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Cancer Stem Cells



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.

In Vivo Generation of Neural Tumors from Neoplastic Pluripotent Stem Cells Models Early Human Pediatric Brain Tumor Formation

From Stem Cells
By Stuart P. Atkinson

Several recent studies (Ben-Porath et al, Somervaille et al and Wong et al) have identified ESC-like gene expression patterns in a variety of malignant tumors suggesting a molecular relationship between aggressive cancers and pluripotency. However, the molecular determinants of such a link have yet to be uncovered. Now using normal human embryonic stem cells (hESCs) and transformed hESCs (t-hESCs), which have acquired features of neoplastic progression, including enhanced self-renewal, proliferation and tumor-initiating cell capacity, and aberrant neural lineage specification (Werbowetski-Ogilvie TE et al. 2009), researchers from the group of Mickie Bhatia at the McMaster University, Hamilton, Ontario, have shown that derived neural progenitors from the transformed cells possess brain tumor-initiating cell capacity, thereby providing a model system to investigate initiation and progression of primitive human neural cancers, such as medulloblastoma that are difficult to assess using somatic sources (Werbowetski-Ogilvie et al 2012).

Interactions between cancer stem cells and their niche govern metastatic colonization

From Nature
By Stuart P. Atkinson

While metastatic tumour growth is the major cause of cancer mortality, this process is very inefficient for many cancers (Kouros-Mehr et al and Nguyen et al) and suggests that a barrier to implantation and growth exists to these few initiatory cancer cells mediated by the distant tissues in which they attempt to colonize. Further studies have demonstrated that metastases have prevalent target sites (Hess et al), again suggesting that normal tissue at the metastatic site may mediate colonisation. Now, researchers from the laboratory of Joerg Huelsken at the École Polytechnique Fédérale De Lausanne (EPFL), Switzerland have shown that cancer stem cells (CSCs), or tumour initiating stem cells (TISCs), are vitally important in metastatic growth but this is reliant on complex interactions between the CSCs and their metastatic niche (Malanchi and Santamaria-Martínez et al).

Pluripotency factor-mediated expression of the leptin receptor (OB-R) links obesity to oncogenesis through tumor-initiating stem cells

By Stuart P. Atkinson

Tumour initiating stem cells (TISCs) are rare, highly malignant cells identified within diverse tumor types that share important similarities with embryonic stem cells (ESCs) (Clark and Fuller, Visvader and Lindeman and Clevers) including the mis-regulated expression of OCT4, SOX2, and NANOG (Chen et al and Kim ­et al). Studies have begun to give insight into the events behind TISC function, such as the loss of function of the type II TGF-β receptor and excessive activation of the IL-6 cytokine-signaling pathway, including the downstream effector STAT3 human hepatocellular carcinoma (HCC) (Baek et al and Tang et al). In a mouse model of HCC, isolation of highly tumourigenic CD133+/Nanog+ liver TISCs (Machida et al) on the basis of cell-surface receptors has suggested that identification of TISC-associated cell surface receptor expression and associated signal transduction pathways may be important for TISC function. Therefore researchers from the laboratories of Douglas Edmund Feldman and Keigo Machida at the University of Southern California sought to study this hypothesis and report that the leptin receptor (OB-R or Lepr), a transmembrane receptor for the adipocyte-derived peptide hormone leptin, is important for the tumourigenic nature of TISCs and also for the pluripotent nature of ESCs and induced pluripotent stem cells (iPSCs) (Feldman et al).

A Step Forward In Understanding Melanoma

A Step Forward In Understanding Melanoma

From Nature and Cell

Two studies, by Roesch et al in Cell and Boiko et al in Nature, have shed more light on the development of this skin cancer, and have also reported two potential biomarkers of a melanoma cancer stem cell, CD271, a stem cell marker, and JARID1B (KDM5B), a lysine 4 histone H3 demethylase.   Identification of these markers may allow for better modeling of this cancer with a view towards better clinical management/treatment.


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