Malignant Astrocytomas Originate from Neural Stem/Progenitor Cells in a Somatic Tumor Suppressor Mouse Model

Llaguno, Sheila Alcantara; Chen, Jian; Kwon, Chil Hun; Jackson, Erica; Li, Yanjiao; Burns, Dennis K.; Álvarez-Buylla, Arturo; Parada, Luis F.

doi:10.1016/j.ccr.2009.02.008

Cited by 73 publications

(96 citation statements)

References 1 publication

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“…The data presented here directly compare the relative susceptibility of bulge cells and their more restricted progeny to serve as cancer cells of origin in SCC; these results are consistent with data from cancers of other tissues, such as the intestine, blood and brain (51)(52)(53). Similar to these other studies, SCs are more likely to serve as cancer cells of origin than their more restricted progeny.…”

Section: Discussionsupporting

confidence: 80%

Defining the origins of Ras/p53-mediated squamous cell carcinoma

White

Tran

Khuu

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

170

158

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The precise identity of cancer cells of origin and the molecular events of tumor initiation in epidermal squamous cell carcinoma (SCC) are unknown. Here we show that malignancy potential is related to the developmental capacity of the initiating cancer cell in a genetically defined, intact, and inducible in vivo model. Specifically, these data demonstrate that SCCs can originate from inside the hair follicle stem cell (SC) niche or from immediate progenitors, whereas more developmentally restricted progeny, the transit amplifying (TA) cells, are unable to generate even benign tumors in the same genetic context. Using a temporal model of tumorigenesis in situ, we highlight the phenotypes of cancer progression from the hair follicle SC niche, including hyperplasia, epithelial to mesenchymal transition, and SCC formation. Furthermore, we provide insights into the inability of hair follicle TA cells to respond to tumorigenic stimuli. mouse models of cancer | tumor initiating cells | epidermal stem cells S quamous cell carcinoma (SCC), a common type of nonmelanoma skin cancer, harbors significant risk of metastasis that can eventually lead to death (1). Permanent treatment and prevention of SCC requires an improved understanding of the unique cell types capable of initiating these malignancies and the mechanisms that underlie their transformation. Mutations in the Ras gene family are found in 30% of all human cancers and are often found in human cases of SCC (2-4). Numerous animal studies have extended the understanding of SCC by demonstrating a causative role for the Ras family in the development of SCC. In these mouse models, Ras signaling has been shown to be sufficient to drive epidermal tumorigenesis through either overexpression or targeted expression of an oncogenic form of Hras or Kras. These studies have targeted broad epidermal cell populations that include stem cells (SCs), as well as cells of the outer root sheath (ORS) and interfollicular epidermis (IFE) (4-9). Among these, a landmark article indicated that the SCC cells of origin reside in the hair follicle rather than the IFE (5). However, the keratin promoter used to drive oncogenic Ras expression did not allow for a direct determination of the cancer cell of origin amongst the different cell types in the hair follicle. The candidates for an SCC cell of origin therefore remained follicular SCs, ORS cells, transit amplifying (TA) cells in the matrix, and the differentiated cells of the inner root sheath (IRS) and hair shaft. In addition, other studies have shown that lineagerestricted or differentiated cells of the IFE are sufficient to serve as cancer cells of origin when subjected to supraphysiological levels of Ras activity at sites of mechanical stress (10). These high levels of Ras expression, however, are not normally found in human cases of SCC (10, 11). Between follicular SCs and TA cells, it is not clear whether one or both are capable of initiating tumorigenesis. Thus, we sought to directly compare the malignancy potential between follicular ...

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Section: Discussionsupporting

confidence: 80%

Defining the origins of Ras/p53-mediated squamous cell carcinoma

White

Tran

Khuu

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

170

158

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“…Finally, p53, which has emerged as an important regulator of mitochondrial metabolism and cellular redox control (15)(16)(17), is often found mutated or functionally inactivated in HGG. Its inactivation in neural progenitor/stem cells (NPCs), which act as HGG cells of origin, contributes to gliomagenesis (18)(19)(20)(21)(22). In particular, deletion of a significant portion of the p53 DNA binding domain induces the accumulation of cooperative oncogenic events, thus leading to HGG (21).…”

Section: Inhibition Of Oxidative Metabolism Leads To P53 Genetic Inacmentioning

confidence: 99%

Inhibition of oxidative metabolism leads to p53 genetic inactivation and transformation in neural stem cells

Bartesaghi

Graziano

Galavotti

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Alterations of mitochondrial metabolism and genomic instability have been implicated in tumorigenesis in multiple tissues. High-grade glioma (HGG), one of the most lethal human neoplasms, displays genetic modifications of Krebs cycle components as well as electron transport chain (ETC) alterations. Furthermore, the p53 tumor suppressor, which has emerged as a key regulator of mitochondrial respiration at the expense of glycolysis, is genetically inactivated in a large proportion of HGG cases. Therefore, it is becoming evident that genetic modifications can affect cell metabolism in HGG; however, it is currently unclear whether mitochondrial metabolism alterations could vice versa promote genomic instability as a mechanism for neoplastic transformation. Here, we show that, in neural progenitor/stem cells (NPCs), which can act as HGG cell of origin, inhibition of mitochondrial metabolism leads to p53 genetic inactivation. Impairment of respiration via inhibition of complex I or decreased mitochondrial DNA copy number leads to p53 genetic loss and a glycolytic switch. p53 genetic inactivation in ETC-impaired neural stem cells is caused by increased reactive oxygen species and associated oxidative DNA damage. ETC-impaired cells display a marked growth advantage in the presence or absence of oncogenic RAS, and form undifferentiated tumors when transplanted into the mouse brain. Finally, p53 mutations correlated with alterations in ETC subunit composition and activity in primary glioma-initiating neural stem cells. Together, these findings provide previously unidentified insights into the relationship between mitochondria, genomic stability, and tumor suppressive control, with implications for our understanding of brain cancer pathogenesis.

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“…This capacity is dictated not only by brain location, but also by the developmental stage. Elegant studies by a number of groups have demonstrated a more limited capacity for accelerated growth following Nf1 inactivation in differentiated astrocytes compared with glial progenitor cells (Zhu et al, 2005;Alcantara Llaguno et al, 2009). Together, these observations establish a regional and developmental context in which bi-allelic Nf1 inactivation will lead to glioma formation.…”

Section: Resultsmentioning

confidence: 82%

The ecology of brain tumors: lessons learned from neurofibromatosis-1

Pong

Gutmann

2010

Oncogene

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Traditionally, cancer studies have primarily focused on mutations that activate growth or survival pathways in susceptible pre-neoplastic/neoplastic cells. However, recent research has revealed a critical role for nonneoplastic cells within the tumor microenvironment in the process of cancer formation and progression. In addition, the existence of regional and developmental variations in susceptible cell types and supportive microenvironments support a model of tumorigenesis in which the dynamic symbiotic relationship between neoplastic and non-neoplastic cell types dictate where and when cancers form and grow. In this review, we highlight advances in neurofibromatosis type 1 (NF1) genetically engineered mouse brain tumor (glioma) modeling to reveal how cellular and molecular heterogeneity in both the pre-neoplastic/ neoplastic and non-neoplastic cellular compartments contribute to gliomagenesis and glioma growth.

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Malignant Astrocytomas Originate from Neural Stem/Progenitor Cells in a Somatic Tumor Suppressor Mouse Model

Cited by 73 publications

References 1 publication

Defining the origins of Ras/p53-mediated squamous cell carcinoma

Defining the origins of Ras/p53-mediated squamous cell carcinoma

Inhibition of oxidative metabolism leads to p53 genetic inactivation and transformation in neural stem cells

The ecology of brain tumors: lessons learned from neurofibromatosis-1

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