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Cancer Stem Cells

Cool-1 Therapy for Glioblastoma

Alternately targeted therapy for the treatment of Glioblastoma multiforme shown to be effective in vitro.

Therapeutic Targets to Limit Glioblastoma Recurrence Uncovered

“Cellular Plasticity Confers Migratory and Invasive Advantages to a Population of Glioblastoma-Initiating Cells that Infiltrate Peritumoral Tissue”

From Stem Cells

Treatment of glioblastoma multiforme (GBM) is often problematic due to infiltration of the peritumoral (PT) parenchyma by tumour cells (Kelly et al, Martiroysan et al and Stevenson et al) leading to tumour regrowth.   Additionally, studies into GBM also support the existence of cancer stem cells (CSCs) which survive traditional treatments and initiate tumour recurrence (Eyler and Rich).   As CSCs from GBM (or Glioblastoma Initiating Cells – GICs) have been found in peritumoral regions (Glas et al), studies into the mechanisms behind the ability of GICs to migrate and infiltrate may allow the development of new therapeutic interventions.   In their current study, researchers from the laboratory of Jose L. Fernandez-Luna at the Hospital Universitario Marqués de Valdecilla and Instituto de Formación e Investigación Marques de Valdecilla (IFIMAV), Santander, Spain have shown that GICs isolated from the PT have an invasive advantage over GICs from the tumour mass (TM), and that this is governed by an upregulation in αVβ3 integrin, which promotes Rac1 activation (Dey et al) and is involved in sensing matrix rigidity during cell spreading (Jiang et al) and the downregulation of p27, which can inhibit RhoA activation (Besson et al) (Ruiz-Ontañon et al).

Vaccine against Tumour Spread?

Original article from STEM CELLS

"Preventive Cancer Stem Cell-Based Vaccination Reduces Liver Metastasis Development in a Rat Colon Carcinoma Syngeneic Model"

Cancer stem cells (CSCs) represent a minor population of self-renewing cells that fuel tumour growth and have recently been identified in solid tumors, including those in the colon (O'Brien et al, Ricci-Vitiani et al and Visvader and Lindeman). Colon carcinoma is the second most common cause of cancer-related morbidity due, in part, to the appearance of metastases in the liver in 50%–60% of patients (Steele and Ravikumar). In a recent study published in Stem Cells, researchers from the group of Valérie Pierrefite-Carle at the Université de Nice Sophia Antipolis, Nice, France, using a rat model of colon carcinoma, demonstrate that a preventive vaccination generated using a CSC lysate can protect against the development of this liver metastasis, suggesting that CSC-based vaccination could be an efficient treatment to reduce tumour relapse in colon carcinoma (Duarte and Momier et al).

 

Tumour Stem Cell Marker Identified

“Dclk1 distinguishes between tumor and normal stem cells in the intestine”

The study of tumour stem cells (TSCs) has been hindered by the lack of selective markers which can differentiate between normal stem cells (NSCs) and TSCs. In the intestine, many markers of NSCs and TSCs are shared (Delarba et al, O’Brien et al, Zhu et al and Todaro et al) and so identifying TSC-specific markers is an important challenge. In the following study, researchers from the laboratory of Tsutomu Chiba at Kyoto University Graduate School of Medicine, Japan have studied the doublecortin-like kinase 1 (Dclk1) gene, previously identified in mouse and human intestine (May et al 2008 and May et al 2009) and associated with mouse intestinal tumors and human colorectal carcinomas (May et al 2008 and Gerbe et al), and have found that Dclk1 does not mark NSCs in the intestine but instead marks TSCs, with specific ablation of Dclk1-positive TSCs leading to the regression of intestinal polyps (Nakanishi et al).

Disrupting Metabolism to Eliminate Cancer Stem Cells

"Effective Elimination of Cancer Stem Cells By a Novel Drug Combination Strategy"

Effective means to target cancer stem cells (CSCs) using pharmaceutical agents have been hindered by their seemingly intrinsic resistance to chemotherapeutic agents (Gilbert and Ross). CSCs in Glioblastoma multiforme (GBM) have been shown to be resistant to common chemotherapeutics and radiation (Kang and Kang and Beier et al), and glioblastoma cancer stem cells (GSCs) have been found to reside in hypoxic niches which further promotes drug resistance (Lei et al, Heddleston et al and Li et al). This suggests that the glycolytic pathway may be utilised in these cells to generate energy, giving researchers a potential target for chemotherapeutic intervention. Now researchers from the laboratories of Peng Huang from the State Key Laboratory of Oncology in South China, Guangdong, China and The University of Texas MD Anderson Cancer Center, Texas, USA, in a study published in Stem Cells, have found that 3-bromo-2-oxopropionate-1-propyl ester (3-BrOP), which affects key enzymes in the glycolytic pathway and reduces ATP generation (Ko et al, Geschwind et al and Xu et al), allows the efficient elimination of CD133+ GSCs when used in combination with other common chemotherapeutic agents (Yuan and Wang et al).

Understanding LGR5 in Colon CSCs

"LGR5-Positive Colon Cancer Stem Cells Interconvert with Drug-Resistant LGR5-Negative cells and are Capable of Tumor Reconstitution"

The existence of a cancer stem cell (CSC) in tumours has been explored thoroughly in recent years, and while evidence mounts in favour of its existence, the debate is far from over (Magee et al., Nguyen et al. and Visvader and Lindeman) although several recent papers have suggested that CSCs do exist in solid tumours in mice (Chen et al., Driessens et al. and Schepers et al.). CSCs in the colon are suggested to be marked specifically by LGR5 (Vermeulen et al.), a Wnt target gene, however the heterogenous nature of normal colon stem cells (Takeda et al.) and CSCs in general (Dieter et al., Gupta et al. and Sharma et al.) have made the definitive identification of cells difficult. Now in a paper published in Stem Cells, researchers from the laboratory of Tatsumi Yamazaki who is associated with Forerunner Pharma Research Co. Ltd. and Chugai Pharmaceutical Co. Ltd. have reported the establishment of human colon cancer cell lines that express LGR5 and possess CSC properties, aided by the generation of LGR5 specific antibodies. Additionally, they show that CSC can interconvert between a proliferative LGR5+ state and a drug-resistant LGR5- state and identify an anti-epiregulin antibody which could mediate a reduction in metastatic disease (Kobayashi and Yamada-Okabe et al.).

A new common target for the treatment of invasive cancers?

‘Rai is a new regulator of neural progenitor migration and glioblastoma invasion’

September 2012 — Glioblastoma multiforme (GBM) is the most common form of brain tumor yet carries an unfortunately poor prognosis owing to its aggressive nature and the high infiltrative capacity of Glioblastoma cells.   Its invasive nature makes it difficult to contain or remove surgically, and also a difficult target for localized radiation and chemotherapy treatment.   Such tumors are initiated by a specific type of cancer stem cells (GBM initiating cells) which share some characteristics of neural stem cells (NSCs) including extensive self-renewal and migration.   Understanding the invasive nature of these cells is of obvious importance for the development of suitable treatments for Glioblastoma patients.   Recent work published in Stem Cells by Ortensi et al. from various centres in Milan has studied the role of Rai, a member of the Shc-like adaptor proteins, in the regulation of cancer cells.   Rai is of particular interest in cancer as, although not normally present in glia, is expressed in high grade gliomas.   Their work has uncovered that Rai is a key promoter of migratory activity and, importantly, that its knockdown can reduce cell invasion as well as the downregulation of pro-invasive genes.

A Long Awaited Magic Bullet for Cancer? - “Identification of Drugs Including a Dopamine Receptor Antagonist that Selectively Target Cancer Stem Cells”

Cancer stem cells (CSCs) are now becoming acknowledged as an important factor in tumor initiation and sustainment (Dick, 2009 and Reya et al) and, unfortunately, it has been shown that conventional chemotherapeutics are often ineffective against human CSCs (Guan et al) and have detrimental effects on healthy stem and progenitor cells (Smith et al). This therefore suggests that residual CSCs can lead to the relapse of disease after long periods of remission and also that current regimes of chemotherapeutics are not well suited to the long term treatment of tumourigenesis and can affect normal cells so that they actually foster tumourigenesis as exemplified by a recent study (Sun et al). Therefore the development of new chemotherapeutics which efficiently target CSCs alone would be highly advantageous. Now, researchers from the group of Mickie Bhatia from McMaster University, Canada, using high content screening of neoplastic and normal human pluripotent stem cells (hPSCs), have discovered that thioridazine, an antipsychotic drug, can selectively target neoplastic cells via their dopamine receptors, while leaving normal cells unaffected (Sachlos et al).

A RSKy Target Pays off for Breast Cancer

Original article from STEM CELLS

Targeting RSK Eliminates Tumor-Initiating Cells by Inactivating YB-1 in Triple-Negative Breast Cancers

Triple-negative breast cancer (TNBC) refers to any breast cancer that does not express the genes for estrogen receptor (ER), progesterone receptor (PR) or Her2/neu andtherefore does not respond to conventional therapeutic approaches.   These tumours become resistant to chemotherapeutic agents and are prone to recurrence, which has been linked to the presence of high numbers of CD44+/CD24 tumour initiating cells (TICs) which are intrinsically resistant to traditional chemotherapy and radiotherapy (Creighton et al, Li et al and Philips et al).  A further concern is that the percentage of TICs increases following chemotherapeutic treatment of breast cancers with agents such as paclitaxel (Creighton et al and Fillmore and Kuperwasser).  This suggests that the targeting of CD44+ TICs may be of value to the treatment of TNBC.   A previous study has shown that the transcription factor YB-1 can regulate the TIC phenotype in TNBC, increasing TIC marker (CD44 and CD49f (or ITGA6)) expression, mammosphere formation and drug resistance (To et al).  YB-1 is phosphorylated and activated, leading to nuclear translocation and transcriptional activation, by the p90 ribosomal S6 kinases (RSK) (To et aland Stratford et al) suggesting that these kinases may be a viable therapeutic target for TNBC.   Now, researchers from the laboratory of Sandra E. Dunn at the University of British Columbia, Vancouver, Canada have reported that blocking the activation of YB-1 via RSK inhibition could be an alternative approach to combating relapse by eliminating TICs present in TNBC (Stratford and Reipas et al).

Insights into a problematic side-effect of anti-cancer therapy

'Radiation-induced Reprogramming of Breast Cancer Cells’

From Stem Cells 
Commentary by Carla B. Mellough

In solid cancer tumors, such as those found in breast cancer and glioma, the cancer stem cell (CSC) component represents only a small number of cells within the tumor - yet these cells are the most highly tumorigenic, being able to completely regenerate the tumor, are associated with higher risk of metastasis and recurrence, and are more resistant to radiation and chemotherapy than their differentiated progeny. Recent reports indicate that an unfortunate result of anti-cancer therapy is the enrichment of these highly tumorigenic CSCs within the tumor mass following treatment, which has been ascribed either to the selective killing of less tumorigenic progeny, or a shift from asymmetric to symmetric CSC division, resulting in an overall increase in CSCs1-3. To investigate this phenomenon, Lagadek et al.4 from UCLA have studied the activity of breast cancer stem cells (BCSCs) in three patient-derived breast cancer samples and several breast cancer cell lines following exposure to ionising radiation in vitro, and their results give us some insight into a problematic radiation-mediated phenomenon that has huge implications for current anti-cancer therapeutic approaches.

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