Heterogeneous cancer-associated fibroblast population potentiates neuroendocrine differentiation and castrate resistance in a CD105-dependent manner.
Heterogeneous cancer-associated fibroblast population potentiates neuroendocrine differentiation and castrate resistance in a CD105-dependent manner.
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DOI：
10.1038/s41388-018-0461-3
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发表时间：
2019-01
期刊：
影响因子：
8
通讯作者：
Bhowmick NA
中科院分区：
文献类型：
--
作者：
Kato M;Placencio-Hickok VR;Madhav A;Haldar S;Tripathi M;Billet S;Mishra R;Smith B;Rohena-Rivera K;Agarwal P;Duong F;Angara B;Hickok D;Liu Z;Bhowmick NA
异质性前列腺癌相关成纤维细胞（CAF）有助于肿瘤进展和对雄激素信号剥夺治疗（ADT）的抵抗。与低传代CAF相比，发现经历延长传代的CAF失去肿瘤扩张潜力和异质性。细胞表面内皮糖蛋白（CD105），已知是表达在增殖内皮细胞和间充质干细胞，减少在高传代CAF。RNA测序显示SFRP 1被肿瘤诱导CAF明确表达，这进一步证明以CD105依赖性方式发生。此外，ADT导致CD 105+成纤维细胞群和下游SFRP 1在三维培养物和患者来源的异种移植物组织中进一步扩增。在患者中，发现CD 105+成纤维细胞限制上皮细胞的神经内分泌分化。由CD 105信号驱动的CAF衍生的SFRP 1是以旁分泌方式诱导前列腺癌神经内分泌分化的必要和充分条件。部分人源化的CD105中和抗体，TRC105，抑制成纤维细胞SFRP 1的表达和上皮神经内分泌分化。在一种新的合成致死性范例中，我们发现，在ADT或TRC105单独作用很小的模型中，分别用ADT和TRC105同时靶向上皮细胞及其微环境，减少了去势抵抗性肿瘤的进展。
Heterogeneous prostatic carcinoma associated fibroblasts (CAF) contribute to tumor progression and resistance to androgen signaling deprivation therapy (ADT). CAF subjected to extended passaging, compared to low passage CAF, were found to lose tumor expansion potential and heterogeneity. Cell surface endoglin (CD105), known to be expressed on proliferative endothelia and mesenchymal stem cells, was diminished in high passage CAF. RNA-sequencing revealed SFRP1 to be distinctly expressed by tumor-inductive CAF, which was further demonstrated to occur in a CD105-dependent manner. Moreover, ADT resulted in further expansion of the CD105+ fibroblastic population and downstream SFRP1 in 3-dimensional cultures and patient derived xenograft tissues. In patients, CD105+ fibroblasts were found to circumscribe epithelia with neuroendocrine differentiation. CAF-derived SFRP1, driven by CD105 signaling, was necessary and sufficient to induce prostate cancer neuroendocrine differentiation in a paracrine manner. A partially humanized CD105 neutralizing antibody, TRC105, inhibited fibroblastic SFRP1 expression and epithelial neuroendocrine differentiation. In a novel synthetic lethality paradigm, we found that simultaneously targeting the epithelia and its microenvironment with ADT and TRC105, respectively, reduced castrate resistant tumor progression, in a model where either ADT or TRC105 alone had little effect.
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影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
DOI：
10.1186/s13058-016-0740-2
发表时间：
2016-08-11
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Bussard KM;Mutkus L;Stumpf K;Gomez-Manzano C;Marini FC
通讯作者：
Marini FC
影响因子：
2.8
作者：
Dayyani, Farshid;Varkaris, Andreas;Gallick, Gary E.
通讯作者：
Gallick, Gary E.
影响因子：
21.3
作者：
通讯作者：
--
影响因子：
11.2
作者：
Franco OE;Jiang M;Strand DW;Peacock J;Fernandez S;Jackson RS 2nd;Revelo MP;Bhowmick NA;Hayward SW
通讯作者：
Hayward SW