EMT impairs breast carcinoma cell susceptibility to CTL-mediated lysis through autophagy induction
Institut de Cancérologie Gustave Roussy Autophagy
(Impact Factor: 11.75).
04/2013; 9(7). DOI: 10.4161/auto.24728
Epithelial to mesenchymal transition (EMT) has become one of the most exciting fields in cancer biology. While its role in cancer cell invasion, metastasis and drug resistance is well established, the molecular basis of EMT-induced immune escape remains unknown. We recently reported that EMT coordinately regulates target cell recognition and sensitivity to specific lysis. In addition to the well-characterized role for EMT in tumor phenotypic change including a tumor-initiating cell phenotype, we provided evidence indicating that EMT-induced tumor cell resistance to cytotoxic T-lymphocytes (CTLs) also correlates with autophagy induction. Silencing of BECN1 in target cells that have gone through the EMT restored CTL susceptibility to CTL-induced lysis. Although EMT may represent a critical target for the development of novel immunotherapy approaches, a more detailed understanding of the interrelationship between EMT and autophagy and their reciprocal regulation will be a key determinant in the rational approach to future tumor immunotherapy design.
Available from: Allan R Brasier
- "SNAI1, the EMT master regulator, promotes immunosuppression by inducing differentiation of immature DCs into regulatory DCs with low MHC class II expression and associated costimulatory molecules and prevents NKG2D expression in NK cells , thus suppressing the innate immune response. Tumor cells also acquire resistance to lysis by antigen-specific CTLs following EMT by induction of autophagy through Beclin 1 . Even though there is overlap between type II and type III EMT signaling and EMT’s effect on immunity, more work is required to determine which features of EMT are shared by the two EMT programs and to understand the role of EMT in modifying the innate immune response, autophagy and immunoediting in asthma. "
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ABSTRACT: A pathological hallmark of asthma is chronic injury and repair, producing dysfunction of the epithelial barrier function. In this setting, increased oxidative stress, growth factor- and cytokine stimulation, together with extracellular matrix contact produces transcriptional reprogramming of the epithelial cell. This process results in epithelial-mesenchymal transition (EMT), a cellular state associated with loss of epithelial polarity, expression of mesenchymal markers, enhanced mobility and extracellular matrix remodeling. As a result, the cellular biology of the EMT state produces characteristic changes seen in severe, refractory asthma: myofibroblast expansion, epithelial trans-differentiation and subepithelial fibrosis. EMT also induces profound changes in epithelial responsiveness that affects innate immune signaling that may have impact on the adaptive immune response and effectiveness of glucocorticoid therapy in severe asthma. We discuss how this complex phenotype is beginning to be understood using systems biology-level approaches through perturbations coupled with high throughput profiling and computational modeling. Understanding the distinct changes induced by EMT at the systems level may provide translational strategies to reverse the altered signaling and physiology of refractory asthma.
World Allergy Organization Journal 06/2014; 7(1):13. DOI:10.1186/1939-4551-7-13
Available from: Kumar Alok Pathak
- "EMT is a form of enhanced epithelial plasticity and known to increase therapeutic resistance of cancer cells to cytotoxic agents and/or radiation. A strong link has recently been demonstrated between EMT, autophagy, stem-like characteristics, and resistance of cancer cells to cytotoxic T cell-induced killing, and targeting autophagy may help avoid immune resistance in breast cancer (73). Whether cancer (stem) cells opt for an aggressive phenotype, choose to enter an inactive state supported by autophagy, or endure cell death depends on the activation of different intracellular pathways and specific changes in gene expression profiles upon external stimuli (74). "
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ABSTRACT: The two main reasons for death of cancer patients, tumor recurrence and metastasis, are multi-stage cellular processes that involve increased cell plasticity and coincide with elevated resistance to anti-cancer treatments. Epithelial-to-mesenchymal transition (EMT) is a key contributor to metastasis in many cancer types, including thyroid cancer and is known to confer stem cell-like properties onto cancer cells. This review provides an overview of molecular mechanisms and factors known to contribute to cancer cell plasticity and capable of enhancing cancer cell resistance to radio- and chemotherapy. We elucidate the role of DNA repair mechanisms in contributing to therapeutic resistance, with a special emphasis on thyroid cancer. Next, we explore the emerging roles of autophagy and damage-associated molecular pattern responses in EMT and chemoresistance in tumor cells. Finally, we demonstrate how cancer cells, including thyroid cancer cells, can highjack the oncofetal nucleoprotein high-mobility group A2 to gain increased transformative cell plasticity, prevent apoptosis, and enhance metastasis of chemoresistant tumor cells.
Frontiers in Endocrinology 03/2014; 5:37. DOI:10.3389/fendo.2014.00037
Available from: Alakananda Basu
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ABSTRACT: Protein kinase C (PKC), a family of serine/threonine kinases, plays critical roles in signal transduction and cell regulation. PKCε, a member of the novel PKC family, is known to be a transforming oncogene and a tumor biomarker for aggressive breast cancers. In this study, we examined the involvement of PKCε in epithelial to mesenchymal transition (EMT), the process that leads the way to metastasis. Overexpression of PKCε was sufficient to induce a mesenchymal phenotype in non-tumorigenic mammary epithelial MCF-10 A cells. This was accompanied by a decrease in the epithelial markers, such as E-cadherin, zonula occludens (ZO)-1, and claudin-1, and an increase in mesenchymal marker vimentin. Transforming growth factor β (TGFβ) induced Snail expression and mesenchymal morphology in MCF-10 A cells, and these effects were partially reversed by the PKCε knockdown. PKCε also mediated cell migration and anoikis resistance, which are hallmarks of EMT. Thus, our study demonstrates that PKCε is an important mediator of EMT in breast cancer.
Breast cancer 03/2014; 8(1):61-7. DOI:10.4137/BCBCR.S13640
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