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Theses & Dissertations: Cancer Research
Theses/dissertations from 2024 2024.
Novel Spirocyclic Dimer (SpiD3) Displays Potent Preclinical Effects in Hematological Malignancies , Alexandria Eiken
Chemotherapy-Induced Modulation of Tumor Antigen Presentation , Alaina C. Larson
Dying Right: Supporting Anti-Cancer Therapy Through Immunogenic Cell Death , Elizabeth Schmitz
Therapeutic Effects of BET Protein Inhibition in B-cell Malignancies and Beyond , Audrey L. Smith
Targeting KSR1 to inhibit stemness and therapy resistance , Heidi M. Vieira
Identifying the Molecular Determinants of Lung Metastatic Adaptation in Prostate Cancer , Grace M. Waldron
Identification of Mitotic Phosphatases and Cyclin K as Novel Molecular Targets in Pancreatic Cancer , Yi Xiao
Theses/Dissertations from 2023 2023
Development of Combination Therapy Strategies to Treat Cancer Using Dihydroorotate Dehydrogenase Inhibitors , Nicholas Mullen
Overcoming Resistance Mechanisms to CDK4/6 Inhibitor Treatment Using CDK6-Selective PROTAC , Sarah Truong
Theses/Dissertations from 2022 2022
Omics Analysis in Cancer and Development , Emalie J. Clement
Investigating the Role of Splenic Macrophages in Pancreatic Cancer , Daisy V. Gonzalez
Polymeric Chloroquine in Metastatic Pancreatic Cancer Therapy , Rubayat Islam Khan
Evaluating Targets and Therapeutics for the Treatment of Pancreatic Cancer , Shelby M. Knoche
Characterization of 1,1-Diarylethylene FOXM1 Inhibitors Against High-Grade Serous Ovarian Carcinoma Cells , Cassie Liu
Novel Mechanisms of Protein Kinase C α Regulation and Function , Xinyue Li
SOX2 Dosage Governs Tumor Cell Identity and Proliferation , Ethan P. Metz
Post-Transcriptional Control of the Epithelial-to-Mesenchymal Transition (EMT) in Ras-Driven Colorectal Cancers , Chaitra Rao
Use of Machine Learning Algorithms and Highly Multiplexed Immunohistochemistry to Perform In-Depth Characterization of Primary Pancreatic Tumors and Metastatic Sites , Krysten Vance
Characterization of Metastatic Cutaneous Squamous Cell Carcinoma in the Immunosuppressed Patient , Megan E. Wackel
Visceral adipose tissue remodeling in pancreatic ductal adenocarcinoma cachexia: the role of activin A signaling , Pauline Xu
Phos-Tag-Based Screens Identify Novel Therapeutic Targets in Ovarian Cancer and Pancreatic Cancer , Renya Zeng
Theses/Dissertations from 2021 2021
Functional Characterization of Cancer-Associated DNA Polymerase ε Variants , Stephanie R. Barbari
Pancreatic Cancer: Novel Therapy, Research Tools, and Educational Outreach , Ayrianne J. Crawford
Apixaban to Prevent Thrombosis in Adult Patients Treated With Asparaginase , Krishna Gundabolu
Molecular Investigation into the Biologic and Prognostic Elements of Peripheral T-cell Lymphoma with Regulators of Tumor Microenvironment Signaling Explored in Model Systems , Tyler Herek
Utilizing Proteolysis-Targeting Chimeras to Target the Transcriptional Cyclin-Dependent Kinases 9 and 12 , Hannah King
Insights into Cutaneous Squamous Cell Carcinoma Pathogenesis and Metastasis Using a Bedside-to-Bench Approach , Marissa Lobl
Development of a MUC16-Targeted Near-Infrared Antibody Probe for Fluorescence-Guided Surgery of Pancreatic Cancer , Madeline T. Olson
FGFR4 glycosylation and processing in cholangiocarcinoma promote cancer signaling , Andrew J. Phillips
Theses/Dissertations from 2020 2020
Cooperativity of CCNE1 and FOXM1 in High-Grade Serous Ovarian Cancer , Lucy Elge
Characterizing the critical role of metabolic and redox homeostasis in colorectal cancer , Danielle Frodyma
Genomic and Transcriptomic Alterations in Metabolic Regulators and Implications for Anti-tumoral Immune Response , Ryan J. King
Dimers of Isatin Derived Spirocyclic NF-κB Inhibitor Exhibit Potent Anticancer Activity by Inducing UPR Mediated Apoptosis , Smit Kour
From Development to Therapy: A Panoramic Approach to Further Our Understanding of Cancer , Brittany Poelaert
The Cellular Origin and Molecular Drivers of Claudin-Low Mammary Cancer , Patrick D. Raedler
Mitochondrial Metabolism as a Therapeutic Target for Pancreatic Cancer , Simon Shin
Development of Fluorescent Hyaluronic Acid Nanoparticles for Intraoperative Tumor Detection , Nicholas E. Wojtynek
Theses/Dissertations from 2019 2019
The role of E3 ubiquitin ligase FBXO9 in normal and malignant hematopoiesis , R. Willow Hynes-Smith
BRCA1 & CTDP1 BRCT Domainomics in the DNA Damage Response , Kimiko L. Krieger
Targeted Inhibition of Histone Deacetyltransferases for Pancreatic Cancer Therapy , Richard Laschanzky
Human Leukocyte Antigen (HLA) Class I Molecule Components and Amyloid Precursor-Like Protein 2 (APLP2): Roles in Pancreatic Cancer Cell Migration , Bailee Sliker
Theses/Dissertations from 2018 2018
FOXM1 Expression and Contribution to Genomic Instability and Chemoresistance in High-Grade Serous Ovarian Cancer , Carter J. Barger
Overcoming TCF4-Driven BCR Signaling in Diffuse Large B-Cell Lymphoma , Keenan Hartert
Functional Role of Protein Kinase C Alpha in Endometrial Carcinogenesis , Alice Hsu
Functional Signature Ontology-Based Identification and Validation of Novel Therapeutic Targets and Natural Products for the Treatment of Cancer , Beth Neilsen
Elucidating the Roles of Lunatic Fringe in Pancreatic Ductal Adenocarcinoma , Prathamesh Patil
Theses/Dissertations from 2017 2017
Metabolic Reprogramming of Pancreatic Ductal Adenocarcinoma Cells in Response to Chronic Low pH Stress , Jaime Abrego
Understanding the Relationship between TGF-Beta and IGF-1R Signaling in Colorectal Cancer , Katie L. Bailey
The Role of EHD2 in Triple-Negative Breast Cancer Tumorigenesis and Progression , Timothy A. Bielecki
Perturbing anti-apoptotic proteins to develop novel cancer therapies , Jacob Contreras
Role of Ezrin in Colorectal Cancer Cell Survival Regulation , Premila Leiphrakpam
Evaluation of Aminopyrazole Analogs as Cyclin-Dependent Kinase Inhibitors for Colorectal Cancer Therapy , Caroline Robb
Identifying the Role of Janus Kinase 1 in Mammary Gland Development and Breast Cancer , Barbara Swenson
DNMT3A Haploinsufficiency Provokes Hematologic Malignancy of B-Lymphoid, T-Lymphoid, and Myeloid Lineage in Mice , Garland Michael Upchurch
Theses/Dissertations from 2016 2016
EHD1 As a Positive Regulator of Macrophage Colony-Stimulating Factor-1 Receptor , Luke R. Cypher
Inflammation- and Cancer-Associated Neurolymphatic Remodeling and Cachexia in Pancreatic Ductal Adenocarcinoma , Darci M. Fink
Role of CBL-family Ubiquitin Ligases as Critical Negative Regulators of T Cell Activation and Functions , Benjamin Goetz
Exploration into the Functional Impact of MUC1 on the Formation and Regulation of Transcriptional Complexes Containing AP-1 and p53 , Ryan L. Hanson
DNA Polymerase Zeta-Dependent Mutagenesis: Molecular Specificity, Extent of Error-Prone Synthesis, and the Role of dNTP Pools , Olga V. Kochenova
Defining the Role of Phosphorylation and Dephosphorylation in the Regulation of Gap Junction Proteins , Hanjun Li
Molecular Mechanisms Regulating MYC and PGC1β Expression in Colon Cancer , Jamie L. McCall
Pancreatic Cancer Invasion of the Lymphatic Vasculature and Contributions of the Tumor Microenvironment: Roles for E-selectin and CXCR4 , Maria M. Steele
Altered Levels of SOX2, and Its Associated Protein Musashi2, Disrupt Critical Cell Functions in Cancer and Embryonic Stem Cells , Erin L. Wuebben
Theses/Dissertations from 2015 2015
Characterization and target identification of non-toxic IKKβ inhibitors for anticancer therapy , Elizabeth Blowers
Effectors of Ras and KSR1 dependent colon tumorigenesis , Binita Das
Characterization of cancer-associated DNA polymerase delta variants , Tony M. Mertz
A Role for EHD Family Endocytic Regulators in Endothelial Biology , Alexandra E. J. Moffitt
Biochemical pathways regulating mammary epithelial cell homeostasis and differentiation , Chandrani Mukhopadhyay
EPACs: epigenetic regulators that affect cell survival in cancer. , Catherine Murari
Role of the C-terminus of the Catalytic Subunit of Translesion Synthesis Polymerase ζ (Zeta) in UV-induced Mutagensis , Hollie M. Siebler
LGR5 Activates TGFbeta Signaling and Suppresses Metastasis in Colon Cancer , Xiaolin Zhou
LGR5 Activates TGFβ Signaling and Suppresses Metastasis in Colon Cancer , Xiaolin Zhou
Theses/Dissertations from 2014 2014
Genetic dissection of the role of CBL-family ubiquitin ligases and their associated adapters in epidermal growth factor receptor endocytosis , Gulzar Ahmad
Strategies for the identification of chemical probes to study signaling pathways , Jamie Leigh Arnst
Defining the mechanism of signaling through the C-terminus of MUC1 , Roger B. Brown
Targeting telomerase in human pancreatic cancer cells , Katrina Burchett
The identification of KSR1-like molecules in ras-addicted colorectal cancer cells , Drew Gehring
Mechanisms of regulation of AID APOBEC deaminases activity and protection of the genome from promiscuous deamination , Artem Georgievich Lada
Characterization of the DNA-biding properties of human telomeric proteins , Amanda Lakamp-Hawley
Studies on MUC1, p120-catenin, Kaiso: coordinate role of mucins, cell adhesion molecules and cell cycle players in pancreatic cancer , Xiang Liu
Epac interaction with the TGFbeta PKA pathway to regulate cell survival in colon cancer , Meghan Lynn Mendick
Theses/Dissertations from 2013 2013
Deconvolution of the phosphorylation patterns of replication protein A by the DNA damage response to breaks , Kerry D. Brader
Modeling malignant breast cancer occurrence and survival in black and white women , Michael Gleason
The role of dna methyltransferases in myc-induced lymphomagenesis , Ryan A. Hlady
Design and development of inhibitors of CBL (TKB)-protein interactions , Eric A. Kumar
Pancreatic cancer-associated miRNAs : expression, regulation and function , Ashley M. Mohr
Mechanistic studies of mitochondrial outer membrane permeabilization (MOMP) , Xiaming Pang
Novel roles for JAK2/STAT5 signaling in mammary gland development, cancer, and immune dysregulation , Jeffrey Wayne Schmidt
Optimization of therapeutics against lethal pancreatic cancer , Joshua J. Souchek
Theses/Dissertations from 2012 2012
Immune-based novel diagnostic mechanisms for pancreatic cancer , Michael J. Baine
Sox2 associated proteins are essential for cell fate , Jesse Lee Cox
KSR2 regulates cellular proliferation, transformation, and metabolism , Mario R. Fernandez
Discovery of a novel signaling cross-talk between TPX2 and the aurora kinases during mitosis , Jyoti Iyer
Regulation of metabolism by KSR proteins , Paula Jean Klutho
The role of ERK 1/2 signaling in the dna damage-induced G2 , Ryan Kolb
Regulation of the Bcl-2 family network during apoptosis induced by different stimuli , Hernando Lopez
Studies on the role of cullin3 in mitosis , Saili Moghe
Characteristics of amyloid precursor-like protein 2 (APLP2) in pancreatic cancer and Ewing's sarcoma , Haley Louise Capek Peters
Structural and biophysical analysis of a human inosine triphosphate pyrophosphatase polymorphism , Peter David Simone
Functions and regulation of Ron receptor tyrosine kinase in human pancreatic cancer and its therapeutic applications , Yi Zou
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Blood-based mrna tests as emerging diagnostic tools for personalised medicine in breast cancer.
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Simple Summary
1. introduction, 2. molecular diagnostic tests and companion diagnostic devices for breast cancer approved by the us food and drug administration (fda), 3. cancer diagnostics based on mrna can offer prognostically useful information beyond dna variation, 4. tissue-based mrna expression assays for breast cancer, 4.1. prosigna breast cancer prognostic gene signature assay (formerly called the pam50 test), 4.2. mammaprint test (also called the 70-gene signature), 4.3. oncotype dx breast recurrence score test, 4.4. breast cancer index, bci, 4.5. endopredict breast cancer prognostic test, 4.6. genesearch breast lymph node (bln) test kit.
Assay Trade Name (Manufacturer) | Number of Genes; Sample Type | Assay Indicated For | Description | Methodology/ Platform | FDA Numbers; References |
---|---|---|---|---|---|
Prosigna Breast Cancer Prognostic Gene Signature Assay (Veracyte, Inc.) | 50 genes; BC tissue (formalin-fixed paraffin embedded—FFPE) | HR+, LN-negative or 1–3 positive nodes, stage I or II cancers | Classification of intrinsic BC subtypes; prognostic; recurrence risk assessment; guides adjuvant endocrine and chemotherapy in postmenopausal patients | nCounter Dx Analysis System (mRNA hybridization to DNA probes) | FDA (K130010); [ , ] |
MammaPrint (Agendia, Inc.) | 70 genes; BC tissue (FFPE or fresh) | HR+ or HR−, LN-negative or 1–3 positive nodes, stage I or II cancers, ≤5.0 cm | Prognostic; recurrence risk assessment; guides adjuvant endocrine and chemotherapy in patients >50 or postmenopausal patients | Microarray-based assay; also available as a targeted RNA next-generation sequencing assay | FDA (K101454, K081092, K080252, K070675); [ , , ] |
Oncotype DX Breast Recurrence Score Test (Genomic Health) | 21 genes (16 cancer-related and 5 reference genes); BC tissue (FFPE) | HR+/HER2−, LN-negative or 1–3 positive nodes, stage I, II or IIIa cancers, ≤5.0 cm | Prognosticates distant recurrence; predicts chemotherapy benefit/guides adjuvant endocrine and chemotherapy in postmenopausal or premenopausal patients | qRT-PCR-based assay | [ , , , , ] |
Breast Cancer Index—BCI (Biotheranostic, Inc.) | 7 genes; BC tissue (FFPE) | HR+, LN-negative or 1–3 positive nodes, stage I–III cancers, invasive BC cases without evidence of recurrence | Prognosticates risk of distant recurrence; predicts likelihood of benefit from extended (>5 years) endocrine therapy; guides adjuvant endocrine and chemotherapy in patients >50 or postmenopausal patients | qRT-PCR-based assay | [ , ] |
EndoPredict (Myriad Genetics) | 12 genes (8 BC-related and 4 reference genes); BC tissue (FFPE) | HR+/HER2−, LN-negative or 1–3 positive nodes, tumour size T1–T3, grade 1–3 | Predicts distant recurrence at 10 years (and up to 15 years); guides adjuvant endocrine and chemotherapy in patients >50 or postmenopausal patients; identifies premenopausal patients who do not need chemotherapy | qRT-PCR-based assay | [ , , ] |
GeneSearch Breast Lymph Node (BLN) Test Kit (Veridex, LLC.) | 3 genes (2 metastasis-related and 1 reference); lymph node(s) removed during surgery | Patients with invasive BC, scheduled for sentinel lymph node dissection | BC metastasis detection | qRT-PCR-based assay | FDA: P060017 S001–S004, [ ] |
5. The Advantages of Using Peripheral Blood (i.e., a Blood-Based Liquid Biopsy) for Cancer Diagnostics
6. research focusing on bc-specific transcriptional profiles in peripheral blood has established their diagnostic and prognostic value, 6.1. identification of blood predictor genes that can distinguish bc patients from other cancer patients and healthy subjects, 6.2. identification of expression signatures that can distinguish between breast cancer and benign breast disease, 6.3. identification of blood expression signatures that can distinguish between lymph-node positive and negative bc, 6.4. blood gene expression alterations years before bc diagnosis, 6.5. peripheral blood transcriptomics may open the way to novel immune bc subtyping, 7. commercially available blood-based mrna tests for breast cancer, 7.1. hereditary breast cancer predisposition, 7.2. breast cancer screening, 8. current status and future perspectives, 8.1. the rna methods used for breast cancer and their expanding diagnostic potential, 8.2. the capability of supplemental blood mrna analyses to improve the diagnostic outcomes of cancer dna testing, 8.3. the potential of blood rna analyses to enable early cancer detection, 8.4. the mrna-based applications in research and under development for personalised bc management, 8.5. the issue of centralised testing and restricted availability of mrna diagnostics for bc, 8.6. the centralisation of testing and the associated individualised standardisation and validation of rna-based diagnostic assays, 8.7. the technical challenges associated with mrna diagnostic testing, 9. conclusions, supplementary materials, author contributions, conflicts of interest.
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Assay Trade Name (Manufacturer) | Number of Genes | Assay Indicated for | Description | Methodology/ Platform | References |
---|---|---|---|---|---|
+RNAinsight (Ambry Genetics) | Up to 91 genes (for maximum coverage) | Assessing hereditary cancer predisposition | +RNAinsight analyses functional RNA data to classify DNA variants and identify deep-intronic mutations; intended for paired RNA/DNA analyses, as a supplement to Ambry Genetics DNA-level hereditary cancer panels CancerNext, CancerNext-Expanded, CustomNext-Cancer. | RNA sequencing | [ ] |
Syantra DX Breast Cancer (Syantra Inc.) | 12-gene multi-biomarker panel | Breast cancer screening for women aged 25–80 | Enables classification of a sample as positive or negative for BC signature; demonstrated utility for early cancer screening, for women with high breast density, and for women under 50. | qRT-PCR-based assay | [ , ] |
Multi-cancer blood test Aristotle (Stage Zero Life Sciences Ltd.) | Multi-biomarker panel | Pan-cancer screening (breast, bladder, colorectum, cervix, endometrium, liver, ovary, prostate, and stomach) | Enables detection of multiple cancer molecular signatures from a single blood sample (early cancer detection). | Microarray-based assay | [ ] |
BCtect (DiaGenic ASA) | 96-assay signature | Breast cancer screening | Enables classification of a sample as positive or negative for BC signature; utility for early BC detection in both pre- and post-menopausal women, and across cancer stages and types. | qRT-PCR-based assay | [ , , ] |
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Čelešnik, H.; Potočnik, U. Blood-Based mRNA Tests as Emerging Diagnostic Tools for Personalised Medicine in Breast Cancer. Cancers 2023 , 15 , 1087. https://doi.org/10.3390/cancers15041087
Čelešnik H, Potočnik U. Blood-Based mRNA Tests as Emerging Diagnostic Tools for Personalised Medicine in Breast Cancer. Cancers . 2023; 15(4):1087. https://doi.org/10.3390/cancers15041087
Čelešnik, Helena, and Uroš Potočnik. 2023. "Blood-Based mRNA Tests as Emerging Diagnostic Tools for Personalised Medicine in Breast Cancer" Cancers 15, no. 4: 1087. https://doi.org/10.3390/cancers15041087
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Molecular Docking as a Therapeutic Approach for Targeting Cancer Stem Cell Metabolic Processes
Babak arjmand.
1 Cell Therapy and Regenerative Medicine Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
Shayesteh Kokabi Hamidpour
Sepideh alavi-moghadam, hanieh yavari, ainaz shahbazbadr, mostafa rezaei tavirani.
2 Proteomics Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
Kambiz Gilany
3 Integrative Oncology Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran
4 Reproductive Immunology Research Center, Avicenna Research Institute, ACECR, Tehran, Iran
Bagher Larijani
5 Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
Cancer stem cells (CSCs) are subpopulation of cells which have been demonstrated in a variety of cancer models and involved in cancer initiation, progression, and development. Indeed, CSCs which seem to form a small percentage of tumor cells, display resembling characteristics to natural stem cells such as self-renewal, survival, differentiation, proliferation, and quiescence. Moreover, they have some characteristics that eventually can demonstrate the heterogeneity of cancer cells and tumor progression. On the other hand, another aspect of CSCs that has been recognized as a central concern facing cancer patients is resistance to mainstays of cancer treatment such as chemotherapy and radiation. Owing to these details and the stated stemness capabilities, these immature progenitors of cancerous cells can constantly persist after different therapies and cause tumor regrowth or metastasis. Further, in both normal development and malignancy, cellular metabolism and stemness are intricately linked and CSCs dominant metabolic phenotype changes across tumor entities, patients, and tumor subclones. Hence, CSCs can be determined as one of the factors that correlate to the failure of common therapeutic approaches in cancer treatment. In this context, researchers are searching out new alternative or complementary therapies such as targeted methods to fight against cancer. Molecular docking is one of the computational modeling methods that has a new promise in cancer cell targeting through drug designing and discovering programs. In a simple definition, molecular docking methods are used to determine the metabolic interaction between two molecules and find the best orientation of a ligand to its molecular target with minimal free energy in the formation of a stable complex. As a comprehensive approach, this computational drug design method can be thought more cost-effective and time-saving compare to other conventional methods in cancer treatment. In addition, increasing productivity and quality in pharmaceutical research can be another advantage of this molecular modeling method. Therefore, in recent years, it can be concluded that molecular docking can be considered as one of the novel strategies at the forefront of the cancer battle via targeting cancer stem cell metabolic processes.
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Introduction
Cancer is considered as one of the worldwide life-threatening and the leading causes of human mortality ( Vineis and Wild, 2014 ; Organization, 2020 ). According to the latest data released by the International Agency for Research on Cancer (IARC) on 14 December 2020, the annual incidence of cancer in 2020 reached 19.3 million cases and 10 million deaths. Furthermore, evidence based on the World Health Organization (WHO) suggests that there would be 29.5 million new cancer diagnoses and 16.4 million cancer deaths per year by 2040 ( Shah et al., 2019 ; Sung et al., 2021 ). Accordingly, given the rapid development of oncology researches and the advancement of novel biotechnology approaches, determining different aspects of cancer progression can pave the way for improved cancer prognosis and treatment alternatives ( Goyal et al., 2006 ; Charmsaz et al., 2018 ; Pucci et al., 2019 ). Herein, one of the challenges in the field of cancer treatment is the heterogeneity of tumor cells, which may lead to anti-cancer drug resistance or cancer treatment failure. Therefore, a full understanding of tumor heterogeneity can provide a clear picture of cancer progression and lead to the discovery of new cancer therapy options by researchers ( y Cajal et al., 2020 ). Tumor heterogeneity is a condition in which tumor cells differ in various biological aspects such as function, differentiation, tumorigenesis, and sensitivity to anti-cancer therapies ( Prager et al., 2019 ). In addition, depending on the type of heterogeneity, heterogeneous groups of tumor cells can have the same or distinct genomic content ( Prager et al., 2019 ). In addition, heterogeneous populations of tumor cells can have the same or different genome content depending on the type of heterogeneity ( Bedard et al., 2013 ). Hereupon, tumor heterogeneity can be divided into three types: 1) intertumor heterogeneity which is related to the variation of tumor cells among different patients, 2) intersite heterogeneity which is referred to the variation of cells among distinct tumors within a patient such as tumors in the primary site and tumors in the metastatic site, and 3) intratumor heterogeneity which is linked with heterogeneous populations of cells in a single tumor ( Piraino et al., 2019 ). Oncology studies were shown that the cancer stem cells (CSCs) model is one of the models responsible for the generation of heterogeneous populations of cells, especially intratumor heterogeneity type ( Prasetyanti and Medema, 2017 ; Turnquist et al. ). Moreover, it can be caused by different factors such as genetics, epigenetics, and various micro-environmental features ( Wang et al., 2015 ). Indeed, CSCs are a subgroup of cancerous tumor cells that display stemness abilities in the same manner as normal stem cells. For instance, they can self-renew to form the same daughter cells and give rise to differentiated multiple lineages of cells which form tumors. Additionally, the quiescence state is one of the distinguishing characteristics of cancer and normal stem cells, and it can play a role in therapeutic resistance and cancer progression ( Hung et al., 2019 ; Lee et al., 2020 ). Furthermore, CSCs can make the treatment process more challenging because of their resistance to therapeutic approaches such as chemo and radiation therapies. The mentioned therapeutic resistance can be due to a variety of factors and mechanisms, including tumor environment, epigenetic effects, multidrug resistance proteins (MRPs) expression, various signaling pathways, effective mechanisms in DNA damage resistance, and the epithelial-to-mesenchymal transition (EMT) process ( Phi et al., 2018 ). On the other hand, the function of metabolic pathways and processes are crucial in the growth, proliferation and survival of CSCs. In this respect, many investigations at the cellular and molecular level were indicated that unique forms of metabolic processes such as oxidative phosphorylation (OXPHOS), carbohydrate, and lipid metabolisms are observed in CSCs ( Chae and Kim, 2018 ; Yadav et al., 2020 ). Therefore, the science of metabolomics, as well as the understanding of alterations associated with metabolic processes, could be useful in recognizing CSC behaviors and developing specific therapeutic methods for various types of cancers ( Gilany et al., 2018 ; Rahim et al., 2018 ; Arjmand, 2019a , 2019b ; Goodarzi et al., 2019 ; Larijani et al., 2019 ; Tayanloo-Beik et al., 2020 ), as well as the understanding of alterations associated with metabolic processes, could be useful in recognizing CSC behaviors and developing specific therapeutic methods for various types of cancers ( Cuyàs et al., 2017 ). Additionally, scientists have been pushed to employ targeted approaches for treating cancer due to the problems in CSCs resistance to therapeutic methods. Molecular docking is one of the targeted approaches that play an important role in drug discovery and pharmaceutical researches. This computer-assisted drug design method is based on mathematical algorithms in which the effective biological binding-conformation between the drug and the target molecule can be evaluated. Indeed, the mentioned drug designing is based on the molecular structure that makes it possible to model and predict the molecular interactions as well as evaluate the biochemical processes ( Meng et al., 2011 ; Phillips et al., 2018 ). Hereupon, in the present study, the cellular and molecular characteristics, signaling pathways, metabolic processes, and drug resistance of CSCs have been reviewed. We have also focused our discussion on molecular docking as a novel therapeutic approach in CSCs targeting.
The Biology of Cancer Stem Cells
CSCs are a subset of cancer cells or tumor-initiating cells (TICs) that serve as stem cells and contribute to the original tumor’s phenotypic variety ( Lobo et al., 2007 ). They are found in variable amounts in different tumors. Furthermore, evaluating cell surface markers is the main strategy for detecting CSCs. Normal stem cells and CSCs have many similar characteristics ( Jin et al., 2017 ; Khatami et al., 2019 ) such as 1) Self-Renewal ( Lobo et al., 2007 ) 2) Differentiation capacity ( Mohr et al., 2015 ) 3) Tumorigenesis ( Zhu and Fan, 2018 ) 4) Capacity of developing resistance to drugs/cytotoxic substances and radiation ( Schöning et al., 2017 ). Despite their similarities, there are some distinctions between cancer and somatic stem cells. The first is the origin of these two types of stem cells: natural somatic stem cells arise during embryonic development and separate from each other. They differentiate and produce a variety of mature cells, while CSCs are differentiated from normal adult stem cells or by multiple mutations in a single cell. The second is the ability to regenerate itself: somatic stem cells regenerate more regular than CSCs, although both types of cells can regenerate themselves. Finally, the organogenesis ability of these two cells is studied: both cells have the ability to organogenesis, but CSCs produce abnormal tissue, whereas somatic stem cells’ organogenesis produces normal tissue ( Gjorevski et al., 2014 ).
Cancer Stem Cells Isolation Markers
Since, CSCs are a small part of a big heterogeneous cell population of human cancer, isolation and division of such small human cancer cells can be a significant step in a delicate study of various aspects of cancer. Herein, identifying CSCs markers is a key factor ( Tang et al., 2007 ). Most of the CSCs markers originate from human embryonic stem cells (hESCs) or adult stem cells ( Jin et al., 2017 ; Najafi et al., 2019 ). The expression of CSCs isolation markers varies depending on a number of factors, including cell lines, tumor histotypes, isolation methods, and survey CSCs markers in vivo or in vitro investigations ( Tirino et al., 2013 ). On the one hand, CSCs markers have a beneficial therapeutic effect on several types of cancers by targeting CSCs in order to eliminate tumor recurrences ( Jin et al., 2017 ; Najafi et al., 2019 ). Moreover, the majority of surface markers can be harmed by interactions between enzymes and tumor tissues, and this destruction could be regarded a disadvantage ( Abbaszadegan et al., 2017 ). Some various CSCs markers with their unique characteristics were reviewed in Table 1 .
Most frequently applied markers for cancer stem cells isolation.
CSCs Marker | Marker type | Expression location | Function | Cancer Type | References |
---|---|---|---|---|---|
CD44 | Surface marker | Leukocytes, Endothelial cells, Hepatocytes, Mesenchymal cells | Activation of tyrosine kinase receptors by binding to extracellular matrix, Cell migration, Distinction, Increasing the speed of tumor cells entrance into blood vessels in metastasis | Breast, prostate, lung | ; |
CD133 | Surface marker | Embryonic epithelial stem cell, Hematopoietic stem cells | Organizer of the plasma membrane topology, Conservation of plasma membrane`s lipid structure, Development of head and neck squamous cell carcinoma | Breast, prostate, lung, head, neck | ; ; |
CD117 | Surface marker | Mesenchymal adult stem cells, Cardiac adult stem cell, Ovary | Stem cell factor`s receptor, Drug target molecules | Ovarian | |
CD90 | Surface marker | Between normal hematopoietic stem cells and leukemic CSCs | Identifying leukemic CSCs from hematopoietic stem cell subpopulation | Leukemia | ; |
CD24 | Surface marker | Pancreatic carcinoma | Identifying CSCs in pancreas cancer | Pancreas | ; |
ALDH1 | Intracellular marker | Normal stem cells, Malignant stem cells, Progenitor cells | Regulator of stem cells propagation and distinction | Breast | ; |
P63 | Basal cell marker | Basal regenerative cells of many epithelial tissues, Prostate, Urothelial | Prostate progression, Diagnostic factor of prostate cancer | Prostate | ; |
ALDH1: Aldehyde dehydrogenase isoform 1; CSCs, Cancer stem cells.
Cancer Stem Cells Signaling Pathways
In general, signaling pathways can help to precisely regulate the biological function of both CSCs and regular stem cells. Numerous signaling pathways such as Wnt, Notch, Hh, nuclear factor-κB (NF-κB), Janus kinase/signal transducers and activators of transcription (JAK-STAT), phosphoinositide 3-kinase/AKT/mammalian target of rapamycin (PI3K/AKT/mTOR), transforming growth factor (TGF)/SMAD, and peroxisome proliferator-activated receptor (PPAR) are among the intracellular factors that make a major contribution in regulating stem cell functions. Therefore, excessive or abnormal activity and even suppression of mentioned signal transduction pathways can convert the normal stem cells into cancerous. These pathways are regulated and controlled by the function of factors such as diverse proteins, microRNAs, long noncoding RNAs, and endogenous or exogenous factors, just as they change the self-renewal, survival, proliferation, differentiation, and usually tumorigenesis of CSCs ( Table2 ). Signaling pathways interact with one another in a large and complicated network known as “crosstalk,” which is a crucial fact. Subsequently, crosstalk between signaling pathways can influence the regulation of several phenotypic features and drug resistance in CSCs ( Matsui, 2016 ; Yang L et al., 2020 ). Hereupon, a deep understanding of the signaling processes underlying CSCs can pave the way for small molecules and pharmacological inhibitors to target them ( Du et al., 2019 ).
CSCs signaling pathways characteristics.
Signaling Pathway | Examples of Ligands | Receptors/Co-receptors | Function in CSCs | Type of Cancer | References | |
---|---|---|---|---|---|---|
Wnt | WNT1, WNT2 | Members of the Frizzled, LRP5and LRP6 | Self-renewal | Ductal breast carcinomas | ; ; | |
WNT2B, WNT3 | ROR1 and ROR2 | Tumorigenesis | Colorectal | |||
WNT3A, WNT4 | PTK7 | Dedifferentiation | Papillary thyroid | |||
WNT5A, WNT5B | RYK | Apoptosis regulation | Esophageal | |||
WNT6, WNT7A | MUSK | Metastasis | Colorectal | |||
WNT7B, WNT8A, WNT8B, WNT9A, WNT9B, WNT10A, WNT10B, WNT11, WNT16 | Proteoglycan families | — | — | |||
Notch | Delta-like proteins (DLL1, DLL3, DLL4) | Notch1 | Proliferation | Glioblastoma | ; | |
Jagged proteins (JAG1 and JAG2) | Notch2 | Cell survival | Leukemia | |||
— | Notch3 | Self-renewal | Ovarian | |||
— | Notch4 | Differentiation | Colon | |||
— | — | Migration | Gastric | |||
— | — | Metastasis | Breast | |||
— | — | Apoptosis inhibition | Pancreatic | |||
— | — | Cell fate specification | Prostate | |||
— | — | Asymmetric division | Skin | |||
— | — | — | Non small-cell lung | |||
— | — | — | Liver | |||
Hh | Shh | Ptch1, and to a lesser extent, Ptch2, Cdon | Self-renewal | CML | ; | |
Ihh | Boc | Tumor growth | AML | |||
Dhh | Gas1 | Differentiate into transient amplifying cells | ALL | |||
— | — | Metastasis | Glioma, Multiple Myeloma | |||
— | — | — | Metastatic Melanoma | |||
— | — | — | Breast | |||
— | — | — | Gastric | |||
— | — | — | Colon | |||
— | — | — | Pancreatic | |||
— | — | — | Prostate | |||
— | — | — | Small Cell and | |||
— | — | — | Non-Small Cell | |||
— | — | — | Lung Cancer | |||
NF-κB | Lipopolysaccharide | TLRs | Inflammation | Gastrointestinal | ||
IL-1β | TNFR | Stress responses | Genitourinary | |||
TNF-α | IL-1R | Cell survival | Gynecological | |||
bacterial cell components | CD40 | Proliferation | Head | |||
— | BAFFR | Tumorigenesis | Neck | |||
— | LTβR | Some key angiogenesis factors and adhesion molecules expression, Self-renewal | Breast | |||
— | — | Metastasis | Multiple myeloma | |||
— | — | Apoptosis regulation | Blood cancer | |||
JAK-STAT | ILE, PDGF-C, OSM, CXCL12, HGF, TGF-β, EGF, Gastrin, IGF, Mk, BDNF, NT-3, gp130 | ILFR, PDGFR, OSMR, CXCR7, c-MET, TGFR, EGFR, GRPR, IGF1R, Notch-1/2, TrkB, TrkC, IL-6/IL-6Rα | Tumorigenesis, Metastasis, Chemoresistance, EMT transition, Proliferation, Inflammation, Survival | Prostate, Breast, Gastric, Lung | ||
PI3K/AKT/mTOR | Insulin and epithelial growth factor | ErbB-1; HER1, HER2 (c-ErbB-2), HER3 (c-ErbB-3), and HER4 (c-ErbB-4) CXCR4, IGF-1R | Cell proliferation, Angiogenesis, Metabolism, Differentiation, Survival, Self-renewal, Tumorigenesis | Ovarian, Cervical, Breast, Glioblastoma, Gastric, Pancreatic, Colorectal, Prostate, Hepatocellular | ; ; | |
TGF/SMAD | TGF-β1, 2 and 3 | TGFβR1, TGFβR2 | Cell proliferation, Epithelial-mesenchymal transition, Differentiation, Angiogenesis, Inflammation | Liver, Breast, Gastric, Skin, Glioblastoma, Leukemia Colorectal | ; | |
PPAR | Lipid-derived substrates | PPAR-α, PPAR-δ, PPAR-γ | Proliferation, Maintenance of sphere-formation ability, Expression of CSC Markers | Colorectal, Ovarian, Glioblastoma, Breast | ; |
ALL: acute lymphocytic leukemia; AML, acute myeloid leukemia; BAFFR, B cell-activating factor receptor; BDNF, Brain-derived neurotrophic factor; Boc, Brother of Cdon; CAM, cell adhesion molecule; CDON, CAM-related downregulated by oncogenes; CML, chronic myeloid leukaemia; c-Met, Mesenchymal-epithelial transition factor; CXCL, C-X-C motif chemokine ligand; CXCR, C-X-C chemokine receptor; Dhh, Desert hedgehog; DLL, Delta-like proteins; EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; EMT, Epithelial-to-mesenchymal transition; ErbB-1, Erythroblastic leukemia viral oncogene homolog 1; GAS1, Growth Arrest Specific 1; Gp130, Glycoprotein 130; GRPR, Gastrin-releasing peptide receptor HER, human epidermal growth factor receptor; HGF, hepatocyte growth factor; IGF, Insulin-like growth factor; IGF1R, Insulin-like growth factor receptor 1; Ihh, Indian hedgehog; IL-1β, Interleukin 1 beta; IL-1R, Interleukin-1 receptor; IL-6, Interleukin 6; IL-6Rα, Interleukin 6 receptor alpha; ILFR, leukemia inhibitory factor receptor; JAG, jagged protein; JAK-STAT, Janus kinase/signal transducer and activator of transcription; LRP, Low-density lipoprotein receptor-related protein; LTβR, lymphotoxin beta receptor; MK, Heparin-binding growth factor Midkine; MUSK, muscle associated receptor tyrosine kinase; NF-κB, Nuclear factor kappa-light-chain-enhancer of activated B cells; NT-3, Neurotrophin-3; OSM, Oncostatin M; OSMR, Oncostatin M receptor; PDGF-C, Platelet-derived growth factor C; PDGF-R, Platelet-derived growth factor receptors; PI3K/AKT/mTOR, Phosphoinositide 3-kinase/AKT/mammalian target of rapamycin; PPAR, Peroxisome proliferator-activated receptor; Ptch, Patched; PTK7, Protein tyrosine kinase 7; ROR, Receptor tyrosine kinase-like orphan receptor; RYK, receptor tyr kinase; SHH, sonic hedgehog; TGF-β, transforming growth factor beta; TGFβR, transforming growth factor beta receptor; TLRs, Toll-like receptors; TNF-α, tumor necrosis factor alpha; TNFR, tumor necrosis factor receptor; TrkB, Tropomyosin receptor kinase B; TrkC, Tropomyosin receptor kinase C.
Cancer Stem Cells Metabolic Processes
Metabolic reprogramming is one of critically important characteristics of CSCs compared to other cancer and non-cancer cells, which plays a pivotal role in demonstration of cell functions such as proliferation, fate determination and the cancer progression. In this process, the cellular energy metabolism used by CSCs, such as different types of hydrophobic natural compounds and organic substances metabolisms, adenosine triphosphate (ATP) production pathways, etc., differs from that of other cells. In other words, the presence of more metabolites and high-energy compounds in CSCs suggests that they have a different metabolic profile compared to the other. Furthermore, studies demonstrate that oncogenic mutations, tumor suppressants, and, particularly tumor microenvironment features, can all have a major impact on the many components engaged in such metabolic processes. Nevertheless, mentioned metabolic processes and the components involved can be considered as therapeutic targets for cancer treatment ( Mukha and Dubrovska, 2020 ; Peixoto and Lima, 2018 ; Zhu et al., 2020 ).
CSCs such as normal cells are used glucose through glycolysis process to gain energy and survive. The methods for glucose metabolism in a CSC include OXPHOS and glycolytic phosphorylation, which are selected based on the presence of oxygen. Moreover, they play an important role in differentiation, self-renewal and homeostasis. Generally, high glucose levels increase the number of CSCs, while low glucose levels lower the quantity of CSCs ( Falahzadeh et al., 2019 ). CSCs are adaptable cells that can cope with a wide range of situations, including low oxygen levels, insufficient blood vessel development, hyperoxidation, and hypoxia ( Luo and Wicha, 2015 ). If the CSCs are in a state of hypoxia (lack of oxygen), the proper metabolic pathway is chosen. Herein, they enter the glycolytic pathway, which eventually leads to the formation of lactate ( Yi et al., 2018 ). According to Warburg, CSCs require more energy than other normal cells due to their high growth and proliferation. Although the glycolytic process provides less energy, CSCs prefer it since it is shorter ( Dando et al., 2015 ). Lactate produced by the glycolytic pathway has the ability to influence CSC function and is involved in processes including metastasis, angiogenesis, and differentiation ( Tamada et al., 2012 ). If the cell is in a state of hyperoxia (low oxygen), it enters the oxidative pathway, where pyruvate created from glucose enters the mitochondria. Then proceeds via the Krebs cycle and OXPHOS pathway to make energy. According to researches, the first alteration in CSC metabolism is a shift from aerobic to anaerobic sugar metabolism, in which oncogenes such as Akt 1 and C-Myc can regulate the glycolytic pathway by acting on the Warburg effect ( Dando et al., 2015 ).
Metabolisms Related to Mitochondria
Almost every cell activity relies on the hydrolysis of energy-rich compounds such as ATP. Hereupon, the continuous production and replenishment of such energetic compounds are prioritized by the cells ( Dunn and Grider, 2020 ). Mitochondria are one of the major organelles of cells in which contributes significantly in energy transduction by producing energy-carrying molecules. The mitochondria play a key role by activating the OXPHOS, tricarboxylic acid cycle (TCA), and fatty acid oxidation (FAO) in the cell. Additionally, biosynthetic precursors production, innate immune activation, modulation of the reactive oxygen species (ROS), control of calcium homeostasis, and trigger to apoptotic process are also some of the major activities of mitochondria within a cell ( Zong et al., 2016 ). Owing to the mitochondria biosynthetic and bioenergetics activities, compelling evidence suggests that it also have a crucial impact on CSCs function ( De Francesco et al., 2018 ). The difference in the amount of energy required for cancer stem cells compare to other cells can lead to differences in the quantity of mitochondrial function in them. Studies show that mitochondrial function can be affected by the type of tumor heterogeneity. Evidence also points that epigenetic and micro environmental features are among the factors that can result in altered mitochondrial function in CSCs ( García-Heredia and Carnero, 2020 ). Investigations at the cellular and molecular level imply that changes leading to the production of cancer stem cells can increase the mitochondrial mass ( Shin and Cheong, 2019 ) and membrane potential which are a reflection of electrical and biochemical alterations in CSCs mitochondria ( Zhang et al., 2015 ). Furthermore, changes in mitochondrial DNA (mtDNA) can also affect the expression of some nuclear genes during the retrograde signaling that ultimately lead to inducing EMT process and producing CSCs ( Guha et al., 2014 ). Reciprocally, many mitochondrial proteins are encoded by nuclear DNA (nDNA). Accordingly, mutations or changes in nDNA may eventually lead to altered mitochondrial activity in CSCs ( Guerra et al., 2017 ). In addition to the interaction between mitochondria and the nucleus, disruption of some signaling pathways can affect the role of mitochondria in tumorigenesis. For instance, one of the major functions of PI3K/AKT/mTOR pathway is the regulation of pre-apoptotic proteins such as B-cell lymphoma 2 Associated X, Apoptosis Regulator (BAX) in relation to mitochondria which ultimately leads to apoptosis through this organelle. However, overexpression of apoptosis inhibitor genes in CSCs causes abnormal activation of the mentioned signaling pathway, which can lead to cancer cell proliferation, survival, and drug resistance of cancer cells ( Frasson et al., 2015 ; Liu et al., 2020 ). Whereas the study of mitochondrial role in relation to other parts of cell on a large scale can be challenging, it should be narrow down the study to the major functions of mitochondria. Therefore, to promote research in the assessment of CSCs, such part particularly focuses on tricarboxylic acid cycle (TCA) and electron transport-linked phosphorylation process, synthesis and degradation of lipids, reactive oxygen species (ROS) generation system, and alternative metabolic pathways such as amino acid metabolism in CSCs.
Tricarboxylic Acid Cycle (TCA) and Electron Transport-Linked Phosphorylation Process
Unlike normal cells, CSCs require metabolic adaptation in order to supply fuel and materials for tumorigenesis purposes. Both TCA and OXPHOS which occur alternately following aerobic glycolysis, play an important role in the development of CSCs features. For instance, a reduction in the amount of TCA enzymes can be seen in some CSCs. Additionally, the TCA cycle is associated with different processes such as FAO, glutamine metabolism, and so on. Hence, the TCA cycle can play a key role in the development of stemness capabilities in CSCs under the influence of other metabolites ( Yadav et al., 2020 ). Along with TCA, OXPHOS has an important role in tumorigenesis. As already mentioned, glycolysis is the preferred energy production process compared to the OXPHOS in many CSCs. Although mitochondrial-related bioenergetics processes can produce higher rates of energy-rich compounds, the glycolysis pathway can provide the factors needed for the growth and proliferation of CSCs more timely and rapidly. However, CSCs in some types of cancers such as leukemia, ovarian, glioblastoma, breast, lung, and pancreatic ductal adenocarcinoma (PDAC) do not comply with this rule and prefer the OXPHOS pathway rather than glycolysis ( Peixoto and Lima, 2018 ; Snyder et al., 2018 ). OXPHOS-dependent CSCs can acquire their needed energy from the uptake and chemical changes on some metabolites such as pyruvate, lactate, ketone bodies, and some amino acids. However, extracellular uptake is not the only way to get the nutrients needed by OXPHOS-dependent CSCs functions ( Gentric et al., 2017 ; Jagust et al., 2019a ). They can also supply the required nutrients through metabolic symbiosis with glycolysis to perform their bioenergetics and biosynthetic processes. Interestingly, the restriction of nutrient levels in the surrounding microenvironment of OXPHOS-dependent CSCs has not a huge impact on cell functions. Because in specific tumor microenvironments, they can counteract this limitation with their selective advantages. Therefore, this strategy can make a significant contribution to CSCs survival ( Krstic et al., 2017 ; Zhu et al., 2020 ). Since mitochondrial-related processes have important effects on the energy and materials supplying of CSCs to grow and develop tumors, targeting different components of these processes can be an efficient approach in the treatment of various types of cancers ( Jagust et al., 2019b ).
Synthesis and Degradation of Lipids
Lipid, as one of the cell membrane`s basic constitutive elements, is necessary for different cell activities, such as signaling conduction, energy production, etc. Sterols, monoglycerides, diacylglycerides, triglycerides, phospholipids, and glycolipids are different components of lipid structure. additionally, most of the lipids originated from fatty acids ( Snaebjornsson et al., 2020 ; Visweswaran et al., 2020 ). Furthermore, lipid droplets (LDs) act as a lipid storage and in comparison with normal cells, cancer cells have more LDs. Regarding the metabolism of lipid, CSCs have been affected by this kind of metabolism through different strategies such as CSCs maintaining, complying energy desire of CSCs ( Visweswaran et al., 2020 ), increasing CSCs numbers ( Mancini et al., 2018 ), and protecting CSCs from chemotherapeutic agents-induced peroxidation ( Begicevic et al., 2019 ). Moreover, NANOG, sterol regulatory element-binding transcription factor 1(SREBP1), MYC, stearoyl-CoA desaturase (SCD), fatty acid synthase (FASN), ACVL3, CD36, carnitine palmitoyltransferase 1 (CPT1A), and carnitine palmitoyltransferase 1B (CPT1B) are some main modulators for this metabolism. In this respect, there are some alterations in lipid metabolism which lead to different outcomes, such as the effectiveness on the capability of self-renewal, invasion, metastasis, and drug resistance ( Giacomini et al., 2020 ). On the other hand, CSC biomass production, stimulation of the Wnt/-catenin, and Hippo/YAP signaling pathways are some of the other effects that have been linked to CSC activity and cancer progression ( Chae and Kim, 2018 ; Yi et al., 2018 ; Jagust et al., 2019b ). In this context, the altered lipid metabolism can also have some therapeutic effects in the field of CSCs by the CSCs blockage and lessen CSCs chemoresistance ultimately, lipid metabolism contains different signaling pathways that conserve undifferentiating status and the survival of CSCs. Some of these signaling pathways are Notch signaling, Hippo cascades, Hedgehog (Hh) signaling, and Wnt signaling ( Giacomini et al., 2020 ).
Reactive Oxygen Species Generation System
In addition to energy production processes, other pathways can play vital roles in multiple aspects of the generation and maintenance of the CSCs function. ROS production is one of these pathways which contribute to cancer recurrence, CSCs metastasis, and resistance to conventional therapies. Generation of ROS can be a consequence of electron transferring through mitochondrial membrane. In addition, enzymes in some other organelles and even immune reactions can play a role in the production of these oxygen species. Studies have also shown that chemotherapy and radiotherapy can eventually lead to increased ROS within cells ( Liou and Storz, 2010 ; Zhou et al., 2014 ). In general, the antioxidant system acts as a defense barrier against increasing ROS. Maintaining a balance between the amount of antioxidants and ROS can play an important role in cell stability and homeostasis. If this balance is upset and the ROS level increases, cellular stress and eventually cell death occurs ( Poljsak et al., 2013 ; Kurutas, 2016 ). In contrast, in the case of CSCs, the expression of antioxidants is much higher than in ROS production and keeps the ROS levels low ( Shi et al., 2012 ). Hence, it can promote self-renewal, survival, and resistance to anti-cancer treatments. According to the stated argumentation, ROS can be an appropriate objective for discovering targeted therapies to fight against cancer. For instance, using approaches to increase ROS levels or disruption of antioxidant systems within CSCs can lead to cell aging and apoptosis. Therefore, an effective step can be taken to treat various types of cancer by extensively and accurately examining of ROS modulation in CSCs ( Zhou et al., 2014 ; Ding et al., 2015 ).
Amino Acid Metabolism as an Alternative Metabolic Pathway
CSCs are flexible cells that rely on alternative fuels such as the amino acid glutamine to maximize their growth and proliferation under different environmental conditions ( De Francesco et al., 2018 ). In glucose deficiency, the growth and survival of CSCs are highly dependent on glutamine, which enters the cell through its specific vectors during the path of glutaminolysis and is converted to glutamate by the enzyme mitochondrial glutaminase, thus entering the Krebs cycle ( Deshmukh et al., 2016 ). Glutamine, as a source of nitrogen, plays an important role in mediating metabolites, which eventually synthesize various substances, including protein, lipids, and nucleotide acids ( Deshmukh et al., 2016 ). CSCs of various tumors, including the pancreas, pancreas, ovaries, and lungs, are glutamine-dependent ( Deshmukh et al., 2016 ). The pentose phosphate (PPP) pathway is also used as an alternative pathway for fuel generation in CSCs. PPP is performed in two forms: reversible (non-oxidative) and irreversible (oxidative) ( Giacomini et al., 2020 ), which is an alternative pathway for glucose metabolism during the irreversible pathway of PPP. In this pathway, glucose 6-phosphate (G6P) is converted to ribose 5-phosphate in several steps with the production of nicotinamide adenine dinucleotide phosphate (NADPH), and finally essential nucleotides are synthesized by forming ribose groups ( Riganti et al., 2012 ; Polat et al., 2021 ). However, in reversible PPP, ribose 5-phosphate is converted to glyceride aldehyde 3 phosphate in a series of reversible reactions and is eventually used for glycolysis ( Polat et al., 2021 ). Ketone bodies (acetone, acetate, 3-hydroxybutyrate) are among the high-energy fuels used by CSCs to grow and propagate metastases ( Jagust et al., 2019b ). When there is not enough glucose in CSCs, ketone bodies are released into the blood and converted directly to Acetyl-CoA by the two enzymes OXCT1 and ACAT1. Then acetyl-CoA enters the citric acid (CAC) cycle and produces more ATP in the cell ( Ozsvari et al., 2017 ). In addition to glutamine, lysine is another amino acid that CSCs use to make fuel, as well as TICs, which contain many enzymes; They perform the process of lysine catabolism ( Jagust et al., 2019b ). As a result of the lysine pathway, glutamate is synthesized and cysteine uptake is increased in CSCs ( Peixoto and Lima, 2018 ).
The Chemoresistance of Cancer Stem Cells
Chemoresistance is defined as a pivotal factor of defeated chemotherapy treatment in various cancers. This factor relapses affected agents of chemotherapy such as cell death and tumor bulk`s size decrement. In this respect, CSCs considerably execute the role of referred relapsing and also it has the capability of showing resistance against chemotherapeutics by its insensitivity ( Abdullah and Chow, 2013 ; Zhao, 2016 ). Chemoresistance of CSCs leads to a high risk of metastases, less survival speed ( Nunes et al., 2018 ), and the permanence of CSCs ( Chuthapisith et al., 2010 ). Furthermore, a comparison between normal cancer cells and CSCs revealed that, CSCs intrinsically have a higher amount of chemotherapy resistance than normal cancer cells ( Thomas et al., 2014 ). Many factors are involved in CSCs resistance occurrence, which some of them are as detailed below:
- • Tumor microenvironment (TME): One of the factors involved in the regulation of stemness characteristics and chemoresistance of CSCs, is the autocrine and paracrine interactions of CSCs with the components of their surrounding environment, which is referred to as the TME. In recent years, the key role of TME and its components including extracellular matrix, immune cells, endothelial cells, cancer-associated adipocytes (CAAs), and cancer-associated fibroblasts (CAFs) in the onset, metastasis, recurrence, and drug resistance of cancer have been investigated. The results of these studies show that targeting the TME can be an effective approach in the treatment of cancer ( Gaggianesi et al., 2021 ).
- • Epigenetics : Another major factor in the chemoresistance of CSCs is the role of mechanisms followed epigenetic alterations. Studies reveal that epigenetic processes such as DNA methylation, nucleosome remodeling, histone modification, and non-coding RNAs changes are generally associated with the development of normal stem cell characteristics. However, disruption in the normal function of epigenetic factors lead to the development of tumorigenic properties in CSCs ( Toh et al., 2017 ).
- • Epithelial Mesenchymal Transition (EMT) : EMT is a biological phenomenon during processes such as embryonic development, wound healing, and tissue regeneration. However, in the case of cancer, EMT can suppress epithelial features and convert the cell into the mesenchymal state through signaling pathways such as Wnt, Notch, and Hedgehog, which can lead to the development of tumor features ( Singh and Settleman, 2010 ).
- • Multidrug resistance (MDR) : High levels of MDR is another main factor involved in the chemoresistance of CSCs that occurs after applying long-term or high-dose treatment for cancer patients. Generally, two mechanisms can be considered for the effect of MDR on CSCs: 1) Preventing the drug from reaching an effective concentration: studies imply that the function of efflux pumps such as P-glycoprotein (P-gp) encoded by ABCB1, transporters, and enzymes such as cytochrome P450 and glutathione S-transferase play significant roles in mediating drug resistance. 2) Drug detoxification: based on studies, it has been realized that avoiding apoptosis and activating DNA repair mechanisms are of fundamental importance to induce continuous growth and proliferation of CSCs. ( Cho and Kim, 2020 ).
- • The quiescent state : Quiescence or dormancy is a survival strategy for CSCs. In the quiescent state, cell division stops for a while, and cells live with minimal metabolic activity, but still retain the ability to reactivate the cell cycle ( Chen et al., 2021 ). In this state, both intrinsic (e.g., p53 signaling, reactive oxygen species, hypoxia inducible factor-1a, nuclear factor of activated T cells c1, and negative regulators of mTOR) and non-intrinsic factors (e.g., Tie2/angiopoietin-1, TGF-b and bone morphogenic proteins, thrombopoietin, N-cadherin and integrins, osteopontin, and Wnt/b-catenin signaling) are involved ( Li and Bhatia, 2011 ). According to studies, TME and epigenetic mechanisms have a major contribution to the maintenance of the quiescentstate of CSCs as well as evade immune surveillance and destruction, and tumor relapse. Therefore, the presence and persistence of the quiescence or dormancy state in CSCs can lead to the survival of CSCs and cell resistance to treatments such as chemotherapy ( Chen et al., 2021 ).
- • Self-renewal : Self-renewal is one of the noted hallmarks of CSCs that results from a malfunction of self-renewal pathways (SRPs). Studies indicate that Hh, Wnt, Notch, and B-cell-specific Moloney murine leukemia virus integration site 1 (BMI1) pathways have a crucial role in inducing the self-renewal in CSCs. In recent years, the targeting of SRPs has attracted attention as an efficient therapeutic approach in cancer treatment to reduce cancer recurrence and chemotherapy resistance possibility ( Borah et al., 2015 ).
It should also be noted that according to metabolic studies, cancer cells that have undergone chemoresistance are metabolically altered and adapted. For example, processes such as fatty acid oxidation, glutaminolysis activation, glycolysis activation, lactate production, adaptive mitochondrial reprogramming, ornithine decarboxylase, and polyamine production, and PPP and NADPH production can be observed in chemoresistance cancer cells ( Chen et al., 2020 ).
Molecular Docking Study; A Therapeutic Approach for Anti-Cancer Drug Designing
Drug Discovery is considered as a multi-process platform in which a specific chemical compound with desired biological activity on the drug target can be selected and eventually enter the drug development as a candidate drug. In this platform, both chemical compounds and biological targets are evaluated from different aspects by using various approaches. Since both drug discovery and development are time-consuming and cost-intensive programs, they pose many challenges for researchers in drug designing and discovering for various diseases such as different types of cancer. Therefore, the use of new technologies can pave the way discovering new drugs with high therapeutic potential and take a big step towards disease treatment. Compound screening assays are one of mentioned methods that can help with hit identification, validation, lead generation, and optimization processes, as well as evaluating the compounds’ effects on the therapeutic target. With the advancement of technology and the integration of computational science with biological and pharmaceutical studies, approaches such as virtual screening are widely applied in drug designing and discovering programs ( Reddy et al., 2007 ; Hughes et al., 2011 ; Mohs and Greig, 2017 ; Cui et al., 2020 ). In this context, virtual screening aims to evaluate and filter a limited number of suitable chemical compounds from large libraries of small molecules by using mathematical calculations. Structure-based virtual screening (SBVS) is one of the virtual screening methods which attempts to model and analyze the efficient biological binding-conformation between a ligand and a target molecule by using the molecular docking technique ( Liao et al., 2013 ). Molecular docking is one of the cutting-edge computational drug designing technologies in which the most effective and stable state form of the ligand-receptor complex can be predicted ( Morris and Lim-Wilby, 2008 ). The determination of the three-dimensional structure of the target and ligand molecules is at the top of the entire process priority list. Therefore, some techniques such as x-ray crystallography, nuclear magnetic resonance (NMR) spectroscopy, cryo-electron microscopy (cryo-EM), and homology modeling are not only useful in determining molecular structure, but also as complementary tools in drug development ( Allen and Stokes, 2013 ; Kershaw et al., 2013 ; Sturlese et al., 2015 ; Lohning et al., 2017 ). Molecular docking includes searching algorithms and scoring function as two fundamental aspects of docking programs. Searching algorithms can be defined as a process that can lead to exploring the predominant and effective matching docking modes of ligand to the molecular target among the myriad configurations. Because a large number of binding modes are actually found between a ligand and a biological target molecule, searching algorithms not only can consider the optimum possible orientations of the ligand with the target but also can be an economical and time-saving solution in the docking process ( Meng et al., 2011 ; Salmaso and Moro, 2018 ). Molecular dynamics, distance geometry methods, point complementary methods, fragment-based methods, Mote Carlo methods, genetic algorithms, systematic searches, and incremental construction, are some of the examples of search algorithms that can be used in modeling and evaluating the binding form of a ligand molecule to the objective receptor .
After the algorithm searching, it is time for the scoring function to step into the docking arena to find the good pose between the ligand and the target molecule. Scoring function refers to a process in which putative docking modes are ranked by evaluating their binding affinity and lowest binding energy to achieve top-ranked poses between a ligand and a target molecule. Force field function, Empirical scoring functions, knowledge based scoring functions, knowledge-based potentials, machine learning based scoring functions, comparative assessment of scoring functions, physics-based methods, and descriptor-based scoring functions are some of the examples of scoring function classifications in molecular docking ( Madhavilatha and Babu, 2019 ; Sethi et al., 2019 ).
Regarding scoring function, the study of Wang et al. (2003) is one of the best examples of meticulous studies of popular scoring functions in molecular docking. In this study, the authors compared 11 popular scoring functions, including four scoring functions of the LigFit module in Cerius2 (LigScore, PLP, PMF, and LUDI), four scoring functions of the CScore module in SYBYL (FScore, G-Score, D-Score, and ChemScore), the scoring function of the AutoDock program, and two stand-alone scoring functions (DrugScore and X-Score) by performing them on 100 protein−ligand complexes to scrutinize their performance and sift the most effective and efficient methods among them. In this regard, after generating a set of docked conformations for each ligand by Autodac software, each 11 scoring function was tested and implemented on the maintained set and significant results were obtained. In this study, the authors used root-mean-square deviation ≤2.0 Å as a criterion for examining those scoring functions. Based on the analysis of the mentioned criterion, it was concluded that six scoring functions, including PLP, F-Score, LigScore, DrugScore, LUDI, and X-Score achieved high success rates (about 66–76%). In addition, the study implied that the combination of some of those scoring functions and generating the consensus scoring scheme can also increase the success rate (about 80%) ( Figures 1 , ,2). 2 ). In addition to success rates, the authors examined the correlation between 100 complexes’ binding scores and experimentally determined protein-ligand binding affinities. As a result of this experiment, X-Score, PLP, DrugScore, and G-Score could represent correlation coefficients of more than 0.50, which demonstrate superiority over other scoring functions. Since the best scoring function should perform excellently in both docking and scoring, the three scoring functions, including X-Score, DrugScore, and PLP, can be considered the top scoring functions in molecular docking, according to the study by Wang et al. ( Wang et al., 2003 ).
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Success rates of double combinations of the six relatively successful scoring functions in consensus scoring. All numbers are in percent ( Wang et al., 2003 ).
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Success rates of triple combinations of the six relatively successful scoring functions in consensus scoring. All numbers are in percent (R. Wang et al., 2003 ).
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Targeting Cancer Stem Cells Metabolic Process by Molecular Docking
Molecular docking is a substantial method for estimating the interaction between macromolecules such as protein and small molecules such as ligand. On the other hand, molecular docking is also capable of analyzing the molecular kinds of behavioral variability for those molecules which are located at the binding site of a targeted protein. Also, molecular docking is a computational approach and some docking programs are required to carry out its many functions. Some of the most considerable docking programs are Gold, Fred, and Flex. Moreover, they are useful in the prevision of protein and ligand`s binding conjunction ( Kumar et al., 2013 ; Pagadala et al., 2017 ). In this respect, molecular docking is applied in different CSCs-related pathways including metabolic pathways and signaling pathways. Shedding light on metabolic pathways, the activity modification which can be applied by cancer cells, result in the production of metabolic precursors which leads to cancer cells anabolic and energetic requirement fulfilling. Furthermore, different metabolic pathways take a part in tumor progression and malignant tumor alterations. Accordingly, metabolic reprogramming is considered as one of the cancer insignias ( Jagust et al., 2019b ).
Herein, there will be a few examples in the context of some molecular docking usages in metabolic pathways such as 1) mitoketoscins application in targeting metabolic tumor promoters (OXCT1 and ACAT1) in both ketone re-utilization and mitochondrial function ( Ozsvari et al., 2017 ). 2) Survivin protein interaction with andrographolide, which can lead to having an influence on human breast CSCs apoptosis ( Wanandi et al., 2020 ). 3) S-phase kinase-associated protein-2 (Skp2) inhibition process by compound #25 which can result in CSCs survival suppression ( Chan et al., 2013 ).
The other molecular docking-affected pathway in CSCs is the signaling pathway. This pathway is useful for targeted CSCs therapies expansion ( Koury et al., 2017 ), embryonic evolvement, maintaining CSCs, etc. ( Karamboulas and Ailles, 2013 ). Some molecular inhibitor agents of Wnt, Notch, Hh, and some other signaling pathways are implying as one of the important effects of molecular docking process on signaling pathways ( Yang Y et al., 2020 ).
Modulating some target proteins is a striking aspect of molecular docking which has done by natural products. Natural products are able to be considered on the ground of multi-targeting drugs. As such, alkaloids are one of the natural products that have the strength to act as an anticancer lead molecule in the molecular docking process of CSCs. In this regard, Jaitak et al. provided an in-depth analysis of multitargeting drugs as an effective strategy to fight against CSCs and prevent disease recurrence. In this study, the authors examined the effect of some alkaloids that have anticancer potentiality by focusing on the Hh pathway in cancer stem cells. After selection and preparation of target ligands and proteins, Grid parameter selection and validation, implementation of glide docking module of Schrö6; dinger Maestro 9.6 suite, and determination of ADME profile for the studied alkanoid ligands, significant results were discovered. For instance, according to the findings of this study, emetine, and cortistatin, were able to target CSCs maintenance feature by binding to sonic Hh, smoothened (Smo) and, gli protein. Therefore, these two drugs can be applied as multi-targeting drugs in a combination with cancer chemotherapy compounds. Moreover, solamargine alkaloid could also have a good effect on gli protein and sonic hedgehog due to its pharmacophores. Furthermore, both solasonine and tylophorine modulated the Hh pathway and exert anticancer effects on CSCs by affecting only gli proteins. However, unlike other drugs, solamargine and solasonine need to improve the properties of ADME features ( Jaitak, 2016 ).
In addition to alkaloids, the targeting of overexpressed CD44 surface marker in triple-negative breast cancer (TNBC) tissues can have an anticancer effect on CSCs. Regarding targeting CD44 surface markers, Yang et al. determined the positive role of drug carriers including Gambogic acid (GA)-loaded, zirconium-89 (89Zr)-labeled, chitosan (CS)-decorated multifunctional liposomes (MLPs) on TNBC CSCs by designing two in vitro and in vivo experiments. In this study, researchers examined 3D mammospheres and TNBC tissues of 32 women who were diagnosed with TNBC and found that the CD44 surface marker was overexpressed in the disease. Therefore, in this study, 89Zr@CS-MLPs were constructed and predicted how the drug carriers interact with CD44 surface markers in TNBC by applying molecular docking and dynamics simulations methods. The results obtained from the in vitro (examination on tumor cell lines) and in vivo (examination on mice) experiments were implied that 89Zr@CS-MLPs has a great potentiality for TNBC-targeted therapy as a drug carrier. Additionally, since Zr has a long half-life, it can also be used as an ideal radiolabel for positron emission tomography (PET) imaging of cancer. Moreover, 89Zr@CS-GA-MLPs have a high ability to target CSCs in vivo ( Yang R et al., 2020 ).
In 2021, Hongwiangchan et al. demonstrated that hydroquinone 5-O-cinnamoyl ester of renieramycin M (CIN-RM) can be recognized as a fundamental approach in targeting lung CSCs which has been confirmed by molecular docking computational analysis. The effect of CIN-RM is based on the reduction of CSCs markers and upstream inhibition of the AKT pathway. As a result of inhibition of Akt, the expression level of transcription factors involved in self-renewal, such as c-Myc, Nanog, Oct4, and Sox2, are decreased. It is, therefore, CSCs are suppressed and tumor growth can be inhibited. To a lesser extent, CIN-RM also induces its inhibitory effect on the mTOR pathway, but the inhibitory effect of CIN-RM on the protein kinase C (PKC) signal pathway was not significant. Another important result obtained in this study is that CIN-RM even has an effect on inactivating the AKT pathway related to c-Myc regulation of lung non-stem cancer cells, which can be a promising therapeutic approach in cancer treatment ( Figure 3 ) ( Hongwiangchan et al., 2021 ).
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Object name is fphar-13-768556-g003.jpg](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8899123/bin/fphar-13-768556-g003.jpg)
Mechanism of action of drugs analyzed by molecular docking on the metabolic processes of CSCs. The ligands and targets have been investigated by molecular docking. Nine effective drugs, including compound #25, andrographolide, mitoketoscins, emetine, cortistatin, solamargine, solasonine, tylophorine, and CIN-RM are known to affect the biological processes and signaling pathways of CSCs. 1) Compound #25 prevents the assembly of the Skp2-SCF complex by binding to Skp2. Hence, it inhibits two pathways including non-proteolytic K63-linked ubiquitination of Akt and ubiquitination and degradation of p27, which ultimately inhibit the development of tumor features. 2) Andrographolide increases intrinsic apoptosis in CSCs (especially in breast cancer) by inhibiting survivin, caspase-9, and caspase-3.3) Mitoketoscins stop the recycling of ketone bodies into Acetyl-CoA by inhibiting two proteins, including OXCT1 and ACAT1. Hence ATP production is stopped and oxidative mitochondrial metabolism in CSCs is inhibited. 4) Emetine and 5) Cortistatin, can target CSCs by binding to sonic Hh, Smo and, gli protein. 6) Solamargine can affect sonic hedgehog and gli proteins by its pharmacophores. 7) Solasonine and 8) Tylophorine modulate the Hh pathway by affecting gli proteins. 9) CIN-RM can lead to upstream inhibition of the Akt pathway and reduction of CSCs markers, which decrease the expression level of transcription factors involved in self-renewal, such as c-Myc, Nanog, Oct4, and Sox2. CIN-RM can inhibit mTOR pathway. Abbreviations: ATP, Adenosine triphosphate; CIN-RM, Hydroquinone 5-O-cinnamoyl ester of renieramycin M; CSCs, Cancer stem cells; Hh, Hedgehog; mTOR, Mammalian target of rapamycin; Smo, smoothened ( Chan et al., 2013 ; Hongwiangchan et al., 2021 ; Jaitak, 2016 ; Liu et al., 2014 ; Madhunapantula et al., 2011 ; Ozsvari et al., 2017 ; Wanandi et al., 2020 ).
Conclusion and Future Perspective
A comprehensive analyzing of CSCs, including signaling pathways and metabolic activities, as well as recognizing their distinctions with normal cells, is an essential technique in cancer targeted treatment ( Bjerkvig et al., 2005 ; Shyh-Chang and Ng, 2017 ). Major obstacles to molecular binding as a targeted therapeutic technique include receptor flexibility, ligand flexibility, and drug resistance, all of which have contributed to cancer therapy failure ( Meng et al., 2011 ). Computational methods or computer tools, which are a form of artificial intelligence (AI), have recently proven to be a useful approach in a variety of domains, including structure prediction, molecular bond modeling, and junction prediction ( Menke et al., 2021 ). The mentioned methods are divided into two groups: classical and machine learning (ML), of which ML is widely used in molecular binding. Computational methods play a key role in molecular binding for drug design and discovery, and results can be analyzed cheaper and often faster than other conventional methods ( Torres et al., 2019 ). Eventually, with the advancement of science and the identification of various computational methods, computing software and hardware are still being updated, and researchers are looking for the most accurate way to target CSCs for cancer treatment ( Phillips et al., 2018 ).
Author Contributions
All authors contributed to the study conception and design. SK Hamidpour, HY, and AS wrote the first draft. MT and KG helped to study and gather information. SA-M extensively edited the manuscript. BL participated in a critical review. BA helped supervise the project and gave final approval of the version to be published.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s Note
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Chemical Society Reviews
Exploring pathological link between antimicrobial and amyloid peptides.
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* Corresponding authors
a Department of Chemical, Biomolecular, and Corrosion Engineering, The University of Akron, Ohio 44325, USA E-mail: [email protected]
b Division of Endocrinology and Diabetes, Department of Pediatrics, School of Medicine, Stanford University, Palo Alto, CA 94304, USA
c The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, Georgia 30332, USA
d Cancer Innovation Laboratory, National Cancer Institute, Frederick, MD 21702, USA
e Computational Structural Biology Section, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA E-mail: [email protected]
f Department of Human Molecular Genetics and Biochemistry Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel
Amyloid peptides (AMYs) and antimicrobial peptides (AMPs) are considered as the two distinct families of peptides, characterized by their unique sequences, structures, biological functions, and specific pathological targets. However, accumulating evidence has revealed intriguing pathological connections between these peptide families in the context of microbial infection and neurodegenerative diseases. Some AMYs and AMPs share certain structural and functional characteristics, including the ability to self-assemble, the presence of β-sheet-rich structures, and membrane-disrupting mechanisms. These shared features enable AMYs to possess antimicrobial activity and AMPs to acquire amyloidogenic properties. Despite limited studies on AMYs–AMPs systems, the cross-seeding phenomenon between AMYs and AMPs has emerged as a crucial factor in the bidirectional communication between the pathogenesis of neurodegenerative diseases and host defense against microbial infections. In this review, we examine recent developments in the potential interplay between AMYs and AMPs, as well as their pathological implications for both infectious and neurodegenerative diseases. By discussing the current progress and challenges in this emerging field, this account aims to inspire further research and investments to enhance our understanding of the intricate molecular crosstalk between AMYs and AMPs. This knowledge holds great promise for the development of innovative therapies to combat both microbial infections and neurodegenerative disorders.
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Y. Tang, Y. Zhang, D. Zhang, Y. Liu, R. Nussinov and J. Zheng, Chem. Soc. Rev. , 2024, Advance Article , DOI: 10.1039/D3CS00878A
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Method enables fast, accurate estimates of cardiovascular state to inform blood pressure management
If patients receiving intensive care or undergoing major surgery develop excessively high or low blood pressures, they could suffer severe organ dysfunction. It's not enough for their care team to know that pressure is abnormal. To choose the correct drug to treat the problem, doctors must know why blood pressure has changed. A new MIT study presents the mathematical framework needed to derive that crucial information accurately and in real time.
The mathematical approach, described in a recent study in IEEE Transactions on Biomedical Engineering , produces proportional estimates of the two critical factors underlying blood pressure changes: the heart's rate of blood output (cardiac output) and the arterial system's resistance to that blood flow (systemic vascular resistance). By applying the new method to previously collected data from animal models, the researchers show that their estimates, derived from minimally invasive measures of peripheral arterial blood pressure, accurately matched estimates using additional information from an invasive flow probe placed on the aorta. Moreover, the estimates accurately tracked the changes induced in the animals by the various drugs physicians use to correct aberrant blood pressure.
"Estimates of resistance and cardiac output from our approach provide information that can readily be used to guide hemodynamic management decisions in real time," the study authors wrote.
With further testing leading to regulatory approval, the authors said, the method would be applicable during heart surgeries, liver transplants, intensive care unit treatment and many other procedures affecting cardiovascular function or blood volume.
"Any patient who is having cardiac surgery could need this," said study senior author Emery N. Brown, Edward Hood Taplin Professor of Medical Engineering and Computational Neuroscience in The Picower Institute for Learning and Memory, the Institute for Medical Engineering and Science and the Department of Brain and Cognitive Sciences at MIT. Brown is also an anesthesiologist at Massachusetts General Hospital and a professor of anesthesiology at Harvard Medical School. "So might any patient undergoing a more normal surgery but who might have a compromised cardiovascular system such as ischemic heart disease. You can't have the blood pressure being all over the place."
The study's lead author is electrical engineering and computer science (EECS) graduate student Taylor Baum, who is co-supervised by Brown and Munther Dahleh, William A. Coolidge Professor in EECS.
Algorithmic advance
The idea that cardiac output and systemic resistance are the two key components of blood pressure comes from the two-element Windkessel model. The new study is not the first to use the model to estimate these components from blood pressure measurements, but previous attempts ran into a tradeoff between quick estimate updates and the accuracy of estimates; methods would either provide more erroneous estimates at every beat or more reliable estimates that are updated at minute time scales. Led by Baum, the MIT team overcame the tradeoff with a new approach of applying statistical and signal processing techniques such as "state-space" modeling.
"Our estimates, updated at every beat, are not just informed by the current beat; but they incorporate where things were in previous beats as well," Baum said. "It's that combination of past history and current observations that produces a more reliable estimate while still at a beat-by-beat time scale."
Notably, the resulting estimates of cardiac output and systemic resistance are "proportional," meaning that they are each inextricably linked in the math with another co-factor, rather than estimated on their own. But application of the new method to data collected in an older study from six animals showed that the proportional estimates from recordings using minimally invasive catheters provide comparable information for cardiovascular system management.
One key finding was that the proportional estimates made based on arterial blood pressure readings from catheters inserted in various locations away from the heart (e.g., the leg or the arm) mirrored estimates derived from more invasive catheters placed within the aorta. The significance of the finding is that a system using the new estimation method could in some cases rely on a minimally invasive catheter in various peripheral arteries, thereby avoiding the need for a riskier placement of a central artery catheter or a pulmonary artery catheter directly in the heart, the clinical gold standard for cardiovascular state estimation.
Another key finding was that when the animals received each of five drugs that doctors use to regulate either systemic vascular resistance or cardiac output, the proportional estimates tracked the resulting changes properly. The finding therefore suggests that the proportional estimates of each factor are accurately reflecting their physiological changes.
Toward the clinic
With these encouraging results, Baum and Brown said, the current method can be readily implemented in clinical settings to inform perioperative care teams about underlying causes of critical blood pressure changes. They are actively pursuing regulatory approval of use of this method in a clinical device.
Additionally, the researchers are pursuing more animal studies to validate an advanced blood pressure management approach that uses this method.
They have developed a closed-loop system, informed by this estimation framework, to precisely regulate blood pressure in an animal model. Upon completion of the animal studies, they will apply for regulatory clearance to test the system in humans.
In addition to Baum, Dahleh and Brown, the paper's other authors are Elie Adam, Christian Guay, Gabriel Schamberg, Mohammadreza Kazemi and Thomas Heldt.
The National Science Foundation, the National Institutes of Health, a Mathworks Fellowship, The Picower Institute for Learning and Memory and The JPB Foundation supported the study.
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- Personalized Medicine
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Journal Reference :
- Taylor E. Baum, Elie Adam, Christian S. Guay, Gabriel Schamberg, Mohammadreza Kazemi, Thomas Heldt, Emery N. Brown. Dynamic Estimation of Cardiovascular State From Arterial Blood Pressure Recordings . IEEE Transactions on Biomedical Engineering , 2024; 1 DOI: 10.1109/TBME.2024.3408808
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Cooler temperatures to come, but air quality expected to stay poor
Allison allsop.
- Jul 26, 2024
- Jul 26, 2024 Updated 5 hrs ago
Smoke fills the sky over Casper on Tuesday, July 23 due to fires in Canada, Oregon and Washington.
After blazing temperatures in the high 90s and low 100s this week, Casper residents and visitors will be thrilled to know that this weekend will only be in the high 80s.
In addition to the hot temperatures, residents were also plagued by a thick smoky haze this week from surrounding wildfires, which will continue into the weekend.
For the last week, the air quality index has been elevated between 60 and 125. When measuring air quality, measurements below 50 are considered “good” meaning it won’t have very much effect on anyone’s health. Measurements of 50-100 are considered moderate. At moderate air quality levels, individuals who are unusually sensitive to air quality.
On Tuesday, air quality in Casper reached measurements of 118 according to AirNow, a website that tracks air quality measurements and trends across the country.
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Measurements of air quality between 101 and 150 are considered unhealthy for sensitive groups such as those with heart or lung disease, older adults, pregnant people and children.
Extended exposure to polluted air can be similar to smoking cigarettes, according to one article published by Berkeley Earth.
Eight hours of exposure in an area with an air quality reading of 120 is equal to smoking 2.3 cigarettes.
In order to reduce exposure, especially for sensitive groups, individuals should lessen the time they spend outdoors. They can also invest in a HEPA air cleaner to remove harmful pollutants from the air inside the home. Windows should also remain closed if possible to further reduce the possibility of smoke particles entering the home. Some air conditioning units may have a recirculation option that will help reduce the amount of outside air coming in.
Air quality measurements are expected to stay within the 50s to 60s this weekend.
Allison Allsop is the education and health reporter for the Casper Star-Tribune. She can be reached at 307-266-0544 or [email protected] . Her Twitter account is @allisonallsop
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- Published: 09 January 2024
Delivery of a sebum modulator by an engineered skin microbe in mice
- Nastassia Knödlseder 1 ,
- María-José Fábrega 1 na1 ,
- Javier Santos-Moreno 1 na1 ,
- Joan Manils ORCID: orcid.org/0000-0001-8429-1295 2 , 3 ,
- Lorena Toloza 1 ,
- Maria Marín Vilar 1 nAff11 ,
- Cristina Fernández 1 ,
- Katrina Broadbent 4 ,
- Julien Maruotti 5 ,
- Hélène Lemenager 5 ,
- Carlo Carolis ORCID: orcid.org/0000-0003-4240-1139 4 ,
- Christos C. Zouboulis ORCID: orcid.org/0000-0003-1646-2608 6 ,
- Concepció Soler ORCID: orcid.org/0000-0001-6502-5012 2 , 7 ,
- Rolf Lood 8 ,
- Holger Brüggemann 9 &
- Marc Güell ORCID: orcid.org/0000-0003-4000-7912 1 , 10
Nature Biotechnology ( 2024 ) Cite this article
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- Applied microbiology
- Genetic engineering
Microorganisms can be equipped with synthetic genetic programs for the production of targeted therapeutic molecules. Cutibacterium acnes is the most abundant commensal of the human skin, making it an attractive chassis to create skin-delivered therapeutics. Here, we report the engineering of this bacterium to produce and secrete the therapeutic molecule neutrophil gelatinase-associated lipocalin, in vivo, for the modulation of cutaneous sebum production.
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Early development of the skin microbiome: therapeutic opportunities
Data availability.
Sequencing datasets generated during this study are available from the NCBI Sequence Read Archive (SRA) with BioProject ID number PRJNA1007560 (ref. 63 ). The mass spectrometry proteomics data were deposited to the ProteomeXchange Consortium via the PRIDE 64 partner repository with the dataset identifier PXD044802 (ref. 65 ). Source data are provided with this paper.
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Acknowledgements
We want to thank C.D. Johnston from the Fred Hutchinson Cancer Center for kindly providing the JMC2 and JMC3 MC producer strains. We would like to thank T.F. Meyer for the opportunity to visit his lab and M. Sörensen for her technical support and time during the research stay. Furthermore, we want to thank B. Paetzold for the interesting discussions. We want to express our gratitude to E. Sabido from the UPF/CRG proteomics unit for proteomic analysis support. We thank the entire Synbio team for their support and helpful discussions. N.K. thanks A. Rahmeh, M. Pallares and M. Pol for useful discussions and input.
This work was funded by the Office of Naval Research (award N62909-18-1-2155), INNOValora (INNOV21-09-1; SynFlora) given by Universitat Pompeu Fabra and Indústria del Coneixement of the Catalan government (AGAUR; IdC 2019 PROD 00057) and SKINDEV ‘Skin microbial devices’ by European Innovation Council (101098826), all granted to M.G., as well as by research grants PID2020-114477RB-I00 to C.S. and PID2021-126249OA-I00 to J.M. from the MCIN/AEI/10.13039/501100011033. N.K. is funded by a Maria Maetzu–UPF fellowship (AEI–MM-CEX2018-000792-M D.COMAS–Programa estatal de fomento investigación científica y técnica de exceléncia, unidades de exceléncia María de Maeztu 2018) and by the Sociedad Española de Químicos Cosméticos (Beca de la SEQC para la presentación de trabajos en el 33rd IFSCC Congress; KNÖDLSEDER, NASTASSIA). M.J.F. is funded by a Juan de la Cierva Fellowship from the Spanish government (award FJC 2018-037096-I). N.K. also received an EMBO short-term fellowship (fellowship no. 8240). J.S.M. is funded by a Marie Skłodowska-Curie Individual Fellowship (European Union’s Horizon 2020 Research and Innovation Program under Marie Skłodowska-Curie grant agreement 882387), a Juan de la Cierva Incorporación Fellowship (IJC2020-043621-I/MCIN/AEI/10.13039/501100011033 and NextGenerationEU/PRTR from the European Union) and a DCEXS MM Postdoc Project (Unidad de Excelencia María de Maeztu, funded by the AEI, ref. CEX2018-000792-M).
The graphic illustrations in this study were generated using BioRender.com . Data plots were generated using GraphPad Prism 9.
Author information
Maria Marín Vilar
Present address: Vall d’Hebron Institute of Oncology, Barcelona, Spain
These authors contributed equally: María José Fábrega, Javier Santos-Moreno.
Authors and Affiliations
Department of Medicine and Life Sciences, Universitat Pompeu Fabra, Barcelona, Spain
Nastassia Knödlseder, María-José Fábrega, Javier Santos-Moreno, Lorena Toloza, Maria Marín Vilar, Cristina Fernández & Marc Güell
Immunity, Inflammation and Cancer Group, Oncobell Program, Institut d’Investigació Biomèdica de Bellvitge, Barcelona, Spain
Joan Manils & Concepció Soler
Serra Húnter Programme, Immunology Unit, Department of Pathology and Experimental Therapy, School of Medicine, Universitat de Barcelona, Barcelona, Spain
Joan Manils
Protein Technologies Facility, Center of Genomic Regulation, Barcelona, Spain
Katrina Broadbent & Carlo Carolis
Phenocell SAS, Grasse, France
Julien Maruotti & Hélène Lemenager
Hochschulklinik für Dermatologie, Venerologie und Allergologie, Immunologisches Zentrum; Städtisches Klinikum Dessau; and Medizinische Hochschule Brandenburg Theodor Fontane und Fakultät für Gesundheitswissenschaften Brandenburg, Dessau-Roßlau, Germany
Christos C. Zouboulis
Immunology Unit, Department of Pathology and Experimental Therapy, School of Medicine, Universitat de Barcelona, Barcelona, Spain
Concepció Soler
Department of Clinical Sciences, Division of Infection Medicine, Lund University, Lund, Sweden
Department of Biomedicine, Aarhus University, Aarhus, Denmark
Holger Brüggemann
ICREA, Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain
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Contributions
N.K. conceptualized, designed and carried out the experiments with the guidance of M.G. M.J.F., L.T. and K.B. contributed to the cell culture work. M.M., L.T. and J.S.M. contributed to the bacterial work. J.S.M. with the help of N.K. designed and created the IIIB methylase-proficient E. coli strain. N.K., J. Manils and C.F. performed the mouse experiments and processed the samples. C.C.Z. provided the SZ95 cell line and guidance. J. Maruotti and H.L. provided the Pci-SEB_Cau cell lines, conducted the initial experiments and provided guidance. H.B. analyzed the 16S datasets and contributed with experimental design and advice. R.L. provided support and guidance for the in vivo production of proteins and acquisition of samples. C.C. and K.B. purified the proteins used in this study. C.S. contributed with advice and guidance. N.K., M.G., M.J.F., J.S.M. and J. Manils drafted the initial manuscript. All authors read, edited, and approved the final manuscript.
Corresponding author
Correspondence to Marc Güell .
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M.G., N.K., M.J.F. and J.S.M. are inventors of a European patent application submitted by University Pompeu Fabra.
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Knödlseder, N., Fábrega, MJ., Santos-Moreno, J. et al. Delivery of a sebum modulator by an engineered skin microbe in mice. Nat Biotechnol (2024). https://doi.org/10.1038/s41587-023-02072-4
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DOI : https://doi.org/10.1038/s41587-023-02072-4
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