Authors:Laurence Booth; Jane L. Roberts; John Kirkwood; Andrew Poklepovic; Paul Dent Abstract: Publication date: Available online 3 January 2018 Source:Advances in Cancer Research Author(s): Laurence Booth, Jane L. Roberts, John Kirkwood, Andrew Poklepovic, Paul Dent For several years, it has been known that histone deacetylase inhibitors have the potential to alter the immunogenicity of tumor cells exposed to checkpoint inhibitory immunotherapy antibodies. HDAC inhibitors can rapidly reduce expression of PD-L1 and increase expression of MHCA in various tumor types that subsequently facilitate the antitumor actions of checkpoint inhibitors. Recently, we have discovered that drug combinations which cause a rapid and intense autophagosome formation also can modulate the expression of HDAC proteins that control tumor cell immunogenicity via their regulation of PD-L1 and MHCA. These drug combinations, in particular those using the irreversible ERBB1/2/4 inhibitor neratinib, can result in parallel in the internalization of growth factor receptors as well as fellow-traveler proteins such as mutant K-RAS and mutant N-RAS into autophagosomes. The drug-induced autophagosomes contain HDAC proteins/signaling proteins whose expression is subsequently reduced by lysosomal degradation processes. These findings argue that cancer therapies which strongly promote autophagosome formation and autophagic flux may facilitate the subsequent use of additional antitumor modalities using checkpoint inhibitor antibodies.
Authors:Stephen L Wechman; Anjan K Pradhan; Rob DeSalle; Swadesh K. Das; Luni Emdad; Devanand Sarkar; Paul B. Fisher Abstract: Publication date: Available online 27 December 2017 Source:Advances in Cancer Research Author(s): Stephen L Wechman, Anjan K Pradhan, Rob DeSalle, Swadesh K. Das, Luni Emdad, Devanand Sarkar, Paul B. Fisher Autophagy is a functionally conserved self-degradation process that facilitates the survival of eukaryotic life via the management of cellular bioenergetics and maintenance of the fidelity of genomic DNA. The first known autophagy inducer was Beclin-1. Beclin-1 is expressed in multicellular eukaryotes ranging throughout plants to animals, comprising a nonmonophyllic group, as shown in this report via aggressive BLAST searches. In humans, Beclin-1 is a haploinsuffient tumor suppressor as biallelic deletions have not been observed in patient tumors clinically. Therefore, Beclin-1 fails the Knudson hypothesis, implicating expression of at least one Beclin-1 allele is essential for cancer cell survival. However, Beclin-1 is frequently monoallelically deleted in advanced human cancers and the expression of two Beclin-1 allelles is associated with greater anticancer effects. Overall, experimental evidence suggests that Beclin-1 inhibits tumor formation, angiogenesis, and metastasis alone and in cooperation with the tumor suppressive molecules UVRAG, Bif-1, Ambra1, and MDA-7/IL-24 via diverse mechanisms of action. Conversely, Beclin-1 is upregulated in cancer stem cells (CSCs), portending a role in cancer recurrence, and highlighting this molecule as an intriguing molecular target for the treatment of CSCs. Many aspects of Beclin-1’s biological effects remain to be studied. The consequences of these BLAST searches on the molecular evolution of Beclin-1, and the eukaryotic branches of the tree of life, are discussed here in greater detail with future inquiry focused upon protist taxa. Also in this review, the effects of Beclin-1 on tumor suppression and cancer malignancy are discussed. Beclin-1 holds significant promise for the development of novel targeted cancer therapeutics and is anticipated to lead to a many advances in our understanding of eukaryotic evolution, multicellularity, and even the treatment of CSCs in the coming decades.
Authors:Sarah P. Short; Christopher S. Williams Pages: 49 - 83 Abstract: Publication date: 2017 Source:Advances in Cancer Research, Volume 136 Author(s): Sarah P. Short, Christopher S. Williams Selenium is a micronutrient essential to human health and has long been associated with cancer prevention. Functionally, these effects are thought to be mediated by a class of selenium-containing proteins known as selenoproteins. Indeed, many selenoproteins have antioxidant activity which can attenuate cancer development by minimizing oxidative insult and resultant DNA damage. However, oxidative stress is increasingly being recognized for its “double-edged sword” effect in tumorigenesis, whereby it can mediate both negative and positive effects on tumor growth depending on the cellular context. In addition to their roles in redox homeostasis, recent work has also implicated selenoproteins in key oncogenic and tumor-suppressive pathways. Together, these data suggest that the overall contribution of selenoproteins to tumorigenesis is complicated and may be affected by a variety of factors. In this review, we discuss what is currently known about selenoproteins in tumorigenesis with a focus on their contextual roles in cancer development, growth, and progression.
Authors:Monica A. Valentovic Abstract: Publication date: Available online 15 December 2017 Source:Advances in Cancer Research Author(s): Monica A. Valentovic Cancer is one of the top three causes of death in the United States. The treatment regimen for controlling cancer includes a number of approaches depending on the classification of the tumor. Treatment may include radiation, surgery, and cancer chemotherapy agents as well as other interventions. Natural products have been identified for centuries to contain active pharmacologic activity and have been a starting point for numerous drugs which are currently on the market. Resveratrol (RES) is a natural product generated in plants in response to environmental stress and growing conditions. RES has been recognized since 1997 to possess anticancer activity. This review discusses the dietary sources of RES and the relative amounts present in the various food sources. A few limited clinical studies have explored RES effects in patients with prostate and colorectal cancer and have suggested some beneficial results. Future studies need to expand the sample size for clinical examination of RES in order to provide a better profile for the potential benefit of RES in cancer patients. This review also describes the potential mechanisms of RES as an antioxidant and in alteration of cell signaling. Another aspect for the role of RES in cancer may be in the interaction with cancer chemotherapy agents. Cisplatin is a cancer chemotherapy agent used for the treatment of bladder, testicular, ovarian, and many other cancers. Cisplatin usage is associated with a high risk of nephrotoxicity. Experimental studies suggest that RES may reduce cisplatin renal toxicity. The proposed mechanisms of protection are reviewed.
Authors:Narsireddy Amreddy; Anish Babu; Ranganayaki Muralidharan; Janani Panneerselvam; Akhil Srivastava; Rebaz Ahmed; Meghna Mehta; Anupama Munshi; Rajagopal Ramesh Abstract: Publication date: Available online 7 December 2017 Source:Advances in Cancer Research Author(s): Narsireddy Amreddy, Anish Babu, Ranganayaki Muralidharan, Janani Panneerselvam, Akhil Srivastava, Rebaz Ahmed, Meghna Mehta, Anupama Munshi, Rajagopal Ramesh Effective and safe delivery of anticancer agents is among the major challenges in cancer therapy. The majority of anticancer agents are toxic to normal cells, have poor bioavailability, and lack in vivo stability. Recent advancements in nanotechnology provide safe and efficient drug delivery systems for successful delivery of anticancer agents via nanoparticles. The physicochemical and functional properties of the nanoparticle vary for each of these anticancer agents, including chemotherapeutics, nucleic acid-based therapeutics, small molecule inhibitors, and photodynamic agents. The characteristics of the anticancer agents influence the design and development of nanoparticle carriers. This review focuses on strategies of nanoparticle-based drug delivery for various anticancer agents. Recent advancements in the field are also highlighted, with suitable examples from our own research efforts and from the literature.
Authors:Santanu Maji; Sanjay Panda; Sabindra K. Samal; Omprakash Shriwas; Rachna Rath; Maurizio Pellecchia; Luni Emdad; Swadesh K. Das; Paul B. Fisher; Rupesh Dash Abstract: Publication date: Available online 6 December 2017 Source:Advances in Cancer Research Author(s): Santanu Maji, Sanjay Panda, Sabindra K. Samal, Omprakash Shriwas, Rachna Rath, Maurizio Pellecchia, Luni Emdad, Swadesh K. Das, Paul B. Fisher, Rupesh Dash Cancer is a daunting global problem confronting the world's population. The most frequent therapeutic approaches include surgery, chemotherapy, radiotherapy, and more recently immunotherapy. In the case of chemotherapy, patients ultimately develop resistance to both single and multiple chemotherapeutic agents, which can culminate in metastatic disease which is a major cause of patient death from solid tumors. Chemoresistance, a primary cause of treatment failure, is attributed to multiple factors including decreased drug accumulation, reduced drug–target interactions, increased populations of cancer stem cells, enhanced autophagy activity, and reduced apoptosis in cancer cells. Reprogramming tumor cells to undergo drug-induced apoptosis provides a promising and powerful strategy for treating resistant and recurrent neoplastic diseases. This can be achieved by downregulating dysregulated antiapoptotic factors or activation of proapoptotic factors in tumor cells. A major target of dysregulation in cancer cells that can occur during chemoresistance involves altered expression of Bcl-2 family members. Bcl-2 antiapoptotic molecules (Bcl-2, Bcl-xL, and Mcl-1) are frequently upregulated in acquired chemoresistant cancer cells, which block drug-induced apoptosis. We presently overview the potential role of Bcl-2 antiapoptotic proteins in the development of cancer chemoresistance and overview the clinical approaches that use Bcl-2 inhibitors to restore cell death in chemoresistant and recurrent tumors.
Authors:Giuseppe Murdolo; Desirée Bartolini; Cristina Tortoioli; Marta Piroddi; Pierangelo Torquato; Francesco Galli Abstract: Publication date: Available online 12 October 2017 Source:Advances in Cancer Research Author(s): Giuseppe Murdolo, Desirée Bartolini, Cristina Tortoioli, Marta Piroddi, Pierangelo Torquato, Francesco Galli Selenium (Se) is an essential micronutrient that functions as “redox gatekeeper” and homeostasis factor of normal and cancer cells. Epidemiology and experimental studies, in the last years suggested that both inorganic and organic forms of Se may have favorable health effects. In this regard, a protective action of Se on cellular systems that may help preventing cancer cell differentiation has been demonstrated, while the hypothesis that Se compounds may cure cancer and its metastatic diffusion appears speculative and is still a matter of investigation. Indeed, the overall actions of Se compounds in carcinogenesis are controversial. The recognition that cancer is a stem cell disease instigated major paradigm shifts in our basic understanding of cancer and attracted a great deal of interest. Although current treatment approaches in cancer are grounded in the need to kill the majority of cancer cells, targeting cancer stem cells (CSCs) may hold great potential in improving cancer treatment. In this respect, Se compounds have been demonstrated modulating numerous signaling pathways involved in CSC biology and these findings are now stimulating further research on optimal Se concentrations, most effective and cancer-specific Se compounds, and inherent pathways involved in redox and metabolic regulation of CSCs. In this review, we summarize the current knowledge about the effects of Se compounds on CSCs, by focusing on redox-dependent pathways and main gene regulation checkpoints that affect self-renewal, differentiation, and migration responses in this subpopulation of cancer cells.
Authors:Desirée Bartolini; Luca Sancineto; Andreza Fabro de Bem; Kenneth D. Tew; Claudio Santi; Rafael Radi; Pierangelo Toquato; Francesco Galli Abstract: Publication date: Available online 28 September 2017 Source:Advances in Cancer Research Author(s): Desirée Bartolini, Luca Sancineto, Andreza Fabro de Bem, Kenneth D. Tew, Claudio Santi, Rafael Radi, Pierangelo Toquato, Francesco Galli In vitro and in vivo experimental models clearly demonstrate the efficacy of Se compounds as anticancer agents, contingent upon chemical structures and concentrations of test molecules, as well as on the experimental model under investigation that together influence cellular availability of compounds, their molecular dynamics and mechanism of action. The latter includes direct and indirect redox effects on cellular targets by the activation and altered compartmentalization of molecular oxygen, and the interaction with protein thiols and Se proteins. As such, Se compounds interfere with the redox homeostasis and signaling of cancer cells to produce anticancer effects that include alterations in key regulatory elements of energy metabolism and cell cycle checkpoints that ultimately influence differentiation, proliferation, senescence, and death pathways. Cys-containing proteins and Se proteins involved in the response to Se compounds as sensors and transducers of anticancer signals, i.e., the pharmacoproteome of Se compounds, are described and include critical elements in the different phases of cancer onset and progression from initiation and escape of immune surveillance to tumor growth, angiogenesis, and metastasis. The efficacy and mode of action on these compounds vary depending on the inorganic and organic form of Se used as either supplement or pharmacological agent. In this regard, differences in experimental/clinical protocols provide options for either chemoprevention or therapy in different human cancers.
Authors:Camile C. Fontelles; Thomas P. Ong Abstract: Publication date: Available online 21 September 2017 Source:Advances in Cancer Research Author(s): Camile C. Fontelles, Thomas P. Ong Selenium (Se) is a micronutrient with promising breast cancer prevention and treatment potential. There is extensive preclinical evidence of Se mammary carcinogenesis inhibition. Evidence from epidemiological studies is, however, unclear and intervention studies are rare. Here, we examine Se chemoprotection, chemoprevention, and chemotherapy effects in breast cancer, focusing on associated cellular and molecular mechanisms. Se exerts its protective actions through multiple mechanisms that involve antioxidant activities, induction of apoptosis, and inhibition of DNA damage, cell proliferation, angiogenesis, and invasion. New aspects of Se actions in breast cancer have emerged such as the impact of genetic polymorphisms on Se metabolism and response, new functions of selenoproteins, epigenetic modulation of gene expression, and long-term influence of early-life exposure on disease risk. Opportunity exists to design interventional studies with Se for breast cancer prevention and treatment taking into consideration these key aspects.
Authors:Jablonska Ewa; Reszka Edyta Abstract: Publication date: Available online 12 September 2017 Source:Advances in Cancer Research Author(s): Jablonska Ewa, Reszka Edyta Chemopreventive activity of selenium (Se) may influence epigenome. In this review, we have discussed two aspects of Se and epigenetics in cancer, related to (1) the association between Se and epigenetic regulation in cancer development and prevention; (2) epigenetic modification of selenoprotein-encoding genes in different cancers. In both issues, we focused on DNA methylation as the most investigated epigenetic mechanism. The existing evidence from experimental data in human cancer cell lines, rodents, and human studies in cancer-free subjects indicates that: high Se exposure leads to the inhibition of DNA methyltransferase expression/activity; the association between Se and global methylation remains unclear and requires further investigation with respect to the underlying mechanisms and possible nonlinear character of this relationship; Se affects methylation of specific tumor suppressor genes, possibly in a sex-dependent manner; and cancer phenotype is often characterized by altered methylation of selenoprotein-encoding genes, mainly glutathione peroxidase 3.
Authors:Michael P. Marciel; Peter R. Hoffmann Abstract: Publication date: Available online 1 September 2017 Source:Advances in Cancer Research Author(s): Michael P. Marciel, Peter R. Hoffmann Cancer survival is largely impacted by the dissemination of cancer cells from the original tumor site to secondary tissues or organs through metastasis. Targets for antimetastatic therapies have recently become a focus of research, but progress will require a better understanding of the molecular mechanisms driving metastasis. Selenoproteins play important roles in many of the cellular activities underlying metastasis including cell adhesion, matrix degradation and migration, invasion into the blood and extravasation into secondary tissues, and subsequent proliferation into metastatic tumors along with the angiogenesis required for growth. In this review the roles identified for different selenoproteins in these steps and how they may promote or inhibit metastatic cancers is discussed. These roles include selenoenzyme modulation of redox tone and detoxification of reactive oxygen species, calcium homeostasis and unfolded protein responses regulated by endoplasmic reticulum selenoproteins, and the multiple physiological responses influenced by other selenoproteins.
Authors:Bastihalli T. Diwakar; Arvind M. Korwar; Robert F. Paulson; K. Sandeep Prabhu Abstract: Publication date: Available online 31 August 2017 Source:Advances in Cancer Research Author(s): Bastihalli T. Diwakar, Arvind M. Korwar, Robert F. Paulson, K. Sandeep Prabhu Cancer is a complex disease where cancer stem cells (CSCs) maintain unlimited replicative potential, but evade chemotherapy drugs through cellular quiescence. CSCs are able to give rise to bulk tumor cells that have the capability to override antiproliferative signals and evade apoptosis. Numerous pathways are dysregulated in tumor cells, where increased levels of prooxidant reactive oxygen and nitrogen species can lead to localized inflammation to exacerbate all three stages of tumorigenesis: initiation, progression, and metastasis. Modulation of cellular metabolism in tumor cells as well as immune cells in the tumor microenvironment (TME) can impact inflammatory networks. Altering these pathways can potentially serve as a portal for therapy. It is well known that selenium, through selenoproteins, modulates inflammatory pathways in addition to regulating redox homeostasis in cells. Therefore, selenium has the potential to impact the interaction between tumor cells, CSCs, and immune cells. In the sections later, we review the current status of knowledge regarding this interaction, with reference to leukemia stem cells, and the importance of selenium-dependent regulation of inflammation as a potential mechanism to affect the TME and tumor cell survival.
Authors:Anna P. Kipp Abstract: Publication date: Available online 23 August 2017 Source:Advances in Cancer Research Author(s): Anna P. Kipp Five out of eight human glutathione peroxidases (GPxes) are selenoproteins and thus their expression depends on the selenium (Se) supply. Most Se-dependent GPxes are downregulated in tumor cells, while only GPx2 is considerably upregulated. Whether expression profiles of GPxes predict tumor development and patient survival is controversially discussed. Also, results from in vitro and in vivo studies modulating the expression of GPx isoforms provide evidence for both anti- and procarcinogenic mechanisms. GPxes are able to reduce hydroperoxides, which otherwise would damage DNA, possibly resulting in DNA mutations, modulate redox-sensitive signaling pathways affecting proliferation, differentiation, and cellular metabolism or initiate cell death. Considering these different processes, the role and functions of individual Se-dependent GPx isoforms will be discussed herein in the context of tumorigenesis.
Authors:Elias S.J. Arnér Abstract: Publication date: Available online 23 August 2017 Source:Advances in Cancer Research Author(s): Elias S.J. Arnér The cytosolic selenoprotein thioredoxin reductase 1 (TrxR1, encoded in human by TXNRD1) is implied to have several different roles in relation to cancer. Its physiologic functions may protect normal cells from carcinogenesis, but may also promote cancer progression if carcinogenesis nonetheless occurs. With distinct links to Nrf2 signaling, ribonucleotide reductase-dependent production of deoxyribonucleotides and its support of several antioxidant systems counteracting oxidative stress, the metabolic pathways regulated, and affected by TrxR1, are altogether of crucial importance in cancer. These pathways and causal relationships are at the same time highly intricate. In spite of the complexity in the cellular redox networks, several observations discussed in this chapter suggest that specific targeting of TrxR1 may be promising as a mechanistic principle for anticancer therapy.
Authors:Katrien Van Roosbroeck; George A. Calin Abstract: Publication date: Available online 12 August 2017 Source:Advances in Cancer Research Author(s): Katrien Van Roosbroeck, George A. Calin Human cancers are characterized by a number of hallmarks, including sustained proliferative signaling, evasion of growth suppressors, activated invasion and metastasis, replicative immortality, angiogenesis, resistance to cell death, and evasion of immune destruction. As microRNAs (miRNAs) are deregulated in virtually all human cancers, they show involvement in each of the cancer hallmarks as well. In this chapter, we describe the involvement of miRNAs in cancer from a cancer hallmarks and targeted therapeutics point of view. As no miRNA-based cancer therapeutics are available to date, and the only clinical trial on miRNA-based cancer therapeutics (MRX34) was terminated prematurely due to serious adverse events, we are focusing on protein-coding miRNA targets for which targeted therapeutics in oncology are already approved by the FDA. For each of the cancer hallmarks, we selected major protein-coding players and describe the miRNAs that target them.
Authors:Alessandra Drusco; Carlo M. Croce Abstract: Publication date: Available online 12 August 2017 Source:Advances in Cancer Research Author(s): Alessandra Drusco, Carlo M. Croce More than six decades ago Watson and Crick published the chemical structure of DNA. This discovery revolutionized our approach to medical science and opened new perspectives for the diagnosis and treatment of many diseases including cancer. Since then, progress in molecular biology, together with the rapid advance of technologies, allowed to clone hundreds of protein-coding genes that were found mutated in all types of cancer. Normal and aberrant gene functions, interactions, and mechanisms of mutations were studied to identify the intricate network of pathways leading to cancer. With the acknowledgment of the genetic nature of cancer, new diagnostic, prognostic, and therapeutic strategies have been attempted and developed, but very few have found their way in the clinical field. In an effort to identify new translational targets, another great discovery has changed our way to look at genes and their functions. MicroRNAs have been the first noncoding genes involved in cancer. This review is a brief chronological history of microRNAs and cancer. Through the work of few of the greatest scientists of our times, this chapter describes the discovery of microRNAs from C. elegans to their debut in cancer and in the medical field, the concurrent development of technologies, and their future translational applications. The purpose was to share the exciting path that lead to one of the most important discoveries in cancer genetics in the past 20 years.
Authors:Marco Vinceti; Tommaso Filippini; Silvia Cilloni; Catherine M. Crespi Abstract: Publication date: Available online 12 August 2017 Source:Advances in Cancer Research Author(s): Marco Vinceti, Tommaso Filippini, Silvia Cilloni, Catherine M. Crespi The relation between selenium and cancer has been one of the most hotly debated topics in human health over the last decades. Early observational studies reported an inverse relation between selenium exposure and cancer risk. Subsequently, randomized controlled trials showed that selenium supplementation does not reduce the risk of cancer and may even increase it for some types, including advanced prostate cancer and skin cancer. An increased risk of diabetes has also been reported. These findings have been consistent in the most methodologically sound trials, suggesting that the early observational studies were misleading. Other studies have investigated selenium compounds as adjuvant therapy for cancer. Though there is currently insufficient evidence regarding the utility and safety of selenium compounds for such treatments, this issue is worthy of further investigation. The study of selenium and cancer is complicated by the existence of a diverse array of organic and inorganic selenium compounds, each with distinct biological properties, and this must be taken into consideration in the interpretation of both observational and experimental human studies.
Authors:Veronica Balatti; Yuri Pekarsky; Carlo M. Croce Abstract: Publication date: Available online 10 August 2017 Source:Advances in Cancer Research Author(s): Veronica Balatti, Yuri Pekarsky, Carlo M. Croce Noncoding RNAs are untranslated RNA molecules that can be divided into two main types: infrastructural, including transfer RNAs (tRNAs) and ribosomal RNAs (rRNAs), and regulatory, including long ncRNAs (lncRNAs) and small ncRNAs (sRNA). Among small ncRNA, the role of microRNAs (miRNAs) and Piwi-interacting RNAs (piRNAs) in cancer is well documented. Recently, other small ncRNAs have been described. In particular, tRNA-derived small RNAs (tsRNA) have been found to be frequently dysregulated in cancer. Since tsRNAs can be considered unique sequences and are able to bind both Argonaute proteins (like miRNAs) and Piwi proteins (like piRNAs), their dysregulation could play a critical role in cancer by interfering with gene expression regulation at different levels. Like microRNAs, ts-53 (previously known as miR-3676) interacts with the 3′UTR of TCL1, therefore supporting a role for tsRNAs on the posttranscriptional regulation of gene expression. Like piRNAs, tsRNAs are produced as single-stranded molecules and can interact with DNA and histone methylation machinery, suggesting a role in the pretranscriptional regulation of gene expression. Herein, we describe the most recent findings about the role of tsRNAs in cancer.
Authors:Arpita S. Pal; Andrea L. Kasinski Abstract: Publication date: Available online 8 August 2017 Source:Advances in Cancer Research Author(s): Arpita S. Pal, Andrea L. Kasinski The discovery of the microRNAs, lin-4 and let-7 as critical mediators of normal development in Caenorhabditis elegans and their conservation throughout evolution has spearheaded research toward identifying novel roles of microRNAs in other cellular processes. To accurately elucidate these fundamental functions, especially in the context of an intact organism, various microRNA transgenic models have been generated and evaluated. Transgenic C. elegans (worms), Drosophila melanogaster (flies), Danio rerio (zebrafish), and Mus musculus (mouse) have contributed immensely toward uncovering the roles of multiple microRNAs in cellular processes such as proliferation, differentiation, and apoptosis, pathways that are severely altered in human diseases such as cancer. The simple model organisms, C. elegans, D. melanogaster, and D. rerio, do not develop cancers but have proved to be convenient systesm in microRNA research, especially in characterizing the microRNA biogenesis machinery which is often dysregulated during human tumorigenesis. The microRNA-dependent events delineated via these simple in vivo systems have been further verified in vitro, and in more complex models of cancers, such as M. musculus. The focus of this review is to provide an overview of the important contributions made in the microRNA field using model organisms. The simple model systems provided the basis for the importance of microRNAs in normal cellular physiology, while the more complex animal systems provided evidence for the role of microRNAs dysregulation in cancers. Highlights include an overview of the various strategies used to generate transgenic organisms and a review of the use of transgenic mice for evaluating preclinical efficacy of microRNA-based cancer therapeutics.
Authors:Anjan K. Pradhan; Luni Emdad; Swadesh K. Das; Devanand Sarkar; Paul B. Fisher Abstract: Publication date: Available online 7 August 2017 Source:Advances in Cancer Research Author(s): Anjan K. Pradhan, Luni Emdad, Swadesh K. Das, Devanand Sarkar, Paul B. Fisher MicroRNAs (miRNAs or miRs) are small 19–22 nucleotide long, noncoding, single-stranded, and multifunctional RNAs that regulate a diverse assortment of gene and protein functions that impact on a vast network of pathways. Lin-4, a noncoding transcript discovered in 1993 and named miRNA, initiated the exploration of research into these intriguing molecules identified in almost all organisms. miRNAs interfere with translation or posttranscriptional regulation of their target gene and regulate multiple biological actions exerted by these target genes. In cancer, they function as both oncogenes and tumor suppressor genes displaying differential activity in various cellular contexts. Although the role of miRNAs on target gene functions has been extensively investigated, less is currently known about the upstream regulatory molecules that regulate miRNAs. This chapter focuses on the factors and processes involved in miRNA regulation.
Authors:Catia Moutinho; Manel Esteller Abstract: Publication date: Available online 4 August 2017 Source:Advances in Cancer Research Author(s): Catia Moutinho, Manel Esteller MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expression mainly at the posttranscriptional level. Similar to protein-coding genes, their expression is also controlled by genetic and epigenetic mechanisms. Disruption of these control processes leads to abnormal expression of miRNAs in cancer. In this chapter, we discuss the supportive links between miRNAs and epigenetics in the context of carcinogenesis. miRNAs can be epigenetically regulated by DNA methylation and/or specific histone modifications. However, they can themselves (epi-miRNAs) repress key enzymes that drive epigenetic remodeling and also bind to complementary sequences in gene promoters, recruiting specific protein complexes that modulate chromatin structure and gene expression. All these issues affect the transcriptional landscape of cells. Most important, in the cancer clinical scenario, knowledge about miRNAs epigenetic dysregulation can not only be beneficial as a prognostic biomarker, but can also help in the design of new therapeutic approaches.
Authors:Ryan Abstract: Publication date: Available online 4 August 2017 Source:Advances in Cancer Research Author(s): Bríd M. Ryan microRNAs (miRNAs) are a small RNA species without protein-coding potential. However, they are key modulators of protein translation. Many studies have linked miRNAs with cancer initiation, progression, diagnosis, and prognosis, and recent studies have also linked them with cancer etiology and susceptibility, especially through single-nucleotide polymorphisms (SNPs). This review discusses some of the recent advances in miRNA-SNP literature—including SNPs in miRNA genes, miRNA target sites, and the processing machinery. In addition, we highlight some emerging areas of interest, including isomiRs and non-3′UTR focused miRNA-binding mechanisms that could provide further novel insight into the relationship between miR-SNPs and cancer. Finally, we note that additional epidemiological and experimental research is needed to close the gap in our understanding of the genotype–phenotype relationship between miRNA-SNPs and cancer.
Authors:R. Casadonte; R. Longuespée; J. Kriegsmann; M. Kriegsmann Abstract: Publication date: Available online 12 January 2017 Source:Advances in Cancer Research Author(s): R. Casadonte, R. Longuespée, J. Kriegsmann, M. Kriegsmann Matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI IMS) technology creates a link between the molecular assessment of numerous molecules and the morphological information about their special distribution. The application of MALDI IMS on formalin-fixed paraffin-embedded (FFPE) tissue microarrays (TMAs) is suitable for large-scale discovery analyses. Data acquired from FFPE TMA cancer samples in current research are very promising, and applications for routine diagnostics are under development. With the current rapid advances in both technology and applications, MALDI IMS technology is expected to enter into routine diagnostics soon. This chapter is intended to be comprehensive with respect to all aspects and considerations for the application of MALDI IMS on FFPE cancer TMAs with in-depth notes on technical aspects.
Authors:R.J.A. Goodwin; J. Bunch; D.F. McGinnity Abstract: Publication date: Available online 10 January 2017 Source:Advances in Cancer Research Author(s): R.J.A. Goodwin, J. Bunch, D.F. McGinnity Over the last decade mass spectrometry imaging (MSI) has been integrated in to many areas of drug discovery and development. It can have significant impact in oncology drug discovery as it allows efficacy and safety of compounds to be assessed against the backdrop of the complex tumour microenvironment. We will discuss the roles of MSI in investigating compound and metabolite biodistribution and defining pharmacokinetic -pharmacodynamic relationships, analysis that is applicable to all drug discovery projects. We will then look more specifically at how MSI can be used to understand tumour metabolism and other applications specific to oncology research. This will all be described alongside the challenges of applying MSI to industry research with increased use of metrology for MSI.
Authors:G. Arentz; P. Mittal; C. Zhang; Y.-Y. Ho; M. Briggs; L. Winderbaum; M.K. Hoffmann; P. Hoffmann Abstract: Publication date: Available online 9 January 2017 Source:Advances in Cancer Research Author(s): G. Arentz, P. Mittal, C. Zhang, Y.-Y. Ho, M. Briggs, L. Winderbaum, M.K. Hoffmann, P. Hoffmann Pathologists play an essential role in the diagnosis and prognosis of benign and cancerous tumors. Clinicians provide tissue samples, for example, from a biopsy, which are then processed and thin sections are placed onto glass slides, followed by staining of the tissue with visible dyes. Upon processing and microscopic examination, a pathology report is provided, which relies on the pathologist's interpretation of the phenotypical presentation of the tissue. Targeted analysis of single proteins provide further insight and together with clinical data these results influence clinical decision making. Recent developments in mass spectrometry facilitate the collection of molecular information about such tissue specimens. These relatively new techniques generate label-free mass spectra across tissue sections providing nonbiased, nontargeted molecular information. At each pixel with spatial coordinates (x/y) a mass spectrum is acquired. The acquired mass spectrums can be visualized as intensity maps displaying the distribution of single m/z values of interest. Based on the sample preparation, proteins, peptides, lipids, small molecules, or glycans can be analyzed. The generated intensity maps/images allow new insights into tumor tissues. The technique has the ability to detect and characterize tumor cells and their environment in a spatial context and combined with histological staining, can be used to aid pathologists and clinicians in the diagnosis and management of cancer. Moreover, such data may help classify patients to aid therapy decisions and predict outcomes. The novel complementary mass spectrometry-based methods described in this chapter will contribute to the transformation of pathology services around the world.
Authors:L.A. McDonnell; P.M. Angel; S. Lou; R.R. Drake Abstract: Publication date: Available online 30 December 2016 Source:Advances in Cancer Research Author(s): L.A. McDonnell, P.M. Angel, S. Lou, R.R. Drake In the last decade mass spectrometry imaging has developed rapidly, in terms of multiple new instrumentation innovations, expansion of target molecules, and areas of application. Mass spectrometry imaging has already had a substantial impact in cancer research, uncovering biomolecular changes associated with disease progression, diagnosis, and prognosis. Many new approaches are incorporating the use of readily available formalin-fixed paraffin-embedded cancer tissues from pathology centers, including tissue blocks, biopsy specimens, and tumor microarrays. It is also increasingly used in drug formulation development as an inexpensive method to determine the distributions of drugs and their metabolites. In this chapter, we offer a perspective in the current and future methodological developments and how these may open up new vistas for cancer research.
Authors:Z. Takats; N. Strittmatter; J.S. McKenzie Abstract: Publication date: Available online 29 December 2016 Source:Advances in Cancer Research Author(s): Z. Takats, N. Strittmatter, J.S. McKenzie Ambient ionization mass spectrometry was developed as a sample preparation-free alternative to traditional MS-based workflows. Desorption electrospray ionization (DESI)-MS methods were demonstrated to allow the direct analysis of a broad range of samples including unaltered biological tissue specimens. In contrast to this advantageous feature, nowadays DESI-MS is almost exclusively used for sample preparation intensive mass spectrometric imaging (MSI) in the area of cancer research. As an alternative to MALDI, DESI-MSI offers matrix deposition-free experiment with improved signal in the lower (<500 m/z) range. DESI-MSI enables the spatial mapping of tumor metabolism and has been broadly demonstrated to offer an alternative to frozen section histology for intraoperative tissue identification and surgical margin assessment. Rapid evaporative ionization mass spectrometry (REIMS) was developed exclusively for the latter purpose by the direct combination of electrosurgical devices and mass spectrometry. In case of the REIMS technology, aerosol particles produced by electrosurgical dissection are subjected to MS analysis, providing spectral information on the structural lipid composition of tissues. REIMS technology was demonstrated to give real-time information on the histological nature of tissues being dissected, deeming it an ideal tool for intraoperative tissue identification including surgical margin control. More recently, the method has also been used for the rapid lipidomic phenotyping of cancer cell lines as it was demonstrated in case of the NCI-60 cell line collection.
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