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Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

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2018 Impact Factor: 1.847

Front. Med.    2019, Vol. 13 Issue (5) : 531-539    https://doi.org/10.1007/s11684-019-0700-1
REVIEW
A reignited debate over the cell(s) of origin for glioblastoma and its clinical implications
Xiaolin Fan, Yanzhen Xiong, Yuan Wang()
Department of Neurology and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China
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Abstract

Glioblastoma (GBM) is the most common and lethal primary neoplasm in the central nervous system. Despite intensive treatment, the prognosis for patients with GBM remains poor, with a median survival of 14--16 months. 90% of GBMs are primary GBMs that are full-blown at diagnosis without evidences of a pre-existing less-malignant precursor lesion. Therefore, identification of the cell(s) of origin for GBM---the normal cell or cell type that acquires the initial GBM-promoting genetic hit(s)---is the key to the understanding of the disease etiology and the development of novel therapies. Neural stem cells and oligodendrocyte precursor cells are the two major candidates for the cell(s) of origin for GBM. Latest data from human samples have reignited the longstanding debate over which cells are the clinically more relevant origin for GBMs. By critically analyzing evidences for or against the candidacy of each cell type, we highlight the most recent progress and debate in the field, explore the clinical implications, and propose future directions toward early diagnosis and preventive treatment of GBMs.

Keywords glioblastoma      cell(s) of origin      neural stem cells      oligodendrocyte precursor cells      subventricular zone      early diagnosis     
Corresponding Author(s): Yuan Wang   
Just Accepted Date: 13 June 2019   Online First Date: 19 July 2019    Issue Date: 14 October 2019
 Cite this article:   
Xiaolin Fan,Yanzhen Xiong,Yuan Wang. A reignited debate over the cell(s) of origin for glioblastoma and its clinical implications[J]. Front. Med., 2019, 13(5): 531-539.
 URL:  
https://academic.hep.com.cn/fmd/EN/10.1007/s11684-019-0700-1
https://academic.hep.com.cn/fmd/EN/Y2019/V13/I5/531
Cell of origin NSC References (NSC) OPC References (OPC)
Makers expression Nestin, GFAP, Sox2 Stiles and Rowitch, 2008 [15] Olig2, NG2, PDGFR Bergles and Richardson, 2015 [11]
Sturm et al., 2014 [1] Sturm et al., 2014 [1]
Xenograft models Driver mutations    
Olig2 Ligon et al., 2007 [19]
Pten Duan et al., 2015 [20]
p53, Akt Hu et al., 2016 [18]
p53, Olig2, EGFRIII Griveau et al., 2018 [17]
GEM models Driver mutations   Driver mutations  
p53, Nf1 Zhu et al., 2005 [21] PDGF Assanah et al., 2006 [47]
p53, Pten Zheng et al., 2008 [23] p53, Nf1 Liu et al., 2011 [41]
p53, Pten Jacques et al., 2010 [29] p53, Nf1 Galvao et al., 2014 [45]
p53 Wang et al., 2009 [30] p53, Pten Lei et al., 2011 [46]
p53, Pten, Nf1 Alcantara Llaguno et al., 2009 [28] Nf1, p53, Pten Alcantara Llaguno et al., 2015 [44]
p53, Pten, Nf1 Chen et al., 2012 [24]  
p53, Pten, Rictor Akgul et al., 2018 [25]
PDGFA, p53, Nf1 Ozawa et al., 2014 [26]
p53, Olig2 Griveau et al., 2018 [17]
Self-renewal and proliferation in adult human brains Hippocampal neurogensis drops to undetectable level during childhood Sorrells et al., 2018 [7] White matter OPCs approach stable numbers at around 5 years Yeung et al., 2014 [48]
SVZ neurogensis fully disappears at around 18 month Sanai et al., 2011 [31] The number of gray matter oligodendrocytes does not plateau until 40 years of age Yeung et al., 2014 [48]
Neurogenesis persists throughout life Boldrini et al., 2018 [8]  
Clinical evidence GBM frequently diagnosed in SVZ-associated areas Barami et al., 2009 [22] GBM frequently diagnosed in the subcortical white matter Louis et al., 2016 [3]
Low level GBM driver mutations in tumor-free SVZ tissue and high level driver mutations in their matching tumors Lee et al., 2018 [6]  
Tab.1  Evidences for and aganist NSCs and OPCs as the cells of origin for GBM
Fig.1  A possible unifying model for the cell(s) of origin for GBM. (A) NSCs are the cells that accumulate multiple oncogenic mutations to give rise to two subtypes of glioblastoma. Left: The normal adult neurogenesis process from NSCs in the brain. Middle: Normal NSCs sequentially accumulate oncogenic events A (red), B (yellow), and C (purple) and transform into mutant NSCs (NSC-ABC). Right: Mutant NSCs with multiple oncogenic mutations directly generate one subtype of glioblastoma (GBM subtype 1) or pass down the mutations to descendant transit amplifying cells (TAP) and OPCs to generate another subtype of GBM (GBM subtype 2). OPCs can only generate GBM subtype 2. (B) Mutant NSCs could directly give rise to GBMs in SVZ-associated areas (left panel), or indirectly through their descendant progenitors in distant brain regions (right panel), while NSCs carrying low-level driver mutations remain in the non-cancerous SVZ.
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