Emergence Of Malignancies Research Articles

Haemophilia and Cancer: A Literature Review.

Opinions in the literature on the impact of cancer on patients with haemophilia are contradictory. There is a lack of data on the clinical presentation and management of cancer in patients with haemophilia (PWH). Papers were found following a comprehensive search in PubMed, Google Scholar, and Scopus using the terms "cancer" and "haemophilia" without time limits and using the English language as a filter. The references from all the retrieved original articles and reviews were assessed for additional relevant articles. The emergence of malignancies is one of the important causes of morbidity and mortality in PWH. In the past decade, the literature mainly focused on the epidemiology and outcome of blood-borne cancers in the haemophilia patient group, as the incidence of hepatitis B virus (HBV), hepatitis C (HCV), and HIV infection were high among them. However, with the introduction of recombinant clotting factor concentrates (CFCs), physicians now pay attention to non-virus-related malignancies. Bleeding and thrombotic complications are important causes of morbidity and mortality in critically ill patients with cancer; replacement therapy with factor VIII or IX or others should be maintained during antitumour treatment. Overall, managing cancer in patients with haemophilia requires careful evaluation and individualised planning involving a multidisciplinary team of physicians experienced in haematology, oncology, and surgery.

Designing an Inhibitor Molecule to Combat Cancer through the Inhibition of Mutant PI3K (P110 α) Subunit Protein

The PI3K pathway plays a crucial role in the development of various types of cancers. Specifically, the P110 α component is frequently modified in the formation of human cancer, leading to disruptions in cell growth regulation and the emergence of malignancies. This research paper delves into the increasing utilization of computational tools to forecast potential molecules capable of inhibiting cancer. To validate stable structures of PI3K (P110α) component protein models, the study employed Ramachandran map analysis, which revealed active regions in close proximity to the mutation site. Through the employment of PyRX software, molecular docking studies were conducted, resulting in the identification of four inhibitor derivatives that exhibited significant effectiveness with the lowest docking energies in preventing the mutated PI3K (P110 α) component protein structures. Furthermore, these inhibitors adhered to Lipinski's rule of five, further enhancing their potential.

LINC02561 promotes metastasis in HCC via HIF1-α/NDRG1/UPF1 axis

In the entire world, hepatocellular carcinoma (HCC) is one of the most frequent cancers that lead to death. Experiments on the function of long non-coding RNAs in the emergence of malignancies, including HCC, are ongoing. As a crucial RNA monitoring mechanism in eucaryotic cells, nonsense-mediated mRNA decay (NMD) can recognize and destroy mRNAs, which has an premature termination codons (PTC) in the open reading frame to prevent harmful buildup of truncated protein products in the cells. Nonsense transcript regulator 1 (Up-frameshift suppressor 1, UPF1), as a highly conserved RNA helicase and ATPase, plays a key role in NMD. Our laboratory screened out the highly expressed lncRNA LINC02561 in HCC from the TCGA database. Further research found that LINC02561 enhanced the invasion and transition abilities of liver cancer cells by regulating the protein N-Myc downstream regulated 1 (NDRG1). Hypoxia inducible factor-1 (HIF-1α) can bonded to LINC02561 promoters under hypoxic conditions, thereby promoting the upregulation of LINC02561 expression in liver cancer cells. LINC02561 competes with NDRG1 mRNA to bind UPF1, thereby preventing the degradation of NDRG1 mRNA to facilitate NDRG1 protein level. Taken together, the HIF1α-LINC02561-UPF1-NDRG1 regulatory axis could be an entirely novel target of liver cancer-related treatment.

Unraveling the Drivers of Tumorigenesis in the Context of Evolution: Theoretical Models and Bioinformatics Tools.

Cancer originates from somatic cells that have accumulated mutations. These mutations alter the phenotype of the cells, allowing them to escape homeostatic regulation that maintains normal cell numbers. The emergence of malignancies is an evolutionary process in which the random accumulation of somatic mutations and sequential selection of dominant clones cause cancer cells to proliferate. The development of technologies such as high-throughput sequencing has provided a powerful means to measure subclonal evolutionary dynamics across space and time. Here, we review the patterns that may be observed in cancer evolution and the methods available for quantifying the evolutionary dynamics of cancer. An improved understanding of the evolutionary trajectories of cancer will enable us to explore the molecular mechanism of tumorigenesis and to design tailored treatment strategies.

Genetic Influences in Cancer-Associated Myositis.

Idiopathic inflammatory myopathies (IIMs) comprise a heterogeneous group of rare immune-mediated disorders that primarily affect muscles but also lead to dysfunction in other organs. Five different clinical subphenotypes of IIM have been distinguished: dermatomyositis, polymyositis, inclusion body myositis, antisynthetase syndrome, and immune-mediated necrotizing myopathy. Excess mortality and morbidity associated with IIM are largely attributed to comorbidities, particularly cancer. The risk of malignancy is not equally distributed among IIM groups and is particularly high among patients with dermatomyositis. The cancer risk peaks around 3 years on either side of the IIM diagnosis and remains elevated even 10 years after the onset of the disease. Lung, colorectal, and ovarian neoplasms typically arise before the onset of IIM, whereas melanoma, cervical, oropharyngeal, and nonmelanoma skin cancers usually develop after IIM diagnosis. Given the close temporal proximity between IIM diagnosis and the emergence of malignancy, it has been proposed that IIM could be a consequence rather than a cause of cancer, a process known as a paramalignant phenomenon. Thus, a separate group of IIMs related to paramalignant phenomenon has been distinguished, known as cancer-associated myositis (CAM). Although the relationship between IIM and cancer is widely recognized, the pathophysiology of CAM remains elusive. Given that genetic factors play a role in the development of IIM, dissection of the molecular mechanisms shared between IIM and cancer presents an opportunity to examine the role of autoimmunity in cancer development and progression. In this review, the evidence supporting the contribution of genetics to CAM will be discussed.

Spatial genome architecture and the emergence of malignancy.

Human chromosomes are large spatially and hierarchically structured entities, the integrity of which needs to be preserved throughout the lifespan of the cell and in conjunction with cell cycle progression. Preservation of chromosomal structure is important for proper deployment of cell type-specific gene expression programs. Thus, aberrations in the integrity and structure of chromosomes will predictably lead to disease, including cancer. Here, we provide an updated standpoint with respect to chromatin misfolding and the emergence of various cancer types. We discuss recent studies implicating the disruption of topologically associating domains, switching between active and inactive compartments, rewiring of promoter-enhancer interactions in malignancy as well as the effects of single nucleotide polymorphisms in non-coding regions involved in long-range regulatory interactions. In light of these findings, we argue that chromosome conformation studies may now also be useful for patient diagnosis and drug target discovery.

Critical behavior of spatial networks as a model of paracrine signaling in tumorigenesis

Recent work on the study of cell populations in mouse tumors has revealed much about the clonal evolution of cancers from the initiated cell to metastasis. Although most cancers are clonal in origin, genetic instability leads to the emergence of new cell clones, some of which show cooperative behavior during progression to metastasis. The nature of these cell-cell interactions is unclear, and in particular it is possible that their spatial distribution could influence the emergence of fully malignant behavior. The spatial distribution would indicate a subtle dependence of the distribution of these cells and the emergence of malignancy. In this paper we model tumor evolution using dynamically evolving spatially embedded random graphs. The dynamic evolution of Spatio-Temporal graphs is not widely studied analytically, particularly when distance based preferences are included. In this paper we present analysis and simulations of such graphs, and demonstrate that the distance function relative to the mixing of the nodes can combine to create phase transitions in connectivity. This result supports the hypothesis that cell to cell interaction is a critical feature of malignancy in tumors.

A web platform for the network analysis of high-throughput data in melanoma and its use to investigate mechanisms of resistance to anti-PD1 immunotherapy

Cellular phenotypes are established and controlled by complex and precisely orchestrated molecular networks. In cancer, mutations and dysregulations of multiple molecular factors perturb the regulation of these networks and lead to malignant transformation. High-throughput technologies are a valuable source of information to establish the complex molecular relationships behind the emergence of malignancy, but full exploitation of this massive amount of data requires bioinformatics tools that rely on network-based analyses.In this report we present the Virtual Melanoma Cell, an online tool developed to facilitate the mining and interpretation of high-throughput data on melanoma by biomedical researches. The platform is based on a comprehensive, manually generated and expert-validated regulatory map composed of signaling pathways important in malignant melanoma. The Virtual Melanoma Cell is a tool designed to accept, visualize and analyze user-generated datasets. It is available at: https://www.vcells.net/melanoma. To illustrate the utilization of the web platform and the regulatory map, we have analyzed a large publicly available dataset accounting for anti-PD1 immunotherapy treatment of malignant melanoma patients.

Behcet's disease associated with malignancy: a report of 41 Chinese cases

To identify the clinical characteristics of Behcet's disease (BD) associated with malignancies. Among 651 BD patients sequentially hospitalized in Peking Union Medical College Hospital from 1995 to 2012, 41 patients developed malignancies. Clinical characteristics were compared between patients with and without malignancies, as well as between patients with hematological and solid malignancies. The numbers of patients with various types of malignancies were listed as follows: (i) 29 cases developed hematologic malignancies which included myelodysplastic syndrome (MDS) as the most common diagnosis in 20 cases, leukemia in seven cases, anaplastic anemia in two cases and lymphoma in one case; (ii) 13 cases developed malignant solid neoplasms which included colorectal cancer in three cases, urothelial carcinoma of bladder in two cases, esophageal cancer, gastric cancer, pancreatic cancer, thyroid cancer, breast cancer, cervical cancer, renal cell carcinoma and metastatic adenocarcinoma of unknown primary in one case each. Female gender, older age and gastrointestinal tract involvement were more frequently observed among patients with malignancy than those without. Older age, longer disease duration were more commonly seen in BD patients with solid neoplasms than in those with hematologic malignancies. Exacerbation of BD manifestations during the emergence of malignancy was more frequently observed among patients with hematologic malignancies than among those with malignant solid neoplasms. This study demonstrated that MDS and colorectal cancer were the most common hematologic malignancy and malignant solid neoplasm associated with BD, respectively. Gastrointestinal involvement is likely to be a risk factor for BD patients to develop malignancy. Further studies will be required to ascertain the pathogenic link between these two entities.

Insertional Mutagenesis by Retroviral Vectors: Current Concepts and Methods of Analysis

Retroviral vectors derived from gammaretroviruses or lentiviruses have now been used extensively in clinical gene therapy trials for several diseases including primary immunodeficiencies, beta thalassaemia and adrenoleukodystrophy. Their utility in this setting has been readily demonstrated by the largely favourable outcomes in recent clinical trials, however this success has been marred by the emergence of malignancies in some trials. These malignancies were a consequence of perturbation of cellular proto-oncogene expression by the integrated retroviral vectors, the process of which is referred to as 'insertional mutagenesis' (IM). In this review, the origins of our understanding of IM are reviewed and applied to the clinical gene therapy trials conducted with retroviral vectors. Old and new methods for assessing this phenomenon are discussed with a view to provide a comprehensive account of this emerging field.

Hematopoietic Stem Cell Expansion, without Exhaustion or Transformation, by Stable Microrna Antagonism in Vivo

Abstract 30The precise mechanisms controlling hematopoietic stem cell (HSC) quiescence, self renewal and differentiation remain incompletely understood, and HSC expansion remains a long sought after goal for cell- and gene therapy. Genetic manipulation of single transcription factors and signal transduction pathways has so far failed to provide sustained HSC expansion, often resulting in stem cell exhaustion or the emergence of malignancy. MicroRNAs (miRNAs) post-transcriptionally regulate multiple genes in a coordinated fashion, making them attractive targets to manipulate signaling networks and complex cellular functions.We have systematically manipulated miR-126, a miRNA enriched in the primitive hematopoietic compartment, in mouse and human HSC by stably knocking down its activity with a sponge lentiviral vector (126/KD LV) or forcing its overexpression by a 126/OE LV. Hematochimeric mice were generated by transplanting 126/OE LV- or 126/KD LV- transduced progenitors into congenic mice (murine HSC) or NSG mice (human HSC), and the effects of altered miR-126 levels on hematopoiesis were investigated in vivo. Steady state hematopoiesis was comparatively normal, with no alterations in complete blood cell counts except a minor skewing towards or against lymphopoiesis upon 126/OE or 126/KD, respectively. Strikingly, under stress conditions such as 5-fluorouracil exposure, secondary transplantation or the NSG xenograft environment, 126/OE resulted in a progressive loss of HSC, while 126/KD increased HSC numbers as measured by immunophenotype and functional output upon competitive transplantation into secondary recipients. Limiting dilution analysis confirmed a 3–4 fold expansion of mouse and human HSC upon miR-126/KD, and the competitive advantage of 126/KD HSC was maintained long-term including post tertiary transplantation.To study the mechanism by which miR-126 regulates HSC numbers, cell cycle analysis was performed on 126/KD- or 126/OE progenitors isolated from steady state bone marrow. Human CD34+CD38-CD90+ and murine Lineage-Kit+Sca+CD150+ HSC were shifted towards the S/G2/M or the G0 phase upon 126/KD or 126/OE, respectively, indicating that miR-126 antagonism increased cycling while excessive levels of miR-126 favoured HSC quiescence within the niche microenvironment. Interestingly, this effect was highly specific for HSC and the most primitive progenitors. An in vitro culture model of HSC-enriched cord blood cells was set up to study the molecular basis of miR-126 mediated control of HSC cycling. This model reproduced key aspects of the HSC phenotype observed in vivo, i.e. increased or decreased proliferation of primitive progenitors upon 126/KD or 126/OE, respectively. Transcriptome analysis indicated that miR-126 manipulation altered several cellular functions and pathways, most significantly the PI3K/AKT/GSK3β signalling axis. We confirmed PIK3R2 and CRKII as direct miR-126 targets in CB CD34+38- cells and show enhanced PI3K pathway activation as reflected by increased AKT and GSK3β phosphorylation upon 126/KD, while 126/OE caused opposite effects. Pharmacologic inhibition of the beta subunit of PI3K abrogated the 126/KD phenotype, indicating that miR-126 mainly acts through the PI3K pathway. In contrast to published studies showing HSC expansion upon hyperactivation of the PI3K pathway using various genetic approaches, miR-126/KD did not cause HSC exhaustion or leukemogenesis. On the contrary, evidence will be provided that 126/OE is oncogenic in hematopoietic cells. Thus, miR-126 represents a principle target for HSC expansion for cell and gene therapy applications. In summary, we propose that in vivo HSC pool size is influenced by endogenous levels of miR-126 through modulation of the HSC quiescence/proliferation equilibrium. Disclosures:No relevant conflicts of interest to declare.

Primary immunodeficiency diseases associated with increased susceptibility to viral infections and malignancies

Primary immunodeficiencies (PIDs) are commonly characterized by an increased susceptibility to specific infections and, in certain instances, a higher than usual incidence of malignancies. Although improved diagnosis and early treatment of PIDs have reduced early morbidity and mortality from infection, the development of cancer remains a significant cause of premature death. The emergence of cancer in patients with PIDs often results from impairments in the immune response that lead to weakened surveillance against oncogenic viruses, premalignant or malignant cells, or both. Here we review the clinical and biologic features of several PIDs associated with enhanced susceptibility to viral infections and cancer, including X-linked lymphoproliferative disease; IL-2-inducible T-cell kinase deficiency; epidermodysplasia verruciformis; warts, hypogammaglobulinemia, infections, and myelokathexis syndrome; autosomal recessive hyper-IgE syndrome; X-linked agammaglobulinemia; and common variable immunodeficiency. It is of importance that we gain in-depth insights into the fundamental molecular nature of these unique PIDs to better understand the pathogenesis of virus-associated malignancies and to develop innovative therapeutic strategies.

Guest editorial: fanconi anemia and the DNA damage response

Every cell in our body other than red blood cells has a genome, the stability of which is crucial for life. The DNA is precisely replicated during cell proliferation, and is stably maintained, even after terminal differentiation, as a repository of information that orchestrates the cell’s metabolism. Unfortunately, our world is full of potential threats to genomic stability. DNA may degrade spontaneously, errors may occur during its replication, or metabolic byproducts, such as oxygen radicals or aldehydes, may chemically modify its nucleotide bases (i.e. DNA adducts). Ionizing radiation, ultraviolet light, and chemotherapeutic drugs are all well-known exogenous sources of DNA damage [1, 2]. To ensure cellular fitness, organisms have developed an elaborate molecular network to detect and repair DNA damage [3]. If deleterious effects of DNA damage exceed the cell’s repair capacity, it accumulates in the genome, leading to activation of cell cycle checkpoints (buying time for repair), cell death (apoptosis or necrosis), or, in the failure of checkpoints or cell death, conversion of DNA damage to mutations. This may result in poor cell proliferation, emergence of malignancy, impaired stem cell maintenance, or early-onset aging [1, 2]. Since all cellular activity in a way relies on the genome, the mechanisms that govern genomic stability are fundamentally important in biomedical research in general. Blood cells are no exception. As our knowledge of genomic stability has expanded massively in recent years, a rare hematological disorder, Fanconi anemia (FA), has become a prototypical example among hereditary conditions involving a defect in the DNA damage response (DDR). FA is one of several disorders discovered by the prominent Swiss pediatrician Guido Fanconi [4]. His first report in 1927 described brothers presenting with a pernicious anemia-like condition, congenital anomalies, and hyper-pigmentation of the skin. In the 1960s and 70s, it was established that FA cells display chromosomal instability, which is particularly pronounced following treatment with mitomycin C [5, 6]. The first molecular cloning of an FA gene was achieved by functional complementation using a cDNA expression library in the early 1990s [7]. However, until quite recently, the true molecular defect in FA, which is now considered to affect the response to replication stress, had not been defined. There seem to be a number of reasons why FA attracts widespread attention today. First of these is that novel FA genes continue to be identified year after year. This trend began at the turn of the 21st century, and has continued into this year, with the current number of the FA genes now totaling 15 [8–10]. This is surprising. Second, FA patients with disparate mutations display essentially similar phenotypes, strongly suggesting the presence of a common signal transduction pathway consisting of the FA gene products (i.e. FA pathway) [11, 12]. This prediction was well confirmed by the identification of the FA core complex (i.e. interactions between the FA core components FANCA/B/C/E/F/G/M/L) as an E3 ubiquitin ligase, and DNA damage-induced monoubiquitination of FANCD2 and FANCI, which is absent in cells lacking the core complex members [11, 12]. Of note, posttranslational protein modifications, such as ubiquitination, are currently the focus of intensive research in this field [13, 14]. Third, the discovery that the FANCD1 gene is the breast cancer M. Takata (&) Laboratory of DNA Damage Signaling, Department of Late Effect Studies, Radiation Biology Center, Kyoto University, Kyoto, Japan e-mail: mtakata@house.rbc.kyoto-u.ac.jp

Estradiol induced inhibition of 11β-hydroxysteroid dehydrogenase 1: an explanation for the postmenopausal hormone replacement therapy effects

The adverse and beneficial effects of postmenopausal hormone replacement therapy include: ischemic heart disease, stroke, pulmonary embolism, breast cancer, an increased rate of onset of asthma as well as reductions in the incidence of diabetes in women with known coronary artery disease and osteoporotic fractures. These varied effects can be explained by the down regulation of 11beta-hydroxysteroid dehydrogenase by estradiol, which results in a reduction of tissue specific cortisol production. The reduction in local cortisol production which diminishes the endogenous anti-inflammatory effects, also allows for the progression of both vascular and pulmonary inflammation. The decrease in cortisol activation reduces insulin resistance and anti-proliferative effects thereby reducing the potential for diabetes but allowing for the emergence of malignancy. Furthermore, the decreased local tissue availability of cortisol reduces the tendency for the development of osteoporosis. New techniques and drugs are being developed to evaluate the modulation of 11beta-HSD1 activity. Further study should result in new ways to control both inflammation and metabolism.