NOTCH1 Activation Depletes the Pool of Side Population Stem Cells in ATL
Journal Title: Journal of Cancer Sciences - Year 2017, Vol 4, Issue 1
Abstract
Background: HTLV-I infection is associated with the development of adult T-cell leukemia (ATL), a malignancy characterized by a highrate of disease relapse and poor survival. Previous studies reported the existence of side population (SP) cells in HTLV-I Tax transgenic mouse models. These studies showed that these ATL-like derived SP cells have both self-renewal and leukemia renewal capacity and represent Cancer Stem Cells (CSC)/ Leukemia-Initiating Cells (LIC). Since CSC/ LIC are resistant to conventional therapies, a better characterization is needed. Methods: We isolated, sorted and characterized SP cells from uncultured PBMCs from ATL patients and from ATL patient-derivedcell lines. We then identified several specific signaling pathways activated or suppressed in these cells. Expression of viral gene HBZ and Tax transcriptional activity was also investigated. Using gammasecretase inhibitor (GSI, Calbiochem) and stably transduced ATL celllines expressing TET-inducible NOTCH 1 intracellular domain (NICD), we characterized the role of activated NOTCH 1 in the maintenance of the SP cells in ATL. Results: Our studies confirm the existence of SP cells in ATL samples. These cells demonstrate lower activation of NOTCH1 and Tax, and reduced expression of STAT3, β-catenin/Wnt3 and viral HBZ. We further show that PI3K and the NOTCH1 signaling pathway have opposite functions, and constitutive activation of NOTCH1 signaling depletes the pool of SP cells in ATL-derived cell lines. Conclusions: Our results suggest that in ATL, a balance between activation of the NOTCH1 and PI3K signaling pathway is the key in the control of SP cells maintenance and may offer therapeutic opportunities.
Authors and Affiliations
Christophe Nicot
Keywords
Related Articles
- EP ID EP244972
- DOI 10.13188/2377-9292.1000013
- Views 142
- Downloads 0
Gemcitabine-Capecitabine Chemotherapy Plus Intra- Arterial Epirubicin-Cisplatin in Pancreatic Cancer Patients after FOLFIRINOX First Line Chemotherapy: A Retrospective Analysis
Background: Most pancreatic cancer patients have disease recurrence/progression within 6 months from firstline chemotherapy end. Today, there is no a standard of care of second-line therapy. Materials (patients) and me...
White Adipose Tissue Browning and Cancer Cachexia
Cachexia or wasting syndrome is often seen in cancer patients. Over half of the patients suffer from this condition although the incidence varies from tumor types. Symptoms of cancer cachexia include progressive weight l...
HTLV-I Tax-Mediated Inactivation of Cell Cycle Checkpoints and DNA Repair Pathways Contribute to Cellular Transformation: “A Random Mutagenesis Model”
To achieve cellular transformation, most oncogenic retroviruses use transduction by proto-oncogene capture or insertional mutagenesis, whereby provirus integration disrupts expression of tumor suppressors or proto-oncoge...
High Dose Vitamin C and Low Dose Chemo Treatment
Research has shown that intravenous high dose vitamin C in cancer therapy cannot be dismissed but that it warrants further investigation. Recent studies have made more inroads into the understanding of the role of vitami...
The Association amongst ‘Triple Negative’ Breast Cancers, Lymph Node Metastasis, Disease Free and Overall Survival
Triple negative’ breast cancer (TNBC) has fewer specific targets for systemic therapy. We hypothesized that patients with TNBC have an increased incidence of sentinel lymph node (SLN) metastases and decreased disease-spe...