Detecting and targeting mesenchymal-like subpopulations within squamous cell carcinomas
Detecting and targeting mesenchymal-like subpopulations within squamous cell carcinomas
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DOI：
10.4161/cc.10.12.15883
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发表时间：
2011-06-15
期刊：
影响因子：
4.3
通讯作者：
Herlyn, Meenhard
中科院分区：
文献类型：
--
作者：
Basu, Devraj;Montone, Kathleen T.;Herlyn, Meenhard
仅靠化疗很难根治癌内的所有细胞。这种限制可能部分归因于肿瘤细胞亚群对当前药物具有内在抗性。在鳞状细胞癌（SCC）细胞系中，我们先前描述了间充质样细胞亚群表现出表型可塑性和对细胞毒性和靶向药物的抗性增强。这些间充质样细胞（Ecad-lo）与上皮样细胞（Ecad-hi）可以根据表面e -钙粘蛋白的缺失和vimentin的表达来区分。尽管它们具有长期的可塑性，但在短期培养中，Ecad-lo和Ecad-hi亚群在纯化后保持了几乎一致的表型。这种稳定性允许分离亚群测试对细胞毒性药物顺铂的相对敏感性，与盐碱霉素相比，盐碱霉素是一种在乳腺癌中具有抗CD44(+)CD24（-）干细胞活性的化合物。与选择性地消耗Ecad-hi细胞的顺铂相比，盐霉素对Ecad-hi细胞和Ecad-lo细胞都显示出相当的疗效。通过对部分晚期SCC患者直接肿瘤异种移植（DTXs）样本中vimentin阳性恶性亚群的免疫组织化学检测，确定了这些间质样Ecad-lo细胞的体内相关性。顺铂治疗已建立DTXs的小鼠引起残留肿瘤中vimentin阳性恶性细胞的富集，而盐碱霉素则减少了同一亚群。这些结果表明，间充质样SCC细胞抵抗目前的化疗，对针对乳腺癌干细胞样亚群的治疗策略有反应。此外，他们提供的证据表明，间充质样亚群在晚期SCCs中有很好的代表性，这表明该亚群的内在耐药性具有很高的临床相关性。
Curative eradication of all cells within carcinomas is seldom achievable with chemotherapy alone. This limitation may be partially attributable to tumor cell subpopulations with intrinsic resistance to current drugs. Within squamous cell carcinoma (SCC) cell lines, we previously characterized a subpopulation of mesenchymal-like cells displaying phenotypic plasticity and increased resistance to both cytotoxic and targeted agents. These mesenchymal-like (Ecad-lo) cells are separable from epithelial-like (Ecad-hi) cells based on loss of surface E-cadherin and expression of vimentin. Despite their long-term plasticity, both Ecad-lo and Ecad-hi subsets in short-term culture maintained nearly uniform phenotypes after purification. This stability allowed testing of segregated subpopulations for relative sensitivity to the cytotoxic agent cisplatin in comparison to salinomycin, a compound with reported activity against CD44(+)CD24(-) stem-like cells in breast carcinomas. Salinomycin showed comparable efficacy against both Ecad-hi and Ecad-lo cells, in contrast to cisplatin, which selectively depleted Ecad-hi cells. An in vivo correlate of these mesenchymal-like Ecad-lo cells was identified by immunohistochemical detection of vimentin-positive malignant subsets across a part of direct tumor xenografts (DTXs) of advanced stage SCC patient samples. Cisplatin treatment of mice with established DTXs caused enrichment of vimentin-positive malignant cells in residual tumors, but salinomycin depleted the same subpopulation. These results demonstrate that mesenchymal-like SCC cells, which resist current chemotherapies, respond to a treatment strategy developed against a stem-like subset in breast carcinoma. Further, they provide evidence of mesenchymal-like subsets being well-represented across advanced stage SCCs, suggesting that intrinsic drug resistance in this subpopulation has high clinical relevance.