Bone morphogenetic proteins inhibit the tumorigenic potential of human brain tumour-initiating cells

Piccirillo, Sara Grazia Maria; Reynolds, Brent A.; Zanetti, Nadia; Lamorte, Giuseppe; Binda, Elena; Broggi, Giovanni; Brem, Henry; Olivi, Alessandro; DiMeco, Francesco; Vescovi, Angelo L.

doi:10.1038/nature05349

Cited by 1,061 publications

(988 citation statements)

References 30 publications

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“…Several reports implicate GSCs in therapy resistance and showed that efficacy of therapy can be improved, if stem-like cells are targeted additionally. 15,16,29 These findings emphasise the need to improve understanding of the biological behaviours of GSCs and their underlying regulatory mechanisms. In that respect, a previous study identified kinases and phosphatases relevant for the survival of GSCs and thereby potential therapeutical targets for glioblastoma.…”

Section: Discussionmentioning

confidence: 96%

Stem cell characteristics in glioblastoma are maintained by the ecto-nucleotidase E-NPP1

et al. 2014

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Glioblastomas are highly aggressive brain tumours and are characterised by substantial cellular heterogeneity within a single tumour. A sub-population of glioblastoma stem-like cells (GSCs) that shares properties with neural precursor cells has been described, exhibiting resistance to therapy and therefore being considered responsible for the high recurrence rate in glioblastoma. To elucidate the underlying cellular processes we investigated the role of phosphatases in the GSC phenotype, using an in vitro phosphatome-wide RNA interference screen. We identified a set of genes, the knockdown of which induces a significant decrease in the glioma stem cell marker CD133, indicating a role in the glioblastoma stem-like phenotype. Among these genes, the ecto-nucleotidase ENPP1 (ectonucleotide pyrophosphatase/phosphodiesterase 1) was found to be highly expressed in GSCs compared with normal brain and neural stem cells. Knockdown of ENPP1 in cultured GSCs resulted in an overall downregulation of stem cell-associated genes, induction of differentiation into astrocytic cell lineage, impairment of sphere formation, in addition to increased cell death, accumulation of cells in G1/G0 cell cycle phase and sensitisation to chemotherapeutic treatment. Genome-wide gene expression analysis and nucleoside and nucleotide profiling revealed that knockdown of ENPP1 affects purine and pyrimidine metabolism, suggesting a link between ENPP1 expression and a balanced nucleoside-nucleotide pool in GSCs. The phenotypic changes in E-NPP1-deficient GSCs are assumed to be a consequence of decreased transcriptional function of E2F1. Together, these results reveal that E-NPP1, by acting upstream of E2F1, is indispensable for the maintenance of GSCs in vitro and hence required to keep GSCs in an undifferentiated, proliferative state. Glioblastoma, classified by the WHO (World Health Organization) as grade IV astrocytoma, 1 is the most common primary malignant brain tumour in adults. Despite progress in surgical resection, radiation and chemotherapy, glioblastoma remains a deadly disease with a median survival time of about 1 year. 2 One particular therapeutic challenge for glioblastoma treatment is posed by their remarkable intratumoural cellular heterogeneity. Several studies indicate the existence of a highly tumourigenic, sub-population of cancer cells with stemlike characteristics. [3][4][5] There is substantial evidence that these so-called cancer stem cells have inherent chemotherapy and radiation resistance. 6,7 These findings suggest that cancer cells harbouring stem cell-like characteristics are responsible for ineffective therapy, explaining high recurrence rates despite significant reduction in tumour volume. Glioblastoma stem-like cells (GSCs) share properties with neural precursor cells, such as a capacity for self-renewal, differentiation and maintained proliferation, as well as stem cell marker expression. 4,5,8,9 GSCs were originally defined by expression of CD133 (Prominin-1) and its extracellular AC133 epitope. 4 Although recent...

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Section: Discussionmentioning

confidence: 96%

Stem cell characteristics in glioblastoma are maintained by the ecto-nucleotidase E-NPP1

et al. 2014

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“…In several types of cancers, BMP ligands are estimated as a novel therapeutic agent, which can induce 'differentiation' of cancer stem cells, attenuate the tumor-forming ability of cancer, and may be used to prevent growth and recurrence of cancers (Piccirillo et al, 2006;Sneddon et al, 2006;Lee et al, 2008). However, BMP-4 reduced neither the expression of ABCG2 in OCUM-2MLN cells nor population of SP cells in these cells (Figure 3a, b and 6a).…”

Section: Reduction Of Sp Cells In Gastric Cancer By Tgf-b S Ehata Et Almentioning

confidence: 99%

Transforming growth factor-β decreases the cancer-initiating cell population within diffuse-type gastric carcinoma cells

et al. 2010

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Stem cells in normal tissues and cancer-initiating cells (CICs) are known to be enriched in side population (SP) cells. However, the factors responsible for the regulation of expression of ABCG2, involved in efflux of dyes, in SP cells have not been fully investigated. Here, we characterized the SP cells within diffuse-type gastric carcinoma, and examined the effects of transforming growth factor-b (TGF-b) on SP cells. Diffuse-type gastric carcinoma cells established from four independent patients universally contained SP cells between 1 and 4% of total cells, which displayed greater tumorigenicity than non-SP cells did. TGF-b repressed the transcription of ABCG2 through direct binding of Smad2/3 to its promoter/enhancer, and the number of SP cells and the tumor-forming ability of cancer cells were decreased by TGF-b, although ABCG2 is not directly involved in the tumor-forming ability of SP cells. Cancer cells from metastatic site expressed much higher levels of ABCG2 and included a greater percentage of SP cells than parental cancer cells did. SP cells are thus responsible for the progression of diffuse-type gastric carcinoma, and TGF-b negatively contributes to maintain the CICs within the cancer.

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“…In malignant human glioma, Smad-dependent BMP4 signaling was able to trigger a reduction in CD133 þ CSCs, resulting in a decrease in tumorigenicity and tumor formation (Piccirillo et al, 2006). In addition, Klose et al (2011) showed that systemic BMP7 treatment inhibited tumor growth in an experimental mouse model of glioma.…”

Section: Introductionmentioning

confidence: 99%

The BMP2/7 heterodimer inhibits the human breast cancer stem cell subpopulation and bone metastases formation

et al. 2011

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Accumulating evidence suggests that a subpopulation of breast cancer cells, referred to as cancer stem cells (CSCs), have the ability to propagate a tumor and potentially seed new metastases. Furthermore, stimulation of an epithelialto-mesenchymal transition by factors like transforming growth factor-b (TGFb) is accompanied with the generation of breast CSCs. Previous observations indicated that bone morphogenetic protein-7 (BMP7) antagonizes the protumorigenic and prometastatic actions of TGFb, but whether BMP7 action is mechanistically linked to breast CSCs has remained elusive. Here, we have studied the effects of BMP7, BMP2 and a BMP2/7 heterodimer on the formation of human breast CSCs (ALDH hi /CD44 hi / CD24 À/low ) and bone metastases formation in a preclinical model of intra-cardiac injection of MDA-MB-231 cells in athymic nude (Balb/c nu/nu) mice. The BMP2/7 heterodimer was the most efficient stimulator of BMP signaling and very effectively reduced TGFb-driven Smad signaling and cancer cell invasiveness. The tested BMPs-particularly the heterodimeric BMP2/7-strongly reduced the size of the ALDH hi /CD44 hi /CD24 À/low CSC subpopulation. In keeping with these in vitro observations, pretreatment of cancer cells with BMPs for 72 h prior to systemic inoculation of the cancer cells inhibited the formation of bone metastases. Collectively, our data support the notion that breast CSCs are involved in bone metastasis formation and describe heterodimeric BMP2/7 as a powerful TGFb antagonist with anti-metastatic potency.

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Bone morphogenetic proteins inhibit the tumorigenic potential of human brain tumour-initiating cells

Cited by 1,061 publications

References 30 publications

Stem cell characteristics in glioblastoma are maintained by the ecto-nucleotidase E-NPP1

Stem cell characteristics in glioblastoma are maintained by the ecto-nucleotidase E-NPP1

Transforming growth factor-β decreases the cancer-initiating cell population within diffuse-type gastric carcinoma cells

The BMP2/7 heterodimer inhibits the human breast cancer stem cell subpopulation and bone metastases formation

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