC) cell spheroids of different sizes and analyzed their gene expression profiles and sensitivity to treatment with 5FU, currently used in therapeutic protocols. Here we identify three MCTS stages, corresponding to defined spheroid sizes, characterized by normoxia, hypoxia, and hypoxia plus necrosis, respectively. Importantly, we show that MCTS including both hypoxic and necrotic areas most closely mimic gene expression profiles of in vivo-developing tumors and display the highest resistance to 5FU. Taken together, our data indicate that MCTS may mimic in vitro generation of ischemic and necrotic areas in highly standardized and controlled conditions, thereby qualifying as relevant models for drug screening purposes.