Slow-Cycling Cancer Stem Cells Regulate Progression and Chemoresistance in Colon Cancer
Slow-Cycling Cancer Stem Cells Regulate Progression and Chemoresistance in Colon Cancer
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DOI：
10.1158/0008-5472.can-20-0378
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发表时间：
2020-10-15
期刊：
影响因子：
11.2
通讯作者：
Okamoto, Koji
中科院分区：
文献类型：
--
作者：
Shiokawa, Daisuke;Sakai, Hiroaki;Okamoto, Koji
癌症化疗耐药性通常归因于癌症干细胞（CSC）样细胞的存在，但它们是否是均匀的化疗耐药性仍不清楚。我们先前表明，在结肠肿瘤中，由TCF 1（TCF 7）驱动的LGR 5（+）CSC样细胞亚群负责致瘤性，TCF 1（TCF 7）是一种Wnt反应性转录因子。在这里，我们证明了小鼠LGR 5（+）细胞的致瘤亚群存在于慢循环状态，并确定了一个独特的22个基因的签名，这些慢循环CSC的特点。其中7个特征基因在异种移植人结肠肿瘤的慢循环LGR 5（+）细胞中特异性表达，并在结肠癌临床标本中上调。在这7个基因中，已知4个基因（APCDD 1、NOTUM、PROX 1和SP 5）是直接Wnt靶基因，并且PROX 1在结肠肿瘤的侵袭性前沿表达。PROX 1被TCF 1激活以诱导CDKN 1C并在结肠癌类器官中维持慢循环状态。引人注目的是，PROX 1是化疗后复发性生长所必需的，这表明通过靶向TCF 1-PROX 1-CDKN 1C通路抑制慢循环CSC是与常规化疗联合治疗难治性结肠癌的有效策略。这些发现说明了慢循环CSC亚群在结肠癌发展和化学抗性中的重要性，这对鉴定的慢循环CSC特征和作为治疗靶点的TCF 1-PROX 1-CDKN 1C途径具有潜在意义。
Cancer chemoresistance is often attributed to the presence of cancer stem cell (CSC)-like cells, but whether they are homogeneously chemoresistant remains unclear. We previously showed that in colon tumors, a subpopulation of LGR5(+) CSC-like cells driven by TCF1 (TCF7), a Wnt-responsive transcription factor, were responsible for tumorigenicity. Here we demonstrate that the tumorigenic subpopulation of mouse LGR5(+) cells exists in a slow-cycling state and identify a unique 22-gene signature that characterizes these slow-cycling CSC. Seven of the signature genes are specifically expressed in slow-cycling LGR5(+) cells from xenografted human colon tumors and are upregulated in colon cancer clinical specimens. Among these seven, four genes (APCDD1, NOTUM, PROX1, and SP5) are known to be direct Wnt target genes, and PROX1 was expressed in the invasive fronts of colon tumors. PROX1 was activated by TCF1 to induce CDKN1C and maintain a slow-cycling state in colon cancer organoids. Strikingly, PROX1 was required for recurrent growth after chemotherapeutic treatment, suggesting that inhibition of slow-cycling CSC by targeting the TCF1-PROX1-CDKN1C pathway is an effective strategy to combat refractory colon cancer in combination with conventional chemotherapy.Significance: These findings illustrate the importance of a slow-cycling CSC subpopulation in colon cancer development and chemoresistance, with potential implications for the identified slow-cycling CSC signatures and the TCF1-PROX1-CDKN1C pathway as therapeutic targets.