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Seminars in Cancer Biology

Abdul Q Khan, Shilpa Kuttikrishnan, Kodappully S Siveen, Kirti S Prabhu, Muralitharan Shanmugakonar, Hamda Al Naemi, Mohammad Haris, Said Dermime, Shahab Uddin
Abnormally activated RAS proteins are the main oncogenic driver that governs the functioning of major signaling pathways involved in the initiation and development of human malignancies. Mutations in RAS genes and or its regulators, most frequent in human cancers, are the main force for incessant RAS activation and associated pathological conditions including cancer. In general, RAS is the main upstream regulator of the highly conserved signaling mechanisms associated with a plethora of important cellular activities vital for normal homeostasis...
March 7, 2018: Seminars in Cancer Biology
Keesha E Erickson, Oleksii S Rukhlenko, Richard G Posner, William S Hlavacek, Boris N Kholodenko
RAS is the most frequently mutated gene across human cancers, but developing inhibitors of mutant RAS has proven to be challenging. Given the difficulties of targeting RAS directly, drugs that impact the other components of pathways where mutant RAS operates may potentially be effective. However, the system-level features, including different localizations of RAS isoforms, competition between downstream effectors, and interlocking feedback and feed-forward loops, must be understood to fully grasp the opportunities and limitations of inhibiting specific targets...
March 5, 2018: Seminars in Cancer Biology
Jakob Nikolas Kather, Niels Halama, Dirk Jaeger
Colorectal cancer (CRC) is a common and lethal disease with a high therapeutic need. For most patients with metastatic CRC, chemotherapy is the only viable option. Currently, immunotherapy is restricted to the particular genetic subgroup of mismatch-repair deficient (MMRd)/microsatellite instable (MSI) CRC. Anti-PD1 therapy was recently FDA-approved as a second-line treatment in this subgroup. However, in a metastatic setting, these MMRd/MSI tumors are vastly outnumbered by mismatch-repair proficient (MMRp)/microsatellite stable (MSS) tumors...
March 1, 2018: Seminars in Cancer Biology
Ruth Nussinov, Chung-Jung Tsai, Hyunbum Jang
Ras signaling initiates at the plasma membrane. Thus, Ras behavior at the membrane and how it relates to its interactions with Raf and PI3Kα, are of immense interest. Here we review factors influencing Ras lateral diffusion. We then ask whether oncogenic Ras diffusion speed in the membrane is important for signaling response times and whether it affects ubiquitously all pathways. We suggest that if Ras expression is sufficiently high to dimerize (or form nanoclusters), signaling response of those pathways where dimers (or nanoclusters) are involved corresponds to the speed with which Ras molecules travel in the membrane...
February 27, 2018: Seminars in Cancer Biology
Nikee Awasthee, Vipin Rai, Srinivas Chava, Palanisamy Nallasamy, Ajaikumar B Kunnumakkara, Anupam Bishayee, Subhash C Chauhan, Kishore B Challagundla, Subash C Gupta
The inhibitory kappa B kinases (IKKs) and IKK related kinases are crucial regulators of the pro-inflammatory transcription factor, nuclear factor kappa B (NF-κB). The dysregulation in the activities of these kinases has been reported in several cancer types. These kinases are known to regulate survival, proliferation, invasion, angiogenesis, and metastasis of cancer cells. Thus, IKK and IKK related kinases have emerged as an attractive target for the development of cancer therapeutics. Several IKK inhibitors have been developed, few of which have advanced to the clinic...
February 24, 2018: Seminars in Cancer Biology
Dominic Esposito, Andrew G Stephen, Thomas J Turbyville, Matthew Holderfield
Development of therapeutic strategies against RAS-driven cancers has been challenging due in part to a lack of understanding of the biology of the system and the ability to design appropriate assays and reagents for targeted drug discovery efforts. Recent developments in the field have opened up new avenues for exploration both through advances in the number and quality of reagents as well as the introduction of novel biochemical and cell-based assay technologies which can be used for high-throughput screening of compound libraries...
February 9, 2018: Seminars in Cancer Biology
Roberto Serna-Blasco, Marta Sanz-Álvarez, Óscar Aguilera, Jesús García-Foncillas
RAS protein family members (KRAS4A, KRAS4B, HRAS and NRAS) function as GDP-GTP-regulated on-off switches, which regulate cytoplasmic-nuclear signaling networks ruling diverse normal cellular processes. Constitutive activating mutations in RAS genes are found in up to 30% of human cancers, and remarkably, the oncogenic Ras mutations and mutations in other components of Ras/MAPK signaling pathways seem to be mutually exclusive in most tumors, pointing out that deregulation of Ras-dependent signaling is an essential requirement for tumorigenesis...
February 9, 2018: Seminars in Cancer Biology
B Allard, S Aspeslagh, S Garaud, F A Dupont, C Solinas, M Kok, B Routy, C Sotiriou, J Stagg, L Buisseret
Cancer immunotherapy is demonstrating impressive clinical benefit in different malignancies and clinical oncologists are increasingly turning their attention to immune-oncology. It is now well recognized that innate and adaptive immune cells infiltrating tumors are associated with clinical outcomes and responses to treatments, and can be harnessed to patients' benefit. Considerable advances have also been made in understanding how cancers escape from immune attack. Targeting of immunological escape processes regulated by the expression of immune checkpoint receptors and ligands and the down-modulation of tumor antigen presentation is the basis of immuno-oncology treatments...
February 8, 2018: Seminars in Cancer Biology
Meera Nair, Sardul Singh Sandhu, Anil Kumar Sharma
Cancer is generally caused by the molecular alterations which lead to specific mutations. Advances in molecular biology have provided an impetus to the study of cancers with valuable prognostic and predictive significance. Over the hindsight various attempts have been undertaken by scientists worldwide, in the management of cancer; where, we have witnessed a number of molecular markers which allow the early detection of cancers and lead to a decrease in its mortality rate. Recent advances in oncology have led to the discovery of cancer markers that has allowed early detection and targeted therapy of tumors...
February 8, 2018: Seminars in Cancer Biology
Larry Mansouri, Justyna Anna Wierzbinska, Christoph Plass, Richard Rosenquist
Deregulated transcriptional control caused by aberrant DNA methylation and/or histone modifications is a hallmark of cancer cells. In chronic lymphocytic leukemia (CLL), the most common adult leukemia, the epigenetic 'landscape' has added a new layer of complexity to our understanding of this clinically and biologically heterogeneous disease. Early studies identified aberrant DNA methylation, often based on single gene promoter analysis with both biological and clinical impact. Subsequent genome-wide profiling studies revealed differential DNA methylation between CLLs and controls and in prognostics subgroups of the disease...
February 7, 2018: Seminars in Cancer Biology
Zhiqiang Ma, Zhenlong Xin, Wei Hu, Shuai Jiang, Zhi Yang, Xiaolong Yan, Xiaofei Li, Yang Yang, Fulin Chen
The epithelial-mesenchymal transition (EMT) is an acknowledged cellular transition process in which epithelial cells acquire mesenchymal-like properties that endow cancer cells with increased migratory and invasive behavior. Forkhead box O (FOXO) proteins have been shown to orchestrate multiple EMT-associated pathways and EMT-related transcription factors (EMT-TFs), thereby modulating the EMT process. The focus of the current review is to evaluate the latest research progress regarding the roles of FOXO proteins in cancer EMT...
February 7, 2018: Seminars in Cancer Biology
Meenakshi Rajpoot, Anil K Sharma, Anil Sharma, Girish Kumar Gupta
The human body is a home to more than 1 trillion microbes with a diverse variety of commensal microbes that play a crucial role towards the health of the individual. These microbes occupy different habitats such as gut, skin, vagina, oral etc. Not only the types and abundance of microbes are different in different organs, but also these may differ in different individuals. The genome of these microbiota and their ecosystem constitute to form a microbiome. Factors such as diet, environment, host genetics etc...
February 6, 2018: Seminars in Cancer Biology
Nagore I Marín-Ramos, Silvia Ortega-Gutiérrez, María L López-Rodríguez
Ras proteins are among the most frequently mutated drivers in human cancer and remain an elusive pharmaceutical targeting. Previous studies have improved the understanding of Ras structure, processing, and signaling pathways in cancer cells and have opened new possibilities for inhibiting Ras function. In this review we discuss the most recent advances towards inhibiting Ras activity with small molecules, highlighting the two approaches: (i) compounds that bind directly to Ras protein and (ii) inhibitors of the enzymes involved in the post-translational modifications of Ras...
February 2, 2018: Seminars in Cancer Biology
Sneha Vivekanandhan, Debabrata Mukhopadhyay
Oncogenic RAS and deregulated transforming growth factor-beta (TGF)-β signaling have been implicated in several cancers. So far, attempts to target either one of them therapeutically have been futile as both of them are involved in multiple fundamental cellular processes and the normal forms are expressed by almost all cells. Hence, their inhibition would disrupt several physiological processes. Besides, their downregulation stimulates the tumor cells to develop adaptive mechanisms and would most likely be ineffective as therapeutic targets...
February 2, 2018: Seminars in Cancer Biology
Jian Ma, Smita Matkar, Xin He, Xianxin Hua
FOXO proteins are a sub-group of a superfamily of forkhead box (FOX)-containing transcription factors (TFs). FOXOs play an important role in regulating a plethora of biological activities ranging from development, cell signaling, and tumorigenesis to cell metabolism. Here we mainly focus on reviewing the role of FOXOs in regulating tumor and metabolism. Moreover, how crosstalk among various pathways influences the function of FOXOs will be reviewed. Further, the paradoxical role for FOXOs in controlling the fate of cancer and especially resistance/sensitivity of cancer to the class of drugs that target PI3 K/AKT will also be reviewed...
February 1, 2018: Seminars in Cancer Biology
F Passiglia, C Caglevic, E Giovannetti, J A Pinto, P Manca, S Taverna, A Listì, I Gil-Bazo, L E Raez, A Russo, C Rolfo
Recent studies with immunomodulatory agents targeting both cytotoxic T-lymphocyte protein 4 (CTLA4) and programmed cell death 1 (PD1)/programmed cell death ligand 1 (PDL1) have shown to be very effective in several cancers revealing an unexpected great activity in patients with both primary and metastatic brain tumors. Combining anti-CTLA4 and anti-PD1 agents as upfront systemic therapy has revealed to further increase the clinical benefit observed with single agent, even at cost of higher toxicity. Since the brain is an immunological specialized area it's crucial to establish the specific composition of the brain tumors' microenvironment in order to predict the potential activity of immunomodulatory agents...
January 31, 2018: Seminars in Cancer Biology
Benjamin Solomon, Richard J Young, Danny Rischin
Head and neck squamous cell carcinoma (HNSCC) comprises a heterogeneous group of tumors that arise from the squamous epithelium of the oral cavity, oropharynx, larynx and hypopharynx. While many HNSCCs are related to classical etiologic factors of smoking and alcohol, a clinically, genomically, and immunologically distinct subgroup of tumors arise from the epithelium of the tonsil and the base of tongue as a result of infection with Human Papilloma Virus (HPV). In this review we describe the genomic and immunologic landscape of HNSCC, highlighting differences between HPV-positive and HPV-negative HNSCC...
January 30, 2018: Seminars in Cancer Biology
Matías González-Quiroz, Hery Urra, Celia María Limia, Claudio Hetz
Cancer cells are exposed to several adverse conditions within the tumor microenvironment that challenge cells to adapt and survive. Several of these homeostatic perturbations insults alter the normal function of the endoplasmic reticulum (ER), resulting in the accumulation of misfolded proteins. ER stress triggers a conserved signaling pathway known as the unfolded protein response (UPR) to cope with the stress or trigger apoptosis of damaged cells. The UPR has been described as a major driver of the acquisition of malignant characteristics that ultimately lead to tumor progression...
January 21, 2018: Seminars in Cancer Biology
Yassen Assenov, David Brocks, Clarissa Gerhäuser
Analogous to life on earth, tumor cells evolve through space and time and adapt to different micro-environmental conditions. As a result, tumors are composed of millions of genetically diversified cells at the time of diagnosis. Profiling these variants contributes to understanding tumors' clonal origins and might help to better understand response to therapy. However, even genetically homogenous cell populations show remarkable diversity in their response to different environmental stimuli, suggesting that genetic heterogeneity does not explain the full spectrum of tumor plasticity...
January 20, 2018: Seminars in Cancer Biology
Dimitry A Chistiakov, Veronika A Myasoedova, Andrey V Grechko, Alexandra A Melnichenko, Alexander N Orekhov
The diagnostics and management of localized prostate cancer is complicated because of cancer heterogeneity and differentiated progression in various subgroups of patients. As a prostate cancer biomarker, FDA-approved detection assay for serum prostate specific antigen (PSA) and its derivatives are not potent enough to diagnose prostate cancer, especially high-grade disease (Gleason ≥7). To date, a collection of new biomarkers was developed. Some of these markers are superior for primary screening while others are particularly helpful for cancer risk stratification, detection of high-grade cancer, and prediction of adverse events...
January 19, 2018: Seminars in Cancer Biology
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