Cancer-Associated Fibroblasts Facilitate Squamous Cell Carcinoma Lung Metastasis in Mice by Providing TGFβ-Mediated Cancer Stem Cell Niche.
Cancer-Associated Fibroblasts Facilitate Squamous Cell Carcinoma Lung Metastasis in Mice by Providing TGFβ-Mediated Cancer Stem Cell Niche.
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癌症相关的成纤维细胞通过提供TGFβ介导的癌症干细胞生态位促进小鼠中的鳞状细胞癌转移。
DOI：
10.3389/fcell.2021.668164
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发表时间：
2021
影响因子：
5.5
通讯作者：
Wang XJ
中科院分区：
文献类型：
--
作者：
Shi X;Luo J;Weigel KJ;Hall SC;Du D;Wu F;Rudolph MC;Zhou H;Young CD;Wang XJ
癌症相关成纤维细胞（CAFs）已被证明可促进鳞状细胞癌（SCC）的生长，但它们是否促进SCC肺转移尚不清楚。我们从K15.KrasG12D.Smad4 - / - 小鼠SCC中生成了CAFs。RNA表达分析表明，与正常组织相关成纤维细胞（NAFs）相比，CAFs的转化生长因子 - β（TGFβ）信号通路更为富集，因此我们评估了富含TGFβ的CAFs如何影响SCC转移。我们将SCC细胞与CAFs共同注射到皮肤、尾静脉或肺部，以模拟肺转移的连续步骤。CAFs仅在肺部共移植时增加了SCC体积，与NAF共移植的SCC相比，其增殖和血管生成增加，凋亡减少。一种具有临床相关性的TGFβ受体抑制剂减弱了这些CAF的作用，这表明CAFs促进了TGFβ依赖性SCC细胞在肺部的定植和存活。当与数量有限的SCC癌症干细胞（CSCs）共同移植到肺部时，CAFs也增加了肿瘤体积。在体外，与共培养的CAFs或CAF条件培养基（其中含有最高浓度的TGFβ1）一起培养时，CSC球形成和侵袭增加，并且这些CAF的作用被TGFβ抑制所阻断。此外，伴有肺转移的原发性人口腔SCC中的TGFβ活化程度高于无肺转移的SCC。类似地，在有微转移的小鼠肺部检测到了TGFβ活化。我们的数据表明，富含TGFβ的CAFs在SCC转移过程中对CSC在肺部的定植和扩增起因果作用，为SCC肺转移提供了一个预后标志物和治疗靶点。
Cancer-associated fibroblasts (CAFs) have been shown to enhance squamous cell carcinoma (SCC) growth, but it is unclear whether they promote SCC lung metastasis. We generated CAFs from K15.KrasG12D.Smad4–/– mouse SCCs. RNA expression analyses demonstrated that CAFs had enriched transforming growth factor-beta (TGFβ) signaling compared to normal tissue-associated fibroblasts (NAFs), therefore we assessed how TGFβ-enriched CAFs impact SCC metastasis. We co-injected SCC cells with CAFs to the skin, tail vein, or the lung to mimic sequential steps of lung metastasis. CAFs increased SCC volume only in lung co-transplantations, characterized with increased proliferation and angiogenesis and decreased apoptosis compared to NAF co-transplanted SCCs. These CAF effects were attenuated by a clinically relevant TGFβ receptor inhibitor, suggesting that CAFs facilitated TGFβ-dependent SCC cell seeding and survival in the lung. CAFs also increased tumor volume when co-transplanted to the lung with limiting numbers of SCC cancer stem cells (CSCs). In vitro, CSC sphere formation and invasion were increased either with co-cultured CAFs or with CAF conditioned media (which contains the highest TGFβ1 concentration) and these CAF effects were blocked by TGFβ inhibition. Further, TGFβ activation was higher in primary human oral SCCs with lung metastasis than SCCs without lung metastasis. Similarly, TGFβ activation was detected in the lungs of mice with micrometastasis. Our data suggest that TGFβ-enriched CAFs play a causal role in CSC seeding and expansion in the lung during SCC metastasis, providing a prognostic marker and therapeutic target for SCC lung metastasis.
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影响因子：
5.2
作者：
Markwell SM;Weed SA
通讯作者：
Weed SA
DOI：
10.3390/ijerph18010192
发表时间：
2020-12-29
影响因子：
--
作者：
Maqsood A;Ali A;Zaffar Z;Mokeem S;Mokeem SS;Ahmed N;Al-Hamoudi N;Vohra F;Javed F;Abduljabbar T
通讯作者：
Abduljabbar T
影响因子：
8
作者：
Kim M;Jang K;Miller P;Picon-Ruiz M;Yeasky TM;El-Ashry D;Slingerland JM
通讯作者：
Slingerland JM
影响因子：
7.4
作者：
Kallergi, Galatea;Tsintari, Vasileia;Georgoulias, Vassilis
通讯作者：
Georgoulias, Vassilis
影响因子：
12.8
作者：
Han, Zhezhu;Kang, Dongxu;Song, Jae J.
通讯作者：
Song, Jae J.