scholarly journals The PARP Enzyme Family and the Hallmarks of Cancer Part 1. Cell Intrinsic Hallmarks

Cancers ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 2042 ◽  
Author(s):  
Máté A. Demény ◽  
László Virág
Keyword(s):  
Cancer Biology ◽  
Cancer Metabolism ◽  
Replicative Senescence ◽  
Synthetic Lethality ◽  
Family Members ◽  
Hallmarks Of Cancer ◽  
Novel Therapy ◽  
Cancer Hallmarks ◽  
Enzyme Family ◽  
Wide Range

The 17-member poly (ADP-ribose) polymerase enzyme family, also known as the ADP-ribosyl transferase diphtheria toxin-like (ARTD) enzyme family, contains DNA damage-responsive and nonresponsive members. Only PARP1, 2, 5a, and 5b are capable of modifying their targets with poly ADP-ribose (PAR) polymers; the other PARP family members function as mono-ADP-ribosyl transferases. In the last decade, PARP1 has taken center stage in oncology treatments. New PARP inhibitors (PARPi) have been introduced for the targeted treatment of breast cancer 1 or 2 (BRCA1/2)-deficient ovarian and breast cancers, and this novel therapy represents the prototype of the synthetic lethality paradigm. Much less attention has been paid to other PARPs and their potential roles in cancer biology. In this review, we summarize the roles played by all PARP enzyme family members in six intrinsic hallmarks of cancer: uncontrolled proliferation, evasion of growth suppressors, cell death resistance, genome instability, reprogrammed energy metabolism, and escape from replicative senescence. In a companion paper, we will discuss the roles of PARP enzymes in cancer hallmarks related to cancer-host interactions, including angiogenesis, invasion and metastasis, evasion of the anticancer immune response, and tumor-promoting inflammation. While PARP1 is clearly involved in all ten cancer hallmarks, an increasing body of evidence supports the role of other PARPs in modifying these cancer hallmarks (e.g., PARP5a and 5b in replicative immortality and PARP2 in cancer metabolism). We also highlight controversies, open questions, and discuss prospects of recent developments related to the wide range of roles played by PARPs in cancer biology. Some of the summarized findings may explain resistance to PARPi therapy or highlight novel biological roles of PARPs that can be therapeutically exploited in novel anticancer treatment paradigms.

scholarly journals Platelets at the interface of thrombosis, inflammation, and cancer

Blood ◽  
2015 ◽  
Vol 126 (5) ◽  
pp. 582-588 ◽  
Author(s):  
Aime T. Franco ◽  
Adam Corken ◽  
Jerry Ware
Keyword(s):  
Animal Models ◽  
Cancer Biology ◽  
Disease Process ◽  
Cell Type ◽  
Platelet Dysfunction ◽  
Hallmarks Of Cancer ◽  
Traditional Role ◽  
Lower Vertebrate ◽  
Vertebrate Cell ◽  
Wide Range

Abstract Although once primarily recognized for its roles in hemostasis and thrombosis, the platelet has been increasingly recognized as a multipurpose cell. Indeed, circulating platelets have the ability to influence a wide range of seemingly unrelated pathophysiologic events. Here, we highlight some of the notable observations that link platelets to inflammation, reinforcing the platelet’s origin from a lower vertebrate cell type with both hemostatic and immunologic roles. In addition, we consider the relevance of platelets in cancer biology by focusing on the hallmarks of cancer and the ways platelets can influence multistep development of tumors. Beyond its traditional role in hemostasis and thrombosis, the platelet’s involvement in the interplay between hemostasis, thrombosis, inflammation, and cancer is likely complex, yet extremely important in each disease process. The existence of animal models of platelet dysfunction and currently used antiplatelet therapies provide a framework for understanding mechanistic insights into a wide range of pathophysiologic events. Thus, the basic scientist studying platelet function can think beyond the traditional hemostasis and thrombosis paradigms, while the practicing hematologist must appreciate platelet relevance in a wide range of disease processes.

Antiangiogenic Resistance and Cancer Metabolism: Opportunities for Synthetic Lethality

2016 ◽  
Vol 17 (15) ◽  
pp. 1714-1727 ◽  
Author(s):  
Simon Lord ◽  
Juan M. Funes ◽  
Adrian L Harris ◽  
Miguel Quintela-Fandino
Keyword(s):  
Cancer Metabolism ◽  
Synthetic Lethality

scholarly journals Establishing a consensus for the hallmarks of cancer based on gene ontology and pathway annotations

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Yi Chen ◽  
Fons. J. Verbeek ◽  
Katherine Wolstencroft
Keyword(s):  
Gene Ontology ◽  
Enrichment Analysis ◽  
Biological Data ◽  
Hallmarks Of Cancer ◽  
High Throughput Analysis ◽  
Knowledge Resources ◽  
Gene Set ◽  
Cancer Hallmarks ◽  
Starting Point ◽  
High Level

Abstract Background The hallmarks of cancer provide a highly cited and well-used conceptual framework for describing the processes involved in cancer cell development and tumourigenesis. However, methods for translating these high-level concepts into data-level associations between hallmarks and genes (for high throughput analysis), vary widely between studies. The examination of different strategies to associate and map cancer hallmarks reveals significant differences, but also consensus. Results Here we present the results of a comparative analysis of cancer hallmark mapping strategies, based on Gene Ontology and biological pathway annotation, from different studies. By analysing the semantic similarity between annotations, and the resulting gene set overlap, we identify emerging consensus knowledge. In addition, we analyse the differences between hallmark and gene set associations using Weighted Gene Co-expression Network Analysis and enrichment analysis. Conclusions Reaching a community-wide consensus on how to identify cancer hallmark activity from research data would enable more systematic data integration and comparison between studies. These results highlight the current state of the consensus and offer a starting point for further convergence. In addition, we show how a lack of consensus can lead to large differences in the biological interpretation of downstream analyses and discuss the challenges of annotating changing and accumulating biological data, using intermediate knowledge resources that are also changing over time.

scholarly journals Development of cancer metabolism as a therapeutic target: new pathways, patient studies, stratification and combination therapy

2019 ◽  
Vol 122 (1) ◽  
pp. 1-3 ◽  
Author(s):  
Adrian L. Harris
Keyword(s):  
Metabolic Pathways ◽  
Trial Design ◽  
Cancer Metabolism ◽  
Aerobic Glycolysis ◽  
Critical Role ◽  
Therapeutic Approaches ◽  
Preclinical Models ◽  
Wide Range ◽  
Patient Studies

AbstractCancer metabolism has undergone a resurgence in the last decade, 70 years after Warburg described aerobic glycolysis as a feature of cancer cells. A wide range of techniques have elucidated the complexity and heterogeneity in preclinical models and clinical studies. What emerges are the large differences between tissues, tumour types and intratumour heterogeneity. However, synergies with inhibition of metabolic pathways have been found for many drugs and therapeutic approaches, and a critical role of window studies and translational trial design is key to success.

scholarly journals Motor and Nonmotor Symptoms of Parkinson’s Disease: Antagonistic Pleiotropy Phenomena Derived from α-Synuclein Evolvability?

2018 ◽  
Vol 2018 ◽  
pp. 1-6 ◽  
Author(s):  
Yoshiki Takamatsu ◽  
Masayo Fujita ◽  
Gilbert J. Ho ◽  
Ryoko Wada ◽  
Shuei Sugama ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Lewy Body ◽  
Gastrointestinal Symptoms ◽  
Lewy Bodies ◽  
Antagonistic Pleiotropy ◽  
Nonmotor Symptoms ◽  
Novel Therapy ◽  
Wide Range ◽  
Lewy Body Diseases

Lewy body diseases, such as Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), are associated with a wide range of nonmotor symptoms (NMS), including cognitive impairment, depression and anxiety, sleep disorders, gastrointestinal symptoms, and autonomic failure. The reason why such diverse and disabling NMS have not been weeded out but have persisted across evolution is unknown. As such, one possibility would be that the NMS might be somehow beneficial during development and/or reproductive stages, a possibility consistent with our recent view as to the evolvability of amyloidogenic proteins (APs) such as α-synuclein (αS) and amyloid-β (Aβ) in the brain. Based on the heterogeneity of protofibrillar AP forms in terms of structure and cytotoxicity, we recently proposed that APs might act as vehicles to deliver information regarding diverse internal and environmental stressors. Also, we defined evolvability to be an epigenetic phenomenon whereby APs are transgenerationally transmitted from parents to offspring to cope with future brain stressors in the offspring, likely benefitting the offspring. In this context, the main objective is to discuss whether NMS might be relevant to evolvability. According to this view, information regarding NMS may be transgenerationally transmitted by heterogeneous APs to offspring, preventing or attenuating the stresses related to such symptoms. On the other hand, NMS associated with Lewy body pathology might manifest through an aging-associated antagonistic pleiotropy mechanism. Given that NMS are not only specific to Lewy body diseases but also displayed in other disorders, including amyotrophic lateral sclerosis (ALS) and Huntington’s disease (HD), these conditions might share common mechanisms related to evolvability. This might give insight into novel therapy strategies based on antagonistic pleiotropy rather than on individual NMS from which to develop disease-modifying therapies.

scholarly journals An in-silico approach to predict and exploit synthetic lethality in cancer metabolism

2017 ◽  
Vol 8 (1) ◽  
Author(s):  
Iñigo Apaolaza ◽  
Edurne San José-Eneriz ◽  
Luis Tobalina ◽  
Estíbaliz Miranda ◽  
Leire Garate ◽  
...  
Keyword(s):  
In Silico ◽  
Cancer Metabolism ◽  
Synthetic Lethality

scholarly journals HUMANIZED MICE: CREATION, MODELS AND USE IN EXPERIMENTAL ONCOLOGY (REVIEW)

Biomeditsina ◽  
2019 ◽  
pp. 67-81
Author(s):  
O. I. Kit ◽  
A. Yu. Maksimov ◽  
T. P. Protasova ◽  
A. S. Goncharova ◽  
D. S. Kutilin ◽  
...  
Keyword(s):  
Cancer Biology ◽  
Human Cancer ◽  
Transgenic Animals ◽  
Humanized Mice ◽  
Humanized Mouse ◽  
Antitumour Agents ◽  
Human Genes ◽  
Oncology Review ◽  
Wide Range ◽  
Humanized Mouse Models

Research laboratories in various countries are constantly endeavouring to improve the existing and to create new biological objects to simulate various human diseases. Immunodefi cient mice with transplanted human functional cells and tissues, as well as transgenic animals with the relevant human genes integrated in their genome — i. e. humanized mice — are increasingly used as test systems in biomedical studies. Humanized mouse models are constantly being improved to fi nd application in studies investigating human biological reactions and identifying the pathogenetic mechanisms behind a wide range of diseases, or as preclinical tools for medicine testing. In particular, such animals play an increasingly important role both in studies of human-specifi c infectious agents, cancer biology research and in the development of new antitumour agents. In addition, humanized mice are increasingly used as translational models in many areas of clinical research, including transplantology, immunology and oncology. Ultimately, the use of humanized animals can lead to the introduction of a truly personalized medicine into clinical practice. In this review, we discuss modern advances in the creation and use of humanized mice, emphasizing their usefulness for the pathogenesis study, as well as the development of new methods for human cancer treatment.

scholarly journals The “ARTS” of Cell Death in Service of Life: How Do We Force Cancer Cells to Commit Suicide?

2021 ◽  
Vol 9 ◽  
Author(s):  
Sarit Larisch
Keyword(s):  
Cell Death ◽  
Cancer Cells ◽  
Novel Therapy ◽  
The Arts ◽  
Wide Range ◽  
Cell Death Program ◽  
Cancerous Cells ◽  
Critical Process ◽  
Cells Death ◽  
Commit Suicide

Every cell in our body contains a “self-destruction” program. This cell death is a critical process allowing replacement of damaged cells with healthy ones to prevent wide range of diseases. When the cell’s death mechanism gets “stuck” and is not activated, cancer can result. In healthy cells there is a balanced system of proteins, some of which activate the normal death mechanism, and some of which inhibit this process. This is like the system of gas and brakes in a car. Researchers have found that cancer cells lack a protein, called ARTS, which is crucial for activating the cells’ death mechanism. The lack of ARTS causes cancer cells to escape death and become “immortal.” Small ARTS-like molecules have been discovered that can penetrate cancerous cells and reactivate the cell death program, effectively making the cancer cells “commit suicide.” We envision that these ARTS-like molecules will provide novel therapy for cancer.

scholarly journals A network-based approach to integrate nutrient environment in the prediction of synthetic lethality in cancer metabolism

2021 ◽  
Author(s):  
Iñigo Apaolaza ◽  
Edurne San José-Enériz ◽  
Luis Valcarcel ◽  
Xabier Agirre ◽  
Felipe Prosper ◽  
...  
Keyword(s):  
Cancer Metabolism ◽  
Synthetic Lethality ◽  
Experimental Proof ◽  
Synthetic Lethal ◽  
New Family ◽  
Novel Approach ◽  
Synthetic Lethal Interactions ◽  
Nutrient Environment ◽  
Tumor Environment ◽  
Definition Of

Synthetic Lethality (SL) is a promising concept in cancer research. A number of computational methods have been developed to predict SL in cancer metabolism, among which our network-based computational approach, based on genetic Minimal Cut Sets (gMCSs), can be found. A major challenge of these approaches to SL is to systematically consider tumor environment, which is particularly relevant in cancer metabolism. Here, we propose a novel definition of SL for cancer metabolism that integrates genetic interactions and nutrient availability in the environment. We extend our gMCSs approach to determine this new family of metabolic synthetic lethal interactions. A computational and experimental proof-of-concept is presented for predicting the lethality of dihydrofolate reductase inhibition in different environments. Finally, our novel approach is applied to identify extracellular nutrient dependences of tumor cells, elucidating cholesterol and myo-inositol depletion as potential vulnerabilities in different malignancies.

scholarly journals Exosomes in the Tumor Microenvironment: From Biology to Clinical Applications

Cells ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 2617
Author(s):  
Vitor Rodrigues da Costa ◽  
Rodrigo Pinheiro Araldi ◽  
Hugo Vigerelli ◽  
Fernanda D’Ámelio ◽  
Thais Biude Mendes ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Cancer Treatment ◽  
Cancer Biology ◽  
Clinical Applications ◽  
Future Prospects ◽  
Hallmarks Of Cancer ◽  
Cancer Heterogeneity ◽  
Important Health ◽  
Clinical Potential

Cancer is one of the most important health problems and the second leading cause of death worldwide. Despite the advances in oncology, cancer heterogeneity remains challenging to therapeutics. This is because the exosome-mediated crosstalk between cancer and non-cancer cells within the tumor microenvironment (TME) contributes to the acquisition of all hallmarks of cancer and leads to the formation of cancer stem cells (CSCs), which exhibit resistance to a range of anticancer drugs. Thus, this review aims to summarize the role of TME-derived exosomes in cancer biology and explore the clinical potential of mesenchymal stem-cell-derived exosomes as a cancer treatment, discussing future prospects of cell-free therapy for cancer treatment and challenges to be overcome.

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