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- Volume 21, Issue 10, 2015
Current Pharmaceutical Design - Volume 21, Issue 10, 2015
Volume 21, Issue 10, 2015
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Role of Epithelial Mesenchymal Transition in Prostate Tumorigenesis
Authors: Mohammad Imran Khan, Abid Hamid, Vaqar Mustafa Adhami, Rahul K Lall and Hasan MukhtarGlobally, the cancer associated deaths are generally attributed to the spread of cancerous cells or their features to the nearby or distant secondary organs by a process known as metastasis. Among other factors, the metastatic dissemination of cancer cells is attributed to the reactivation of an evolutionary conserved developmental program known as epithelial to mesenchymal transition (EMT). During EMT, fully differentiated epithelial cells undergo a series of dramatic changes in their morphology, along with loss of cell to cell contact and matrix remodeling into less differentiated and invasive mesenchymal cells. Many studies provide evidence for the existence of EMT like states in prostate cancer (PCa) and suggest its possible involvement in PCa progression and metastasis. At the same time, the lack of conclusive evidence regarding the presence of full EMT in human PCa samples has somewhat dampened the interest in the field. However, ongoing EMT research provides new perspectives and unveils the enormous potential of this field in tailoring new therapeutic regimens for PCa management. This review summarizes the role of many transcription factors and other molecules that drive EMT during prostate tumorigenesis
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Pancreatic Cancer Metastasis: Are we being Pre-EMTed?
Authors: Srustidhar Das and Surinder K. BatraPancreatic cancer, often considered a metastatic disease at the time of clinical diagnosis due to lack of any reliable early diagnostic marker(s), is refractory to conventional chemo- and radiotherapy and has a dismal 5-year survival rate of only 6%. Although surgical removal of the primary tumor is considered to be curative, the 5-year survival rate is no more than 20% even in patients with clear resection margins (R0). The recurrence of local and metastatic disease (primarily liver metastasis) post resection is considered to be the leading cause of mortality in these patients. In addition, instances of metastatic disease without any local recurrence post resection have also been observed. Cancer metastasis is the primary cause of mortality in cancer patients and is classically viewed as a late event during the progression of the disease, which is supported by the genetic studies used to understand the evolution of pancreatic cancer. However, this view has recently been challenged by studies using mathematical modeling and genetically labeled mouse models of pancreatic cancer to understand the dynamics of tumor cell dissemination and epithelial to mesenchymal transition (EMT) of tumor cells well before the primary tumor is formed. Given that EMT is a hallmark process that initiates the metastatic seeding of cancer cells and the dismal prognosis of pancreatic cancer patients even after efficient removal of the primary tumor (99.9%), an early dissemination hypothesis of cancer cells cannot be undermined. In this review, we will discuss the current views regarding pancreatic cancer metastasis with particular emphasis on the epithelial to mesenchymal transition, its influence on the selection of patients for surgical resection and the therapeutic intervention.
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Twist-BRD4 Complex: Potential Drug Target for Basal-like Breast Cancer
Authors: Jian Shi, Jingying Cao and Binhua P. ZhouAs an important basic helix-loop-helix (bHLH) transcription factor, Twist associates with several physiological processes such as mesodermal development, and pathological processes such as Saethre-Chotzen syndrome. During cancer progression, Twist induces epithelial-mesenchymal transition (EMT), potentiating cancer cell invasion and metastasis. Although many studies have revealed its multiple biological roles, it remained unclear how Twist transcriptionally acti vates targeted genes. Recently we discovered tip60-mediated Twist di-acetylation in the ‘‘histone H4-mimic’’ GK-X-GK motif. The di-acetylated Twist recruits BRD4 and related transcriptional components to super-enhancer of its targeted genes during progression of basal-like breast cancer (BLBC). Here, we review this new advance of regulation and functional mechanism of Twist.
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Vitamin D Receptor Signaling and Pancreatic Cancer Cell EMT
Authors: Zhiwei Li, Junli Guo, Keping Xie and Shaojiang ZhengPancreatic ductal adenocarcinoma (PDAC) still remains one of the most fatal human malignant tumors. Long-term survival rate is still extremely pathetic even for patients who receive surgery. Epithelial-to-mesenchymal transition (EMT), which is a physiologic process of morphological as well as genetic changes in carcinoma cells, plays a vital role in aggressiveness of PDAC. Meanwhile EMT is also the reason why pancreatic cancer cells achieve such huge metastatic potentials. Many tumor microenvironmental factors such as cytokines, growth factors, as well as chemotherapeutic agents may induce EMT. Our study provides evidence regarding effects of EMT on pancreatic cancer progression, focusing on the correlation between EMT and other pathways which are crucial to tumor progression, especially vitamin D receptor signaling pathway. Research on signal pathways resulting in EMT inactivation during these disease processes may offer innovative ideas on plasticity of cellular phenotypes as well as possible therapeutic interventions.
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Glioblastoma Multiforme Formation and EMT: Role of FoxM1 Transcription Factor
Authors: Zhongyong Wang, Sicong Zhang, Timothy L Siu and Suyun HuangGlioblastoma multiforme (GBM) is one of the most malignant cancers in human brain. The prognosis of GBM is extremely poor because it is resistant to radiotherapy and chemotherapy. Improving understanding of the tumor biology brings some new hope to the treatment of GBM. In this review, we discuss the evidence that FoxM1 promotes the development and progression of GBM by regulating key factors involved in cell proliferation, epithelial to mesenchymal transition (EMT), invasion, angiogenesis and upregulating Wnt/β-catenin signalling. Our recent experimental findings are also summarized to prove that FoxM1 is a novel therapeutic target against GBM.
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Epigenetic Regulation of Epithelial-Mesenchymal Transition by Hypoxia in Cancer: Targets and Therapy
Authors: Jian -Qiu Wang and Kou -Juey WuIntratumoral hypoxia followed by stabilization/activation of hypoxia-inducible factor 1 (HIF-1) and its downstream transcriptional factors, is one of the most important mechanisms inducing epithelial-mesenchymal transition (EMT), which has been widely accepted as a crucial step to generate early stage of tumor metastasis. Accumulating evidence suggests that epigenetic mechanisms play important roles in hypoxia-induced EMT and metastasis. These epigenetic regulations are mediated by various players including chromatin modifiers, transcriptional co-regulators, microRNAs, etc. In this review, we discuss how his tone-modifying enzymes and transcriptional co-regulators regulate EMT under hypoxic conditions. Developed or potential anticancer agents targeting epigenetic molecules regulating hypoxia-induced EMT are also discussed.
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The Epithelial-Mesenchymal Transition and Cancer Stem Cells: Functional and Mechanistic Links
Authors: Xiangqiang Liu and Daiming FanThe epithelial-mesenchymal transition (EMT) is a highly conserved cellular process that transforms epithelial cells into mesenchymal cells; EMT is involved in normal embryogenesis and tissue repair and contributes to tumor progression, including tumor metastasis, therapy resistance and disease recurrence. Cancer stem cells (CSCs) represent a fraction of undifferentiated cancer cells that exhibit stem cell-like features. They have the ability to self-renew and can seed new tumors. Thus, CSCs might represent the cellular resource that causes metastases and accounts for therapy resistance. Recent studies have highlighted a link between EMT and CSC formation. EMT is relevant to the acquisition and maintenance of stem cell-like characteristics and is sufficient to endow differentiated normal and cancer cells with stem cell properties. Moreover, CSCs often exhibit EMT properties. This reciprocal relationship between EMT and CSCs might have many implications in tumor progression. In this paper, we review current studies related to EMT and CSCs in tumor progression and therapeutic resistance, with a special focus on the common characteristics and links between these processes, and explore the importance of these links in the development of improved antitumor therapies.
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Cancer/Testis Antigens Trigger Epithelial-Mesenchymal Transition and Genesis of Cancer Stem-Like Cells
Authors: Ping Yang, Zihe Huo, Huaidong Liao and Quansheng ZhouMalignant tumors aberrantly overexpress various embryonic genes and proto-oncogenes, including a variety of cancer-testis antigens (CTAs). CTAs belong to a class of testis-derived proteins which are only expressed in germ cells in the male testis, and the expression of CTA genes is entirely silenced in the adult somatic tissues. They are, however, aberrantly overexpressed in a variety of malignant tumor tissues. Emerging evidence shows that a number of CTAs promote epithelialmesenchymal transition (EMT) and genesis of cancer stem like cells, escalating tumorigenesis, invasion, and metastasis. The can cer-testis antigens, such as SSX, MAGE-D4B, CAGE, piwil2, and CT45A1, upregulate EMT and metastatic genes, promoting EMT and tumor dissemination. In addition, certain members of CTAs, including Piwil2, DNAJB8, CT45A1, MAGE-A, GAGE, and SPANX, are implicated in the initiation or maintenance, of cancer stem-like cells, promoting tumorigenesis and malignant progression. Clinically CTAs are closely associated with poor prognosis in cancer patients. Intriguely, CTAs are strongly immunogenic and normally restricted to the male testis after birth, however, these proteins are aberrantly overexpressed in cancer stem-like cells and in a variety of cancers, suggesting their target potential for cancer immunotherapy, as diagnostic biomarkers, and as targets for novel anticancer drug discovery. Thus, the targeting of tumorigenic CTAs is a promising strategy to eradicate cancer stem-like cells and inhibit tumorigenesis for effective cancer treatment.
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Epithelial-Mesenchymal Plasticity of Breast Cancer Stem Cells: Implications for Metastasis and Therapeutic Resistance
Authors: Ming Luo, Michael Brooks and Max S. WichaOver the past several decades the traditional view of cancer being a homogeneous mass of rapid proliferating malignant cells is being replaced by a model of ever increasing complexity, which points out that cancers are complex tissues composed of multiple cell types. A large variety of immune and other host cells constitute the tumor microenvironment, which supports the growth and progression of the tumor where individual cancer cells evolve with increasing phenotypic and genetic heterogeneity. Furthermore, it has also become clear that, in addition to this cellular and genetic heterogeneity, most tumors exhibit a hierarchical organization composed of tumor cells displaying divergent lineage markers and at the apex of this hierarchy are cells capable of self-renewal. These “cancer stem cells” not only drive tumor growth, but also mediate metastasis and contribute to treatment resistance. Besides displaying remarkable genetic and phenotypic heterogeneity, cancer stem cells maintain plasticity to transition between mesenchymal-like (EMT) and epithelial-like (MET) states in a process regulated by the tumor microenvironment. These stem cell state transitions may play a fundamental role in the process of tumor metastasis. In this review, we will discuss emerging knowledge regarding the plasticity of cancer stem cells and the role that this plasticity plays in tumor metastasis. We also discuss the implications of these findings for the development of cancer stem cell targeted therapeutics.
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The Functions of F-box Proteins in Regulating the Epithelial to Mesenchymal Transition
Authors: Jingna Su, Xuyuan Yin, Xiuxia Zhou, Wenyi Wei and Zhiwei WangEpithelial to mesenchymal transition (EMT) has been unraveled to regulate the tumor invasion and metastasis processes. In this review, in order to better understand the regulatory mechanisms of EMT, we describe that F-box pr oteins could be critically involved in regulating the EMT process in human cancers. Specifically, we discuss how th ese F-box proteins directly control the stability of EMT regulators such as E-cadherin, β-catenin, Twist, Slug, Snail and ZEB. Moreover, we summary mechanistically how the F-box proteins govern EMT progression through regulation of EMT inducers including Notch, NF-κB, Akt, Hedgehog, mTOR, and HIF-1α. Therefore, targeting these F-box proteins could be useful for treating human cancers.
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Design of Small Molecules Targeting I-BAR Proteins
Authors: Meng Cao, Weiwei Chang, Ming Zheng, Li Xie, Yu Zhang, Jin Cai, Junqing Chen, Xi Zhan, Min Ji and Ning GuMissing in metastasis (MIM, also MTSS1) is a member of the inverse Bin-Amphiphysin-Rvs (I-BAR) family that senses and stabilizes negative membrane protrusions. Abnormal expression of MIM has been frequently associated with a subset of human cancers and may play different roles in different stages of tumor progression. Overexpression of MIM-I-BAR in 293A cells potentiated the cell growth and increased the toxic response to paclitaxel. To modulate the function of MIM within cells, we designed several short peptide derivatives to target I-BAR dimerization. One of these derivatives had a cyclic configuration with a potency to disrupt the dimerization of MIM or ABBA proteins in vitro, and to be readily internalized into cells. Exposure of cells expressing MIM-I-BAR to this compound abolished increased susceptibility to paclitaxel and partially inhibited the IBAR- mediated endocytosis. Our data suggests that this cyclic peptide can be used as a tool to study the function of intracellular MIM and as a lead to develop a therapy targeting human diseases involving abnormal MIM expressions.
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Strategies for Skeletal Muscle Targeting in Drug Discovery
Authors: David C. Ebner, Peter Bialek, Ayman F. El-Kattan, Catherine M. Ambler and Meihua TuThe targeting of drugs to skeletal muscle is an emerging area of research. Driven by the need for new therapies to treat a range of muscle-associated diseases, these strategies aim to provide improved drug exposure at the site of action in skeletal muscle with reduced concentration in other tissues where unwanted side effects could occur. By interacting with muscle-specific cell surface recognition elements, both tissue localization and selective uptake into skeletal muscle cells can be achieved. The design of molecules that are substrates for muscle uptake transporters can provide concentration in m uscle tissue. For example, drug conjugates with carnitine can provide improved muscle uptake via OCTN2 transport. Binding to muscle surface recognition elements followed by endocytosis can allow even large molecules such as antibodies to enter muscle cells. Monoclonal antibody 3E10 demonstrated selective uptake into skeletal muscle in vivo. Hybrid adeno-associated viral vectors have recently shown promise for high skeletal muscle selectivity in gene transfer applications. Delivery technology methods, including electroporation of DNA plasmids, have also been investigated for selective muscle uptake. This review discusses challenges and opportunities for skeletal muscle targeting, highlighting specific examples and areas in need of additional research.
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The Role of White Matter Abnormalities in Treatment-Resistant Depression: A Systematic Review
Background: Patients with treatment-resistant depression (TRD) commonly report significant disability together with an increased risk of functional impairment. Neuroimaging techniques have been used to investigate the neuropathology of this complex illness, but it is still quite unknown whether abnormalities in the integrity of white matter (WM) of specific brain areas may be considered as trait markers of TRD. Methods: Electronic databases were searched from 1980 to 2013. Nine studies - comprising a total of 228 subjects and 171 controls - fulfilled our inclusion criteria and were analyzed in the present overview. Results: Several cross-sectional studies showed the association between WM abnormalities and TRD. According to the selected studies, sub-callosal cingulated cortex (SCC) WM abnormalities were largely implicated in the pathogenesis of both major depressive disorder and TRD. However, alterations in cortical-limbic or cortical-subcortical circuits, particularly the left middle frontal gyrus (which is thought to have a major role in emotional regulation) may also be involved in the pathophysiology of TRD. Conclusion: TRD may be related to the presence of specific microstructural WM abnormalities. WM abnormalities of specific brain regions such as SCC may have a major involvement in the pathogenesis of TRD.
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Polo-Like Kinase 1 as a Potential Therapeutic Target for Osteosarcoma
Authors: Li Cheng, Chongchong Wang and Juehua JingOsteosarcoma is the most common primary bone malignancy of adolescents and young adults. Existing treatment options and surgical intervention are unable to effectively manage this tumor. Therefore, novel mechanism-based targets and strategies need to be rationally established to strive for improvement in the survival of patients diagnosed with osteosarcoma. The serine/threonine kinases Polo-like kinase (Plk) 1 is a key regulator of cell division in eukaryotic cells. Plk1 gene and protein expression has been proposed as a new prognostic marker for many types of malignancies, and Plk1 is a potential target for cancer therapy. In this review, we shall discuss the studies which indicate that Plk1 could be an excellent target for the treatment of osteosarcoma.
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The Cell-Type Specificity and Endosomal Escape of Cell-Penetrating Peptides
Authors: Jing Feng and Liling TangCell-penetrating peptides (CPPs) have become a great potential non-invasive carrier candidate for the delivery of various cell-impermeable therapeutic cargoes such as proteins, polypeptides and nucleic acid. However, the lack of tissue specificity and entrapment in the endocytic vesicles is the primary limitation to the application of these peptides in cargo delivery. Emphasis should be placed on developing novel methods to overcome these barriers. In this review, several current strategies to promote tissue specificity and endosomal escape of CPPs will be described, as well as the comparison of different approaches in efficacy and security. Finally, this review will be attributed to new ideas to improve the tissue specificity and cytosolic availability of CPP-cargoes.
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Volumes & issues
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Volume 30 (2024)
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Volume 29 (2023)
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Volume 28 (2022)
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Volume 27 (2021)
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Volume 26 (2020)
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Volume 25 (2019)
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Volume 24 (2018)
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Volume 23 (2017)
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Volume 22 (2016)
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Volume 21 (2015)
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Volume 20 (2014)
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Volume 19 (2013)
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Volume 18 (2012)
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Volume 17 (2011)
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Volume 16 (2010)
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Volume 15 (2009)
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Volume 14 (2008)
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Volume 13 (2007)
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Volume 12 (2006)
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Volume 11 (2005)
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Volume 10 (2004)
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Volume 9 (2003)
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Volume 8 (2002)
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Volume 7 (2001)
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Volume 6 (2000)