Targeting Notch to Target Cancer Stem Cells

Pannuti, Antonio; Foreman, Kimberly E.; Rizzo, Paola; Osipo, Clodia; Golde, Todd E.; Osborne, Barbara A.; Miele, Lucio

doi:10.1158/1078-0432.ccr-09-2823

Cited by 411 publications

(332 citation statements)

References 109 publications

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“…The Notch pathway can promote self-renewal of GCSCs and inhibit their differentiation. 12 In our study, treating HCMV-infected GBM cells with GSI to inhibit Notch signaling prevented neurosphere formation. Although this drug can affect other pathways, it is possible that Notch 1 downstream signaling is a key pathway controlled by HCMV to induce and maintain stemness.…”

Section: Discussionmentioning

confidence: 52%

“…25 The Notch pathway is essential for cell-cell communication and can maintain GCSCs in an immature state by promoting their self-renewal and inhibiting their differentiation. 12 Nestin overexpression increases the growth rate and migration of glioma cells and their adhesion to the extracellular matrix. 11 Both SOX2 and Oct4 participate in the reprogramming of differentiated cells into induced pluripotent stem cells and are overexpressed in various types of cancer.…”

Section: Discussionmentioning

confidence: 99%

“…Although this drug can affect other pathways, it is possible that Notch 1 downstream signaling is a key pathway controlled by HCMV to induce and maintain stemness. In fact, inhibition of Notch signaling significantly reduces GBM growth in vitro and in vivo, 12 likely by reducing the size or functionality of the cancer stem cell population. 33 This and other 17,34 innovative strategies indicate that translational therapies targeting GCSCs could significantly improve the prognosis of patients with GBM.…”

Section: Discussionmentioning

confidence: 99%

“…10 These cells often express markers associated with stem cells such as Sox2, Notch, and Oct-4. [11][12][13] This intratumoral heterogeneity and the resulting aggressiveness of GBMs are influenced by the location of the tumor within the brain and by tumor-associated microenvironmental factors (reviewed in Stopschinski et al 14 ). While the general validity of CD133 as a major GCSC marker is still debated and its exact function in gliomagenesis remains poorly understood, other GCSC markers have been identified, including Notch1, Oct4, Sox2, and Nestin.…”

mentioning

confidence: 99%

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Cytomegalovirus infection induces a stem cell phenotype in human primary glioblastoma cells: prognostic significance and biological impact

et al. 2015

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Glioblastoma (GBM) is associated with poor prognosis despite aggressive surgical resection, chemotherapy, and radiation therapy. Unfortunately, this standard therapy does not target glioma cancer stem cells (GCSCs), a subpopulation of GBM cells that can give rise to recurrent tumors. GBMs express human cytomegalovirus (HCMV) proteins, and previously we found that the level of expression of HCMV immediate-early (IE) protein in GBMs is a prognostic factor for poor patient survival. In this study, we investigated the relation between HCMV infection of GBM cells and the presence of GCSCs. Primary GBMs were characterized by their expression of HCMV-IE and GCSCs marker CD133 and by patient survival. The extent to which HCMV infection of primary GBM cells induced a GCSC phenotype was evaluated in vitro. In primary GBMs, a large fraction of CD133-positive cells expressed HCMV-IE, and higher co-expression of these two proteins predicted poor patient survival. Infection of GBM cells with HCMV led to upregulation of CD133 and other GSCS markers (Notch1, Sox2, Oct4, Nestin). HCMV infection also promoted the growth of GBM cells as neurospheres, a behavior typically displayed by GCSCs, and this phenotype was prevented by either chemical inhibition of the Notch1 pathway or by treatment with the anti-viral drug ganciclovir. GBM cells that maintained expression of HCMV-IE failed to differentiate into neuronal or astrocytic phenotypes. Our findings imply that HCMV infection induces phenotypic plasticity of GBM cells to promote GCSC features and may thereby increase the aggressiveness of this tumor. GBM is the most prevalent and the most aggressive primary malignancy of the central nervous system in adults. It is a highly vascularized and infiltrating tumor, rarely cured and prone to recurrence. The median duration of survival after diagnosis is less than 15 months, despite aggressive therapy consisting of surgical resection and concomitant radiotherapy and chemotherapy. 1 Surgical resection of GBMs is typically incomplete, as they are located in the brain and are highly infiltrative. Postoperative radiotherapy and chemotherapy fail to eradicate all remaining GBM cells. Thus, a breakthrough in identifying a new treatment option leading to a cure of this disease is still lacking.GBMs contain a subpopulation of highly tumorigenic cells with unlimited capacity for self-renewal that are commonly resistant to standard therapy. Phenotypically and functionally, these cells resemble neural stem cells and, when implanted in immunodeficient mice, can generate new tumors. As a result, they are referred to as glioma cancer initiating cells or glioma cancer stem cells (GCSCs) (reviewed in Lima et al. 2 ).Because of their apparent pivotal role in gliomagenesis and tumor recurrence after therapy, GCSCs are a major focus of research whose ultimate goal is to identify more effective therapies for GBM patients.GCSCs were first identified by their surface expression of CD133, based on the findings that these cells grow as neurospheres under nonadher...

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Section: Discussionmentioning

confidence: 52%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Cytomegalovirus infection induces a stem cell phenotype in human primary glioblastoma cells: prognostic significance and biological impact

et al. 2015

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“…Another group has demonstrated a relationship between EMT and Notch pathway activation in gemcitabine-resistant pancreatic cancer cells, and as cells undergoing EMT acquire stem cell properties, there may be a link between stemmness and EMT in pancreatic cancer (Wang et al, 2009). These results suggest targeting Notch pathway with inhibitors like GSIs or monoclonal antibodies to Notch receptor or Delta-4 ligand may be effective in eradicating CSCs and preventing chemotherapy or radiotherapy resistance (Pannuti et al, 2010).…”

Section: Targeted Therapy Directed Toward Cscsmentioning

confidence: 97%

Cancer Stem Cells and Response to Therapy

Tabarestani¹,

Ghafouri‐Fard²

2012

Asian Pacific Journal of Cancer Prevention

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The cancer stem cell (CSC) model states that cancers are organized in cellular hierarchies, which explains the functional heterogeneity often seen in tumors. Like normal tissue stem cells, CSCs are capable of self-renewal, either by symmetric or asymmetric cell division, and have the exclusive ability to reproduce malignant tumors indefinitely. Current systemic cancer therapies frequently fail to eliminate advanced tumors, which may be due to their inability to effectively target CSC populations. It has been shown that embryonic pathways such as Wnt, Hedgehog, and Notch control self-renewal and cell fate decisions of stem cells and progenitor cells. These are evolutionary conserved pathways, involved in CSC maintenance. Targeting these pathways may be effective in eradicating CSCs and preventing chemotherapy or radiotherapy resistance.

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Notch signalling is a potential resistance mechanism of progenitor cells within patient‐derived prostate cultures following ROS‐inducing treatments

et al. 2019

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Edited by Barry HalliwellLow Temperature Plasma (LTP) generates reactive oxygen and nitrogen species, causing cell death, similarly to radiation. Radiation resistance results in tumour recurrence, however mechanisms of LTP resistance are unknown. LTP was applied to patient-derived prostate epithelial cells and gene expression assessed. A typical global oxidative response (AP-1 and Nrf2 signalling) was induced, whereas Notch signalling was activated exclusively in progenitor cells. Notch inhibition induced expression of prostatic acid phosphatase (PAP), a marker of prostate epithelial cell differentiation, whilst reducing colony forming ability and preventing tumour formation. Therefore, if LTP is to be progressed as a novel treatment for prostate cancer, combination treatments should be considered in the context of cellular heterogeneity and existence of cell type-specific resistance mechanisms.

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Targeting Notch to Target Cancer Stem Cells

Abstract: The cellular heterogeneity of neoplasms has been at the center of considerable interest since the "cancer stem cell hypothesis", originally formulated for hematologic malignancies, was extended to solid tumors.

Cited by 411 publications

References 109 publications

Cytomegalovirus infection induces a stem cell phenotype in human primary glioblastoma cells: prognostic significance and biological impact

Cytomegalovirus infection induces a stem cell phenotype in human primary glioblastoma cells: prognostic significance and biological impact

Cancer Stem Cells and Response to Therapy

Notch signalling is a potential resistance mechanism of progenitor cells within patient‐derived prostate cultures following ROS‐inducing treatments

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