TGF-β-Induced Quiescence Mediates Chemoresistance of Tumor-Propagating Cells in Squamous Cell Carcinoma.
TGF-β-Induced Quiescence Mediates Chemoresistance of Tumor-Propagating Cells in Squamous Cell Carcinoma.
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TGF-β诱导的静止介导了鳞状细胞癌中肿瘤传播细胞的化学抗性。
DOI：
10.1016/j.stem.2017.10.001
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发表时间：
2017-11-02
期刊：
影响因子：
23.9
通讯作者：
Schober M
中科院分区：
文献类型：
--
作者：
Brown JA;Yonekubo Y;Hanson N;Sastre-Perona A;Basin A;Rytlewski JA;Dolgalev I;Meehan S;Tsirigos A;Beronja S;Schober M
鳞状细胞癌 (SCC) 是由肿瘤增殖癌细胞 (TPC) 维持的异质性肿瘤。鳞状细胞癌经常通过仍未知的机制抵抗化疗。在这里，我们将基于 H2BGFP 的脉冲追踪与细胞表面标记相结合，以区分 SCC 内的静止 TPC 和增殖 TPC。我们发现，静止的 TPC 能够抵抗 DNA 损伤，并在化疗后表现出增加的致瘤潜力，而增殖的 TPC 则会发生凋亡。静止由 TGFβ/SMAD 信号传导调节，该信号传导直接调节细胞周期基因转录以控制可逆的 G1 细胞周期停滞，与 p21CIP 功能无关。事实上，遗传或药理学抑制 TGFβ 会增加 TPC 对化疗的敏感性，因为它可以防止进入静止状态。这些发现提供了直接证据，表明 TPC 可以可逆地进入静止、化疗耐药状态，这强调了需要采用组合方法来改善化疗耐药 SCC 的治疗。异质性肿瘤，例如鳞状细胞癌，通常具有化学抗性，并且由特征较差的肿瘤增殖性癌细胞 (TPC) 亚群组成。布朗等人。证明 TPC 可逆地进入静止、耐药状态，抑制 TGFβ 信号传导可以通过防止肿瘤细胞周期退出来增加其对化疗的敏感性。
Squamous cell carcinomas (SCCs) are heterogeneous tumors that are sustained by tumor propagating cancer cells (TPCs). SCCs frequently resist chemotherapy through mechanisms that are still unknown. Here, we combine H2BGFP based pulse-chasing with cell surface markers to distinguish quiescent from proliferative TPCs within SCCs. We find that quiescent TPCs resist DNA damage and exhibit increased tumorigenic potential in response to chemotherapy, whereas proliferative TPCs undergo apoptosis. Quiescence is regulated by TGFβ/SMAD signaling, which directly regulates cell cycle gene transcription to control a reversible G1 cell cycle arrest, independent of p21CIP function. Indeed, genetic or pharmacological TGFβ inhibition increases the susceptibility of TPCs to chemotherapy as it prevents entry into a quiescent state. These findings provide direct evidence that TPCs can reversibly enter a quiescent, chemoresistant state which underscores the need for combinatorial approaches to improve treatment of chemotherapy-resistant SCCs. Heterogeneous tumors, such as squamous cell carcinomas, are often chemoresistant and comprised of subpopulations of poorly-characterized tumor propagating cancer cells (TPCs). Brown et al. demonstrate that TPCs reversibly enter a quiescent, chemoresistant state and inhibiting TGFβ signaling can increase their susceptibility to chemotherapy by preventing cell cycle withdrawal in tumors.
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DOI：
10.1126/science.1180794
发表时间：
2010-01-29
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Li L;Clevers H
通讯作者：
Clevers H
影响因子：
64.8
作者：
Boumahdi, Soufiane;Driessens, Gregory;Blanpain, Cedric
通讯作者：
Blanpain, Cedric
影响因子：
158.5
作者：
Bonner, JA;Harari, PM;Ang, KK
通讯作者：
Ang, KK
影响因子：
64.8
作者：
Driessens G;Beck B;Caauwe A;Simons BD;Blanpain C
通讯作者：
Blanpain C
影响因子：
56.9
作者：
Di Cunto, F;Topley, G;Dotto, GP
通讯作者：
Dotto, GP