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Function of oncogenes in cancer development: A changing paradigm
Abstract and Figures
Tumour-associated oncogenes induce unscheduled proliferation as well as genomic and chromosomal instability. According to current models, therapeutic strategies that block oncogene activity are likely to selectively target tumour cells. However, recent evidences have revealed that oncogenes are only essential for the proliferation of some specific tumour cell types, but not all. Indeed, the latest studies of the interactions between the oncogene and its target cell have shown that oncogenes contribute to cancer development not only by inducing proliferation but also by developmental reprogramming of the epigenome. This provides the first evidence that tumorigenesis can be initiated by stem cell reprogramming, and uncovers a new role for oncogenes in the origin of cancer. Here we analyse these evidences and propose an updated model of oncogene function that can explain the full range of genotype-phenotype associations found in human cancer. Finally, we discuss how this vision opens new avenues for developing novel anti-cancer interventions.
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... This hypothesis has been supported by recent studies of patients with MDS, which revealed the presence of germlinepredisposing mutations in patients of all ages (45), suggesting that oncogenic changes affecting different developmental hematopoietic compartments might determine differential susceptibility to transformation explaining age-linked disease specificity and disease phenotype. In this context, the influence of the cell of origin where the oncogenic mutation first exerts its action is also paramount, because not all development stages are equally susceptible to the preleukemic potential of each given predisposing gene (46,47). These aspects further suggest that the predisposing mutations themselves, and their cellular context, may be more influential than the timing of gene/environment interaction in promoting leukemia development. ...
The recognition of host genetic factors underlying susceptibility to hematopoietic malignancies has increased greatly over the last decade. Historically, germline predisposition was thought to primarily affect the young. However, emerging data indicate that hematopoietic malignancies that develop in people of all ages across the human lifespan can derive from germline predisposing conditions and are not exclusively observed in younger individuals. The age at which hematopoietic malignancies manifest appears to correlate with distinct underlying biological pathways. Progression from having a deleterious germline variant to being diagnosed with overt malignancy involves complex, multistep gene–environment interactions with key external triggers, such as infection and inflammatory stimuli, driving clonal progression. Understanding the mechanisms by which predisposed clones transform under specific pressures may reveal strategies to better treat and even prevent hematopoietic malignancies from occurring.
Recent unbiased genome-wide sequencing studies of children and adults with hematopoietic malignancies have revealed novel genes in which disease-causing variants are of germline origin. This paradigm shift is spearheaded by findings in myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) as well as acute lymphoblastic leukemia, but it also encompasses other cancer types. Although not without challenges, the field of genetic cancer predisposition is advancing quickly, and a better understanding of the genetic basis of hematopoietic malignancies risk affects therapeutic decisions as well as genetic counseling and testing of at-risk family members.
... Oncogenes are a functionally heterogeneous group of genes whose products regulate multiple cellular processes (Pappou and Ahuja, 2010). Despite this heterogeneity, oncogenes also participate in common molecular mechanisms that are known to be cancer-related, e.g., cell proliferation (Vicente-Dueñas et al., 2013). Thus, we propose to consider as cancer-related the most representative biological functions in which the oncogenes participate (detailed below). ...
Motivation:
Advances in omics technologies have revolutionized cancer research by producing massive datasets. Common approaches to deciphering these complex data are by embedding algorithms of molecular interaction networks. These algorithms find a low-dimensional space in which similarities between the network nodes are best preserved. Currently available embedding approaches mine the gene embeddings directly to uncover new cancer-related knowledge. However, these gene-centric approaches produce incomplete knowledge, since they do not account for the functional implications of genomic alterations. We propose a new, function-centric perspective and approach, to complement the knowledge obtained from omic data.
Results:
We introduce our Functional Mapping Matrix to explore the functional organization of different tissue-specific and species-specific embedding spaces generated by a Non-negative Matrix Tri-Factorization algorithm. Also, we use our FMM to define the optimal dimensionality of these molecular interaction network embedding spaces. For this optimal dimensionality, we compare the FMMs of the most prevalent cancers in human to FMMs of their corresponding control tissues. We find that cancer alters the positions in the embedding space of cancer-related functions, while it keeps the positions of the non-cancer-related ones. We exploit this spacial "movement" to predict novel cancer-related functions. Finally, we predict novel cancer-related genes that the currently available methods for gene-centric analyses cannot identify; we validate these predictions by literature curation and retrospective analyses of patient survival data.
Availability:
Data and source code can be accessed at https://github.com/gaiac/FMM.
Supplementary information:
Supplementary data are available at Bioinformatics online.
... Despite the effort employed in the study of cancer biology, the specific trigger that induces cell transformation and tumor initiation is still unclear (Vicente-Duenas et al., 2013). In the past, the study of biological processes related to the biology of cancer has been focused on finding molecular pathways and genetic alterations, at the SC compartment level, trying to shed light on the molecular basis responsible for initiation, promotion and progression of cancer. ...
Oncogenes or tumor suppressor genes are rarely mutated in several pediatric tumors and some early stage adult cancers. This suggests that an aberrant epigenetic reprogramming may crucially affect the tumorigenesis of these tumors. Compelling evidence support the hypothesis that cancer stem cells (CSCs), a cell subpopulation within the tumor bulk characterized by self-renewal capacity, metastatic potential and chemo-resistance, may derive from normal stem cells (NSCs) upon an epigenetic deregulation. Thus, a better understanding of the specific epigenetic alterations driving the transformation from NSCs into CSCs may help to identify efficacious treatments to target this aggressive subpopulation. Moreover, deepening the knowledge about these alterations may represent the framework to design novel therapeutic approaches also in the field of regenerative medicine in which bioengineering of NSCs has been evaluated. Here, we provide a broad overview about: 1) the role of aberrant epigenetic modifications contributing to CSC initiation, formation and maintenance, 2) the epigenetic inhibitors in clinical trial able to specifically target the CSC subpopulation, and 3) epigenetic drugs and stem cells used in regenerative medicine for cancer and diseases.
... Tumor cells are well-known to become resistant to some chemotherapeutic drugs (143), and many molecular processes contribute to the development of chemoresistance (143). More than 70 oncogenes have been identified that promote cell growth (144,145). Mutations in these oncogenes affect various molecular mechanisms; oncogenes have been identified that encode membrane growth factor receptors, involved in the growth factor signaling pathway, whereas others encode cytoplasmic signaling molecules. ...
Cancer is one of the leading causes of death worldwide. Several treatments are available for cancer treatment, but many treatment methods are ineffective against multidrug-resistant cancer. Multidrug resistance (MDR) represents a major obstacle to effective therapeutic interventions against cancer. This review describes the known MDR mechanisms in cancer cells and discusses ongoing laboratory approaches and novel therapeutic strategies that aim to inhibit, circumvent, or reverse MDR development in various cancer types. In this review, we discuss both intrinsic and acquired drug resistance, in addition to highlighting hypoxia- and autophagy-mediated drug resistance mechanisms. Several factors, including individual genetic differences, such as mutations, altered epigenetics, enhanced drug efflux, cell death inhibition, and various other molecular and cellular mechanisms, are responsible for the development of resistance against anticancer agents. Drug resistance can also depend on cellular autophagic and hypoxic status. The expression of drug-resistant genes and the regulatory mechanisms that determine drug resistance are also discussed. Methods to circumvent MDR, including immunoprevention, the use of microparticles and nanomedicine might result in better strategies for fighting cancer.
Cell invasion is an important process in cancer progression and recurrence. Invasion and implantation of cancer cells from their original place to other tissues, by disabling vital organs, challenges the treatment of cancer patients. Given the importance of the matter, many molecular treatments have been developed to inhibit cancer cell invasion. Because of their low production cost and ease of production, peptides are valuable therapeutic molecules for inhibiting cancer cell invasion. In recent years, advances in the field of computational biology have facilitated the design of anti-cancer peptides. In our investigation, using computational biology approaches such as evolutionary analysis, residue scanning, protein–peptide interaction analysis, molecular dynamics, and free energy analysis, our team designed a peptide library with about 100 000 candidates based on A6 (acetyl-KPSSPPEE-amino) sequence which is an anti-invasion peptide. During computational studies, two of the designed peptides that give the highest scores and showed the greatest sequence similarity to A6 were entered into the experimental analysis workflow for further analysis. In experimental analysis steps, the anti-metastatic potency and other therapeutic effects of designed peptides were evaluated using MTT assay, RT-qPCR, zymography analysis, and invasion assay. Our study disclosed that the IK1 (acetyl-RPSFPPEE-amino) peptide, like A6, has great potency to inhibit the invasion of cancer cells.
Objective
To study the in vitro and in vivo antitumor effects of the polysaccharide of Alocasia cucullata (PAC) and the underlying mechanism.MethodsB16F10 and 4T1 cells were cultured with PAC of 40 µg/mL, and PAC was withdrawn after 40 days of administration. The cell viability was detected by cell counting kit-8. The expression of Bcl-2 and Caspase-3 proteins were detected by Western blot and the expressions of ERK1/2 mRNA were detected by quantitative real-time polymerase chain reaction (qRT-PCR). A mouse melanoma model was established to study the effect of PAC during long-time administration. Mice were divided into 3 treatment groups: control group treated with saline water, positive control group (LNT group) treated with lentinan at 100 mg/(kg·d), and PAC group treated with PAC at 120 mg/(kg·d). The pathological changes of tumor tissues were observed by hematoxylin-eosin staining. The apoptosis of tumor tissues was detected by TUNEL staining. Bcl-2 and Caspase-3 protein expressions were detected by immunohistochemistry, and the expressions of ERK1/2, JNK1 and p38 mRNA were detected by qRT-PCR.ResultsIn vitro, no strong inhibitory effects of PAC were found in various tumor cells after 48 or 72 h of administration. Interestingly however, after 40 days of cultivation under PAC, an inhibitory effect on B16F10 cells was found. Correspondingly, the long-time administration of PAC led to downregulation of Bcl-2 protein (P<0.05), up-regulation of Caspase-3 protein (P<0.05) and ERK1 mRNA (P<0.05) in B16F10 cells. The above results were verified by in vivo experiments. In addition, viability of B16F10 cells under long-time administration culture in vitro decreased after drug withdrawal, and similar results were also observed in 4T1 cells.Conclusions
Long-time administration of PAC can significantly inhibit viability and promote apoptosis of tumor cells, and had obvious antitumor effect in tumor-bearing mice.
Background
Protein MUTYH, encoded by the gene MUTYH, is an important mismatch repair enzyme in the base-excision repair pathway of DNA repair. When genetically altered, different neoplastic conditions can arise. One of the widely known syndromes associated with MUTYH mutations is MUTYH-associated polyposis, a form of familial colorectal cancer syndrome. MUTYH may also be a driver in other familial cancer syndromes, as well as breast cancer and spontaneous cancer cases. However, some controversies about the role of these alterations in oncogenesis remain, especially when affected in a heterozygous way. Most available data on MUTYH mutations are on Caucasian patients.
Material and Methods
We analyzed a small cohort of non-Caucasian, Colombian cancer patients with MUTYH germline heterozygous mutations, clinical features suggestive of familial cancer, and extensive genetic studies with no other mutations and without MUTYH-associated polyposis.
Conclusion
With this case series, we intended to provide important data for the understanding of MUTYH as a possible driver of familial cancer, even when only heterozygous mutations are found.
Adult stem cells (ASCs) are pluripotent and make up a small percentage of healthy tissue. ASCs are essential for tissue repair, regeneration and growth. ASCs divide into identical stem cells or transiently proliferating cells. The latter cells mature after a number of divisions and become adult differentiating cells. There are different types of cells in cancerous tissue, as in normal, healthy tissue. Most cancer tissues contain three types of cells: (I) cancer stem cells (CSC); (II) cancer initiating cells; and (III) “differentiated”, non-proliferating cancer cells. In the review, the authors present experimental evidences for the presence of CSC, describe cell surface and intracellular markers of CSC. These markers allow for the appropriate identification and isolation of CSC. In addition, the possible location of these cells and theories of their formation are considered. It should be noted, that the theories of CSC originating are in fact theories of neoplasm formation. Many factors and processes may be involved in the formation of CSC. These include: (I) mutations of oncogenes or tumor suppressor genes in spoczynadult differentiated cells; (II) expression of different regulatory RNA types (microRNAs or long non-coding RNAs); processes of epithelial-mesenchymal transition and mesenchymalepithelial transition; (IV) CSC formation from differentiated cancer cells in a consequence of cancer therapy; (V) formation of CSC in conditions of hypoxy and during cell aging. The presented work synthetically characterizes the features, localization and formation of cancer stem cells. Furthermore, the research on these cells is still ongoing and many properties of CSC have not been fully understood.
As Douglas Hanahan and Robert Weinberg compiled, there are nine hallmarks of cancer that are conducive to cancer cell development and survival. Previous studies showed that brother of the regulator of imprinted sites (BORIS) might promote cancer progression through these aspects. The competition between BORIS and CCCTC-binding factor (CTCF), which is crucial in the formation of chromatin loops, affects the normal function of CTCF and leads to neoplasia and deformity. In addition, BORIS belongs to the cancer-testis antigen families, which are potential targets in cancer diagnosis and treatment. Herein, we discuss the function and mechanisms of BORIS, especially in cancer development.
In clinical trials, the tyrosine kinase inhibitor STI571 has proven highly effective in reducing leukemic cell burden in chronic myeloid leukemia (CML). The overall sensitivity of CML CD34+ progenitor cells to STI571 and the degree to which cell death was dependent on cell cycle status were determined. Stem cells (Lin−CD34+) from the peripheral blood of patients with CML in chronic phase and from granulocyte–colony-stimulating factor–mobilized healthy donors were labeled with carboxy-fluorescein diacetate succinimidyl diester dye to enable high-resolution tracking of cell division. Then they were cultured for 3 days with and without growth factors ± STI571. After culture, the cells were separated by fluorescence-activated cell sorting into populations of viable quiescent versus cycling cells for genotyping. For healthy controls, in the presence of growth factors, STI571 affected neither cell cycle kinetics nor recovery of viable cells. In the absence of growth factors, normal cells were unable to divide. For CML samples, in the presence or absence of growth factors, the response to STI571 was variable. In the most sensitive cases, STI571 killed almost all dividing cells; however, a significant population of viable CD34+ cells was recovered in the undivided peak and confirmed to be part of the leukemic clone. STI571 also appeared to exhibit antiproliferative activity on the quiescent population. These studies confirm that CML stem cells remain viable in a quiescent state even in the presence of growth factors and STI571. Despite dramatic short-term responses in vivo, such in vitro insensitivity to STI571, in combination with its demonstrated antiproliferative activity, could translate into disease relapse after prolonged therapy.
