Proteomics and metabolomics applications in cancer biology

2019 ◽  
pp. 363-374
Author(s):  
Pedro Cutillas ◽  
Benedikt M. Kessler
Keyword(s):  
Mass Spectrometry ◽  
Molecular Biology ◽  
Precision Medicine ◽  
Clinical Outcomes ◽  
Cancer Progression ◽  
Cancer Biology ◽  
Cancer Metabolism ◽  
State Of The Art ◽  
Technical Challenges ◽  
Survival Mechanisms

Methodologies for proteomics and metabolomics are providing an unprecedented wealth of insights into cancer molecular biology. Although different techniques for proteomics and metabolomics exist, molecular snapshots in cancer metabolism and alterations in the proteome are mainly possible due to advancements in state-of-the-art mass spectrometry technologies. In this chapter, we describe examples of how proteo-metabolomic approaches are contributing to our understanding of the molecular biology of cancer progression, signalling, survival mechanisms, angiogenesis, and metastasis. We also provide an overview of the translational information (including biomarkers) and clinically relevant insights that proteomics and metabolomics strategies may be able to deliver, despite limitations and technical challenges that still exist. A better understanding of cancer progression and an improvement of clinical outcomes will benefit from precision medicine initiatives, in which appropriate application of proteo-metabolomic methods are key for their success.

scholarly journals Characterization and Quantification of Selenoprotein P: Challenges to Mass Spectrometry

2021 ◽  
Vol 22 (12) ◽  
pp. 6283
Author(s):  
Jérémy Lamarche ◽  
Luisa Ronga ◽  
Joanna Szpunar ◽  
Ryszard Lobinski
Keyword(s):  
Mass Spectrometry ◽  
State Of The Art ◽  
Animal Health ◽  
Primary Standard ◽  
Selenoprotein P ◽  
Primary Standards ◽  
Analytical Approaches ◽  
Careful Investigation ◽  
Accurate Quantification

Selenoprotein P (SELENOP) is an emerging marker of the nutritional status of selenium and of various diseases, however, its chemical characteristics still need to be investigated and methods for its accurate quantitation improved. SELENOP is unique among selenoproteins, as it contains multiple genetically encoded SeCys residues, whereas all the other characterized selenoproteins contain just one. SELENOP occurs in the form of multiple isoforms, truncated species and post-translationally modified variants which are relatively poorly characterized. The accurate quantification of SELENOP is contingent on the availability of specific primary standards and reference methods. Before recombinant SELENOP becomes available to be used as a primary standard, careful investigation of the characteristics of the SELENOP measured by electrospray MS and strict control of the recoveries at the various steps of the analytical procedures are strongly recommended. This review critically discusses the state-of-the-art of analytical approaches to the characterization and quantification of SELENOP. While immunoassays remain the standard for the determination of human and animal health status, because of their speed and simplicity, mass spectrometry techniques offer many attractive and complementary features that are highlighted and critically evaluated.

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 APOE: The New Frontier in the Development of a Therapeutic Target towards Precision Medicine in Late-Onset Alzheimer’s

2021 ◽  
Vol 22 (3) ◽  
pp. 1244
Author(s):  
Anna Yang ◽  
Boris Kantor ◽  
Ornit Chiba-Falek
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Precision Medicine ◽  
Antisense Oligonucleotides ◽  
State Of The Art ◽  
Late Onset ◽  
Base Editing ◽  
Medical Need ◽  
New Frontier ◽  
Amyloid Cascade

Alzheimer’s disease (AD) has a critical unmet medical need. The consensus around the amyloid cascade hypothesis has been guiding pre-clinical and clinical research to focus mainly on targeting beta-amyloid for treating AD. Nevertheless, the vast majority of the clinical trials have repeatedly failed, prompting the urgent need to refocus on other targets and shifting the paradigm of AD drug development towards precision medicine. One such emerging target is apolipoprotein E (APOE), identified nearly 30 years ago as one of the strongest and most reproduceable genetic risk factor for late-onset Alzheimer’s disease (LOAD). An exploration of APOE as a new therapeutic culprit has produced some very encouraging results, proving that the protein holds promise in the context of LOAD therapies. Here, we review the strategies to target APOE based on state-of-the-art technologies such as antisense oligonucleotides, monoclonal antibodies, and gene/base editing. We discuss the potential of these initiatives in advancing the development of novel precision medicine therapies to LOAD.

scholarly journals LOXL2 Inhibitors and Breast Cancer Progression

Antioxidants ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 312
Author(s):  
Sandra Ferreira ◽  
Nuno Saraiva ◽  
Patrícia Rijo ◽  
Ana S. Fernandes
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Cancer Biology ◽  
Breast Cancer Cells ◽  
Lysyl Oxidase ◽  
Breast Cancer Progression ◽  
Special Focus ◽  
Amine Oxidases ◽  
Cross Link ◽  
Promising Strategy

LOX (lysyl oxidase) and lysyl oxidase like-1–4 (LOXL 1–4) are amine oxidases, which catalyze cross-linking reactions of elastin and collagen in the connective tissue. These amine oxidases also allow the cross-link of collagen and elastin in the extracellular matrix of tumors, facilitating the process of cell migration and the formation of metastases. LOXL2 is of particular interest in cancer biology as it is highly expressed in some tumors. This protein also promotes oncogenic transformation and affects the proliferation of breast cancer cells. LOX and LOXL2 inhibition have thus been suggested as a promising strategy to prevent metastasis and invasion of breast cancer. BAPN (β-aminopropionitrile) was the first compound described as a LOX inhibitor and was obtained from a natural source. However, novel synthetic compounds that act as LOX/LOXL2 selective inhibitors or as dual LOX/LOX-L inhibitors have been recently developed. In this review, we describe LOX enzymes and their role in promoting cancer development and metastases, with a special focus on LOXL2 and breast cancer progression. Moreover, the recent advances in the development of LOXL2 inhibitors are also addressed. Overall, this work contextualizes and explores the importance of LOXL2 inhibition as a promising novel complementary and effective therapeutic approach for breast cancer treatment.

scholarly journals Trends in Research on Exosomes in Cancer Progression and Anticancer Therapy

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 326
Author(s):  
Dona Sinha ◽  
Sraddhya Roy ◽  
Priyanka Saha ◽  
Nabanita Chatterjee ◽  
Anupam Bishayee
Keyword(s):  
Cancer Progression ◽  
Targeted Delivery ◽  
Cancer Biology ◽  
Vaccine Development ◽  
Immune Escape ◽  
Immune Therapy ◽  
Bioactive Molecules ◽  
Successful Implementation ◽  
Scale Production ◽  
Exosome Biogenesis

Exosomes, the endosome-derived bilayered extracellular nanovesicles with their contribution in many aspects of cancer biology, have become one of the prime foci of research. Exosomes derived from various cells carry cargoes similar to their originator cells and their mode of generation is different compared to other extracellular vesicles. This review has tried to cover all aspects of exosome biogenesis, including cargo, Rab-dependent and Rab-independent secretion of endosomes and exosomal internalization. The bioactive molecules of the tumor-derived exosomes, by virtue of their ubiquitous presence and small size, can migrate to distal parts and propagate oncogenic signaling and epigenetic regulation, modulate tumor microenvironment and facilitate immune escape, tumor progression and drug resistance responsible for cancer progression. Strategies improvised against tumor-derived exosomes include suppression of exosome uptake, modulation of exosomal cargo and removal of exosomes. Apart from the protumorigenic role, exosomal cargoes have been selectively manipulated for diagnosis, immune therapy, vaccine development, RNA therapy, stem cell therapy, drug delivery and reversal of chemoresistance against cancer. However, several challenges, including in-depth knowledge of exosome biogenesis and protein sorting, perfect and pure isolation of exosomes, large-scale production, better loading efficiency, and targeted delivery of exosomes, have to be confronted before the successful implementation of exosomes becomes possible for the diagnosis and therapy of cancer.

scholarly journals Clinical and prognostic significances of cancer stem cell markers in gastric cancer patients: a systematic review and meta-analysis

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Mahdieh Razmi ◽  
Roya Ghods ◽  
Somayeh Vafaei ◽  
Maryam Sahlolbei ◽  
Leili Saeednejad Zanjani ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Stem Cell ◽  
Cancer Stem Cell ◽  
Clinical Outcomes ◽  
Cancer Progression ◽  
Poor Prognosis ◽  
Meta Analysis ◽  
Disease Free Survival ◽  
Stem Cell Markers ◽  
Free Survival

Abstract Background Gastric cancer (GC) is considered one of the most lethal malignancies worldwide, which is accompanied by a poor prognosis. Although reports regarding the importance of cancer stem cell (CSC) markers in gastric cancer progression have rapidly developed over the last few decades, their clinicopathological and prognostic values in gastric cancer still remain inconclusive. Therefore, the current meta-analysis aimed to quantitatively re-evaluate the association of CSC markers expression, overall and individually, with GC patients’ clinical and survival outcomes. Methods Literature databases including PubMed, Scopus, ISI Web of Science, and Embase were searched to identify the eligible articles. Hazard ratios (HRs) or odds ratios (ORs) with 95% confidence intervals (CIs) were recorded or calculated to determine the relationships between CSC markers expression positivity and overall survival (OS), disease-free survival (DFS)/relapse-free survival (RFS), disease-specific survival (DSS)/ cancer-specific survival (CSS), and clinicopathological features. Results We initially retrieved 4,425 articles, of which a total of 66 articles with 89 studies were considered as eligible for this meta-analysis, comprising of 11,274 GC patients. Overall data analyses indicated that the overexpression of CSC markers is associated with TNM stage (OR = 2.19, 95% CI 1.84–2.61, P = 0.013), lymph node metastasis (OR = 1.76, 95% CI 1.54–2.02, P < 0.001), worse OS (HR = 1.65, 95% CI 1.54–1.77, P < 0.001), poor CSS/DSS (HR = 1.69, 95% CI 1.33–2.15, P < 0.001), and unfavorable DFS/RFS (HR = 2.35, 95% CI 1.90–2.89, P < 0.001) in GC patients. However, CSC markers expression was found to be slightly linked to tumor differentiation (OR = 1.25, 95% CI 1.01–1.55, P = 0.035). Sub-analysis demonstrated a significant positive relationship between most of the individual markers, specially Gli-1, Oct-4, CD44, CD44V6, and CD133, and clinical outcomes as well as the reduced survival, whereas overexpression of Lgr-5, Nanog, and sonic hedgehog (Shh) was not found to be related to the majority of clinical outcomes in GC patients. Conclusion The expression of CSC markers is mostly associated with worse outcomes in patients with GC, both overall and individual. The detection of a combined panel of CSC markers might be appropriate as a prognostic stratification marker to predict tumor aggressiveness and poor prognosis in patients with GC, which probably results in identifying novel potential targets for therapeutic approaches.

scholarly journals The metabolic adaptation mechanism of metastatic organotropism

2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Chao Wang ◽  
Daya Luo
Keyword(s):  
Cancer Cells ◽  
Cancer Cell ◽  
Cancer Progression ◽  
Cancer Metabolism ◽  
Cancer Metastasis ◽  
Tumour Microenvironment ◽  
Metabolic Adaptation ◽  
Adaptation Mechanism ◽  
Metastatic Sites ◽  
The Impact

AbstractMetastasis is a complex multistep cascade of cancer cell extravasation and invasion, in which metabolism plays an important role. Recently, a metabolic adaptation mechanism of cancer metastasis has been proposed as an emerging model of the interaction between cancer cells and the host microenvironment, revealing a deep and extensive relationship between cancer metabolism and cancer metastasis. However, research on how the host microenvironment affects cancer metabolism is mostly limited to the impact of the local tumour microenvironment at the primary site. There are few studies on how differences between the primary and secondary microenvironments promote metabolic changes during cancer progression or how secondary microenvironments affect cancer cell metastasis preference. Hence, we discuss how cancer cells adapt to and colonize in the metabolic microenvironments of different metastatic sites to establish a metastatic organotropism phenotype. The mechanism is expected to accelerate the research of cancer metabolism in the secondary microenvironment, and provides theoretical support for the generation of innovative therapeutic targets for clinical metastatic diseases.

scholarly journals State-of-the-Art Native Mass Spectrometry and Ion Mobility Methods to Monitor Homogeneous Site-Specific Antibody-Drug Conjugates Synthesis

2021 ◽  
Vol 14 (6) ◽  
pp. 498
Author(s):  
Evolène Deslignière ◽  
Anthony Ehkirch ◽  
Bastiaan L. Duivelshof ◽  
Hanna Toftevall ◽  
Jonathan Sjögren ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Gas Phase ◽  
Ion Mobility ◽  
State Of The Art ◽  
Native Mass Spectrometry ◽  
Site Specific ◽  
Drug Conjugates ◽  
Conjugation Process ◽  
Antibody Drug

Antibody-drug conjugates (ADCs) are biotherapeutics consisting of a tumor-targeting monoclonal antibody (mAb) linked covalently to a cytotoxic drug. Early generation ADCs were predominantly obtained through non-selective conjugation methods based on lysine and cysteine residues, resulting in heterogeneous populations with varying drug-to-antibody ratios (DAR). Site-specific conjugation is one of the current challenges in ADC development, allowing for controlled conjugation and production of homogeneous ADCs. We report here the characterization of a site-specific DAR2 ADC generated with the GlyCLICK three-step process, which involves glycan-based enzymatic remodeling and click chemistry, using state-of-the-art native mass spectrometry (nMS) methods. The conjugation process was monitored with size exclusion chromatography coupled to nMS (SEC-nMS), which offered a straightforward identification and quantification of all reaction products, providing a direct snapshot of the ADC homogeneity. Benefits of SEC-nMS were further demonstrated for forced degradation studies, for which fragments generated upon thermal stress were clearly identified, with no deconjugation of the drug linker observed for the T-GlyGLICK-DM1 ADC. Lastly, innovative ion mobility-based collision-induced unfolding (CIU) approaches were used to assess the gas-phase behavior of compounds along the conjugation process, highlighting an increased resistance of the mAb against gas-phase unfolding upon drug conjugation. Altogether, these state-of-the-art nMS methods represent innovative approaches to investigate drug loading and distribution of last generation ADCs, their evolution during the bioconjugation process and their impact on gas-phase stabilities. We envision nMS and CIU methods to improve the conformational characterization of next generation-empowered mAb-derived products such as engineered nanobodies, bispecific ADCs or immunocytokines.

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