Glioblastoma stem cells exploit the αvβ8 integrin-TGFβ1 signaling axis to drive tumor initiation and progression

被引:46
作者
Guerrero, P. A. [1 ]
Tchaicha, J. H. [1 ]
Chen, Z. [1 ]
Morales, J. E. [1 ]
McCarty, N. [2 ]
Wang, Q. [3 ,4 ]
Sulman, E. P. [3 ,4 ,5 ]
Fuller, G. [6 ]
Lang, F. F. [1 ]
Rao, G. [1 ]
McCarty, J. H. [1 ]
机构
[1] Univ Texas MD Anderson Canc Ctr, Dept Neurosurg, 1515 Holcombe Blvd,Unit 1004, Houston, TX 77030 USA
[2] Univ Texas Hlth Sci Ctr Houston, Brown Inst Mol Med, Houston, TX 77030 USA
[3] Univ Texas MD Anderson Canc Ctr, Dept Radiat Oncol, Houston, TX 77030 USA
[4] Univ Texas MD Anderson Canc Ctr, Dept Genom Med, Houston, TX 77030 USA
[5] Univ Texas MD Anderson Canc Ctr, Dept Translat Mol Pathol, Houston, TX 77030 USA
[6] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA
关键词
GROWTH-FACTOR-BETA; ANTI-VEGF THERAPY; TGF-BETA; INTEGRIN ALPHA-V-BETA-8; ANTIANGIOGENIC THERAPY; CEREBRAL-HEMORRHAGE; SELF-RENEWAL; BRAIN; CANCER; EXPRESSION;
D O I
10.1038/onc.2017.248
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Glioblastoma (GBM) is a primary brain cancer that contains populations of stem-like cancer cells (GSCs) that home to specialized perivascular niches. GSC interactions with their niche influence self-renewal, differentiation and drug resistance, although the pathways underlying these events remain largely unknown. Here, we report that the integrin alpha v beta 8 and its latent transforming growth factor beta 1 (TGF beta 1) protein ligand have central roles in promoting niche co-option and GBM initiation. alpha v beta 8 integrin is highly expressed in GSCs and is essential for self-renewal and lineage commitment in vitro. Fractionation of beta 8(high) cells from freshly resected human GBM samples also reveals a requirement for this integrin in tumorigenesis in vivo. Whole-transcriptome sequencing reveals that alpha v beta 8 integrin regulates tumor development, in part, by driving TGF beta 1-induced DNA replication and mitotic checkpoint progression. Collectively, these data identify the av beta 8 integrin-TGF beta 1 signaling axis as crucial for exploitation of the perivascular niche and identify potential therapeutic targets for inhibiting tumor growth and progression in patients with GBM.
引用
收藏
页码:6568 / 6580
页数:13
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