TGF-β2 dictates disseminated tumour cell fate in target organs through TGF-β-RIII and p38α/β signalling

被引：372

作者：

Bragado, Paloma ^{[1
]}

Estrada, Yeriel ^{[1
]}

Parikh, Falguni ^{[1
]}

Krause, Sarah ^{[2
]}

Capobianco, Carla ^{[3
]}

Farina, Hernan G. ^{[3
]}

Schewe, Denis M. ^{[1
,2
]}

Aguirre-Ghiso, Julio A. ^{[1
,4
]}

机构：

[1] Mt Sinai Sch Med, Tisch Canc Inst, Dept Otolaryngol, Div Hematol & Oncol,Dept Med, New York, NY 10029 USA

[2] Univ Hosp Schleswig Holstein, Dept Gen Pediat, D-24118 Kiel, Germany

[3] Quilmes Natl Univ, Dept Sci & Technol, Lab Mol Oncol, Buenos Aires, DF, Argentina

[4] Mt Sinai Sch Med, Black Family Stem Cell Inst, New York, NY 10029 USA

来源：

NATURE CELL BIOLOGY | 2013年 / 15卷 / 11期

关键词：

HEMATOPOIETIC STEM; CANCER METASTASIS; UP-REGULATION; IN-VIVO; RECEPTOR; GROWTH; KINASE; BONE; INTRAVASATION; DORMANCY;

D O I：

10.1038/ncb2861

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

In patients, non-proliferative disseminated tumour cells (DTCs) can persist in the bone marrow (BM) while other organs (such as lung) present growing metastasis. This suggested that the BM might be a metastasis 'restrictive soil' by encoding dormancy-inducing cues in DTCs. Here we show in a head and neck squamous cell carcinoma (HNSCC) model that strong and specific transforming growth factor-beta (TGF-beta) signalling in the BM activates the MAPK p38cdp, inducing an (ERK/p38 alpha/beta signalling ratio. This results in induction of DEC2/SHARP1 and p27, downregulation of cyclin-dependent kinase 4 (CDK4) and dormancy of malignant DTCs. TGF-02-induced dormancy required TGF-beta receptor-I (TGF-beta-R1), TGF-beta-RIII and SMAD1/5 activation to induce p27. In lungs, a metastasis 'permissive soil' with low TGF-beta levels, DTC dormancy was short-lived and followed by metastatic growth. Importantly, systemic inhibition of TGF-beta-RI or p38cdp activities awakened dormant DTCs, fuelling multi-organ metastasis. Our work reveals a 'seed and soil' mechanism where TGF-beta and TGF-beta-RII signalling through p38cdp regulates DTC dormancy and defines restrictive (BM) and permissive (lung) microenvironments for HNSCC metastasis.

引用

页码：1351 / U210

页数：28

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