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Qusairy Z, Rada M. Glycosylation in cancer: mechanisms, diagnostic markers, and therapeutic applications. Mol Cell Biochem 2025:10.1007/s11010-025-05303-1. [PMID: 40389792 DOI: 10.1007/s11010-025-05303-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2025] [Accepted: 05/04/2025] [Indexed: 05/21/2025]
Abstract
Glycosylation, a key post-translational modification, plays a pivotal role in cancer progression by influencing critical processes such as protein folding, immune modulation, and intercellular signaling. Altered glycosylation patterns are increasingly recognized as fundamental drivers of tumorigenesis, contributing to key cancer hallmarks like enhanced tumor migration, metastasis, and immune evasion. These aberrant glycosylation signatures not only offer insights into cancer biology but also serve as valuable diagnostic markers and potential therapeutic targets across a range of malignancies. This review explores the mechanisms underlying glycosylation alterations in cancer. We discuss the molecular basis of these changes, including genetic mutations, epigenetic regulation, and oncogene-driven shifts in glycosylation pathways. Additionally, we highlight recent advancements in glycomics research, with a focus on how these alterations influence tumor progression, angiogenesis, and the tumor microenvironment. Furthermore, the review considers the clinical implications of glycosylation changes, including their role in resistance to anti-cancer therapies and their potential as biomarkers for personalized treatment strategies. By bridging fundamental glycosylation research with clinical applications, this review underscores the promise of glycosylation as both a diagnostic tool and a therapeutic target in oncology, offering new avenues for improved patient stratification and precision medicine.
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Affiliation(s)
- Zahraa Qusairy
- McGill University Health Center Research Institute, Montreal, QC, H4A 3J1, Canada
| | - Miran Rada
- Medical Laboratory Science, Komar University of Science and Technology, Qularaisi, Sulaimani, Sulaymaniyah, Kurdistan Region, Iraq.
- Komar Cancer Research Program, Komar University of Science and Technology, Qularaisi, Sulaimani, Sulaymaniyah, Kurdistan Region, Iraq.
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2
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Jia YP, Liu DC, Cao TL, Jiang HZ, Li T, Li Y, Ding X. Advances and global trends of precancerous lesions of gastric cancer: A bibliometric analysis. World J Gastrointest Oncol 2025; 17:102111. [PMID: 40092937 PMCID: PMC11866257 DOI: 10.4251/wjgo.v17.i3.102111] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Revised: 11/22/2024] [Accepted: 12/30/2024] [Indexed: 02/14/2025] Open
Abstract
BACKGROUND Precancerous lesions of gastric cancer (PLGC) represent a critical pathological stage in the development of intestinal gastric cancer. Early detection and diagnosis are key to reducing the incidence of gastric cancer. Substantial advancements have been made in PLGC research in recent years, making it necessary to provide updated reviews using bibliometric methods. We hypothesize that this review will identify emerging trends, key research areas, and gaps in PLGC research, providing insights that could guide future studies and enhance prevention strategies. AIM To comprehensively review the current state of research on PLGC, examining development trends and research hotspots. METHODS We conducted a bibliometric analysis of PLGC-related studies published between 2004 and 2023 using the Web of Science Core Collection database. We employed Software, including VOSviewer, CiteSpace, R software, and SCImago Graphica, to map scientific networks and visualize knowledge trends in terms of publication volume, countries/regions, institutions, journals, authors, and keywords. RESULTS A total of 4097 articles were included, and overall publication volume showed an increasing trend. Over the past two decades, China published the most articles, followed by the United States, Japan, South Korea, and Italy. Among the top 10 contributors, the United States ranked highest in institutions, authors, and citations and demonstrated the strongest international collaboration. Research keywords in this field were clustered into three main categories: Risk factors, pathogenesis, and diagnosis and treatment. Pathogenesis and molecular biomarkers remain key areas of focus. Future research should explore the mechanisms of gut microbiota, immune microenvironment, metabolic reprogramming, and epigenetics. Advanced technologies, including single-cell sequencing, spatially resolved analysis, multi-omics approaches, artificial intelligence, and machine learning, will likely accelerate in-depth investigations of PLGC. CONCLUSION PLGC research has rapidly developed in recent years, gaining considerable attention. This bibliometric analysis reveals research state and emerging trends over the past 20 years, providing insights for future studies.
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Affiliation(s)
- Yuan-Ping Jia
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100700, China
| | - Dian-Chun Liu
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Ting-Lan Cao
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Hui-Zhong Jiang
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100700, China
| | - Tao Li
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Yuan Li
- National Institute of Traditional Chinese Medicine Constitution and Preventive Treatment of Diseases, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Xia Ding
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, China
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Moghaddam SJ, Savai R, Salehi-Rad R, Sengupta S, Kammer MN, Massion P, Beane JE, Ostrin EJ, Priolo C, Tennis MA, Stabile LP, Bauer AK, Sears CR, Szabo E, Rivera MP, Powell CA, Kadara H, Jenkins BJ, Dubinett SM, Houghton AM, Kim CF, Keith RL. Premalignant Progression in the Lung: Knowledge Gaps and Novel Opportunities for Interception of Non-Small Cell Lung Cancer. An Official American Thoracic Society Research Statement. Am J Respir Crit Care Med 2024; 210:548-571. [PMID: 39115548 PMCID: PMC11389570 DOI: 10.1164/rccm.202406-1168st] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2024] [Indexed: 08/13/2024] Open
Abstract
Rationale: Despite significant advances in precision treatments and immunotherapy, lung cancer is the most common cause of cancer death worldwide. To reduce incidence and improve survival rates, a deeper understanding of lung premalignancy and the multistep process of tumorigenesis is essential, allowing timely and effective intervention before cancer development. Objectives: To summarize existing information, identify knowledge gaps, formulate research questions, prioritize potential research topics, and propose strategies for future investigations into the premalignant progression in the lung. Methods: An international multidisciplinary team of basic, translational, and clinical scientists reviewed available data to develop and refine research questions pertaining to the transformation of premalignant lung lesions to advanced lung cancer. Results: This research statement identifies significant gaps in knowledge and proposes potential research questions aimed at expanding our understanding of the mechanisms underlying the progression of premalignant lung lesions to lung cancer in an effort to explore potential innovative modalities to intercept lung cancer at its nascent stages. Conclusions: The identified gaps in knowledge about the biological mechanisms of premalignant progression in the lung, together with ongoing challenges in screening, detection, and early intervention, highlight the critical need to prioritize research in this domain. Such focused investigations are essential to devise effective preventive strategies that may ultimately decrease lung cancer incidence and improve patient outcomes.
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Shi X, Gekas C, Verduzco D, Petiwala S, Jeffries C, Lu C, Murphy E, Anton T, Vo AH, Xiao Z, Narayanan P, Sun BC, D'Souza AL, Barnes JM, Roy S, Ramathal C, Flister MJ, Dezso Z. Building a translational cancer dependency map for The Cancer Genome Atlas. NATURE CANCER 2024; 5:1176-1194. [PMID: 39009815 PMCID: PMC11358024 DOI: 10.1038/s43018-024-00789-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Accepted: 05/31/2024] [Indexed: 07/17/2024]
Abstract
Cancer dependency maps have accelerated the discovery of tumor vulnerabilities that can be exploited as drug targets when translatable to patients. The Cancer Genome Atlas (TCGA) is a compendium of 'maps' detailing the genetic, epigenetic and molecular changes that occur during the pathogenesis of cancer, yet it lacks a dependency map to translate gene essentiality in patient tumors. Here, we used machine learning to build translational dependency maps for patient tumors, which identified tumor vulnerabilities that predict drug responses and disease outcomes. A similar approach was used to map gene tolerability in healthy tissues to prioritize tumor vulnerabilities with the best therapeutic windows. A subset of patient-translatable synthetic lethalities were experimentally tested, including PAPSS1/PAPSS12 and CNOT7/CNOT78, which were validated in vitro and in vivo. Notably, PAPSS1 synthetic lethality was driven by collateral deletion of PAPSS2 with PTEN and was correlated with patient survival. Finally, the translational dependency map is provided as a web-based application for exploring tumor vulnerabilities.
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Affiliation(s)
- Xu Shi
- AbbVie Bay Area, South San Francisco, CA, USA
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Mistry JJ, Young KA, Colom Díaz PA, Maestre IF, Levine RL, Trowbridge JJ. Mesenchymal Stromal Cell Senescence Induced by Dnmt3a -Mutant Hematopoietic Cells is a Targetable Mechanism Driving Clonal Hematopoiesis and Initiation of Hematologic Malignancy. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.03.28.587254. [PMID: 38585779 PMCID: PMC10996614 DOI: 10.1101/2024.03.28.587254] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/09/2024]
Abstract
Clonal hematopoiesis (CH) can predispose to blood cancers due to enhanced fitness of mutant hematopoietic stem and progenitor cells (HSPCs), but the mechanisms driving this progression are not understood. We hypothesized that malignant progression is related to microenvironment-remodelling properties of CH-mutant HSPCs. Single-cell transcriptomic profiling of the bone marrow microenvironment in Dnmt3a R878H/+ mice revealed signatures of cellular senescence in mesenchymal stromal cells (MSCs). Dnmt3a R878H/+ HSPCs caused MSCs to upregulate the senescence markers SA-β-gal, BCL-2, BCL-xL, Cdkn1a (p21) and Cdkn2a (p16), ex vivo and in vivo . This effect was cell contact-independent and can be replicated by IL-6 or TNFα, which are produced by Dnmt3a R878H/+ HSPCs. Depletion of senescent MSCs in vivo reduced the fitness of Dnmt3a R878H/+ hematopoietic cells and the progression of CH to myeloid neoplasms using a sequentially inducible Dnmt3a ; Npm1 -mutant model. Thus, Dnmt3a -mutant HSPCs reprogram their microenvironment via senescence induction, creating a self-reinforcing niche favoring fitness and malignant progression. Statement of Significance Mesenchymal stromal cell senescence induced by Dnmt3a -mutant hematopoietic stem and progenitor cells drives clonal hematopoiesis and initiation of hematologic malignancy.
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Pardo-Cea MA, Farré X, Esteve A, Palade J, Espín R, Mateo F, Alsop E, Alorda M, Blay N, Baiges A, Shabbir A, Comellas F, Gómez A, Arnan M, Teulé A, Salinas M, Berrocal L, Brunet J, Rofes P, Lázaro C, Conesa M, Rojas JJ, Velten L, Fendler W, Smyczynska U, Chowdhury D, Zeng Y, He HH, Li R, Van Keuren-Jensen K, de Cid R, Pujana MA. Biological basis of extensive pleiotropy between blood traits and cancer risk. Genome Med 2024; 16:21. [PMID: 38308367 PMCID: PMC10837955 DOI: 10.1186/s13073-024-01294-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2023] [Accepted: 01/22/2024] [Indexed: 02/04/2024] Open
Abstract
BACKGROUND The immune system has a central role in preventing carcinogenesis. Alteration of systemic immune cell levels may increase cancer risk. However, the extent to which common genetic variation influences blood traits and cancer risk remains largely undetermined. Here, we identify pleiotropic variants and predict their underlying molecular and cellular alterations. METHODS Multivariate Cox regression was used to evaluate associations between blood traits and cancer diagnosis in cases in the UK Biobank. Shared genetic variants were identified from the summary statistics of the genome-wide association studies of 27 blood traits and 27 cancer types and subtypes, applying the conditional/conjunctional false-discovery rate approach. Analysis of genomic positions, expression quantitative trait loci, enhancers, regulatory marks, functionally defined gene sets, and bulk- and single-cell expression profiles predicted the biological impact of pleiotropic variants. Plasma small RNAs were sequenced to assess association with cancer diagnosis. RESULTS The study identified 4093 common genetic variants, involving 1248 gene loci, that contributed to blood-cancer pleiotropism. Genomic hotspots of pleiotropism include chromosomal regions 5p15-TERT and 6p21-HLA. Genes whose products are involved in regulating telomere length are found to be enriched in pleiotropic variants. Pleiotropic gene candidates are frequently linked to transcriptional programs that regulate hematopoiesis and define progenitor cell states of immune system development. Perturbation of the myeloid lineage is indicated by pleiotropic associations with defined master regulators and cell alterations. Eosinophil count is inversely associated with cancer risk. A high frequency of pleiotropic associations is also centered on the regulation of small noncoding Y-RNAs. Predicted pleiotropic Y-RNAs show specific regulatory marks and are overabundant in the normal tissue and blood of cancer patients. Analysis of plasma small RNAs in women who developed breast cancer indicates there is an overabundance of Y-RNA preceding neoplasm diagnosis. CONCLUSIONS This study reveals extensive pleiotropism between blood traits and cancer risk. Pleiotropism is linked to factors and processes involved in hematopoietic development and immune system function, including components of the major histocompatibility complexes, and regulators of telomere length and myeloid lineage. Deregulation of Y-RNAs is also associated with pleiotropism. Overexpression of these elements might indicate increased cancer risk.
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Affiliation(s)
- Miguel Angel Pardo-Cea
- ProCURE, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, 08908, Barcelona, Catalonia, Spain
| | - Xavier Farré
- Genomes for Life - GCAT Lab Group, Institut Germans Trias i Pujol (IGTP), Badalona, 08916, Barcelona, Catalonia, Spain
| | - Anna Esteve
- Badalona Applied Research Group in Oncology (B-ARGO), Catalan Institute of Oncology, Institut Germans Trias i Pujol (IGTP), Badalona, 08916, Barcelona, Catalonia, Spain
| | - Joanna Palade
- Cancer and Cell Biology, Translational Genomics Research Institute (TGen), Arizona, Phoenix, AZ, 85004, USA
| | - Roderic Espín
- ProCURE, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, 08908, Barcelona, Catalonia, Spain
| | - Francesca Mateo
- ProCURE, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, 08908, Barcelona, Catalonia, Spain
| | - Eric Alsop
- Cancer and Cell Biology, Translational Genomics Research Institute (TGen), Arizona, Phoenix, AZ, 85004, USA
| | - Marc Alorda
- ProCURE, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, 08908, Barcelona, Catalonia, Spain
| | - Natalia Blay
- Genomes for Life - GCAT Lab Group, Institut Germans Trias i Pujol (IGTP), Badalona, 08916, Barcelona, Catalonia, Spain
| | - Alexandra Baiges
- ProCURE, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, 08908, Barcelona, Catalonia, Spain
| | - Arzoo Shabbir
- ProCURE, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, 08908, Barcelona, Catalonia, Spain
| | - Francesc Comellas
- Department of Mathematics, Technical University of Catalonia, Castelldefels, 08860, Barcelona, Catalonia, Spain
| | - Antonio Gómez
- Department of Biosciences, Faculty of Sciences and Technology (FCT), University of Vic - Central University of Catalonia (UVic-UCC), Vic, 08500, Barcelona, Catalonia, Spain
| | - Montserrat Arnan
- Department of Hematology, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, 08908, Barcelona, Catalonia, Spain
| | - Alex Teulé
- Hereditary Cancer Program, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, 08908, Barcelona, Catalonia, Spain
| | - Monica Salinas
- Hereditary Cancer Program, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, 08908, Barcelona, Catalonia, Spain
| | - Laura Berrocal
- OncoGir, Catalan Institute of Oncology, Girona Biomedical Research Institute (IDIBGI), 17190, Salt, Catalonia, Spain
| | - Joan Brunet
- Hereditary Cancer Program, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, 08908, Barcelona, Catalonia, Spain
- OncoGir, Catalan Institute of Oncology, Girona Biomedical Research Institute (IDIBGI), 17190, Salt, Catalonia, Spain
- Biomedical Research Network Centre in Cancer (CIBERONC), Instituto de Salud Carlos III, 28222, Madrid, Spain
| | - Paula Rofes
- Hereditary Cancer Program, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, 08908, Barcelona, Catalonia, Spain
- Biomedical Research Network Centre in Cancer (CIBERONC), Instituto de Salud Carlos III, 28222, Madrid, Spain
| | - Conxi Lázaro
- Hereditary Cancer Program, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, 08908, Barcelona, Catalonia, Spain
- Biomedical Research Network Centre in Cancer (CIBERONC), Instituto de Salud Carlos III, 28222, Madrid, Spain
| | - Miquel Conesa
- Department of Pathology and Experimental Therapies, University of Barcelona (UB), Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, 08908, Barcelona, Catalonia, Spain
| | - Juan Jose Rojas
- Department of Pathology and Experimental Therapies, University of Barcelona (UB), Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, 08908, Barcelona, Catalonia, Spain
| | - Lars Velten
- Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology (BIST), 08003, Barcelona, Spain
- University Pompeu Fabra (UPF), 08002, Barcelona, Spain
| | - Wojciech Fendler
- Department of Biostatistics and Translational Medicine, Medical University of Lodz, 92-215, Lodz, Poland
| | - Urszula Smyczynska
- Department of Biostatistics and Translational Medicine, Medical University of Lodz, 92-215, Lodz, Poland
| | - Dipanjan Chowdhury
- Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA, 02115, USA
- Center for BRCA and Related Genes, Dana-Farber Cancer Institute, Boston, MA, 02115, USA
- Harvard Medical School, Boston, MA, 02115, USA
| | - Yong Zeng
- Princess Margaret Cancer Center, University Health Network, Toronto, ON, M5G 2C4, Canada
| | - Housheng Hansen He
- Princess Margaret Cancer Center, University Health Network, Toronto, ON, M5G 2C4, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, ON, M5G 1L7, Canada
| | - Rong Li
- Department of Biochemistry and Molecular Medicine, School of Medicine and Health Sciences, The George Washington University, Washington, DC, 20052, USA
| | - Kendall Van Keuren-Jensen
- Cancer and Cell Biology, Translational Genomics Research Institute (TGen), Arizona, Phoenix, AZ, 85004, USA.
| | - Rafael de Cid
- Genomes for Life - GCAT Lab Group, Institut Germans Trias i Pujol (IGTP), Badalona, 08916, Barcelona, Catalonia, Spain.
| | - Miquel Angel Pujana
- ProCURE, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, 08908, Barcelona, Catalonia, Spain.
- Biomedical Research Network Centre in Respiratory Diseases (CIBERES), Instituto de Salud Carlos III, 28222, Madrid, Spain.
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Stuckey R, Bilbao-Sieyro C, Segura-Díaz A, Gómez-Casares MT. Molecular Studies for the Early Detection of Philadelphia-Negative Myeloproliferative Neoplasms. Int J Mol Sci 2023; 24:12700. [PMID: 37628880 PMCID: PMC10454334 DOI: 10.3390/ijms241612700] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2023] [Revised: 08/07/2023] [Accepted: 08/09/2023] [Indexed: 08/27/2023] Open
Abstract
JAK2 V617F is the predominant driver mutation in patients with Philadelphia-negative myeloproliferative neoplasms (MPN). JAK2 mutations are also frequent in clonal hematopoiesis of indeterminate potential (CHIP) in otherwise "healthy" individuals. However, the period between mutation acquisition and MPN diagnosis (known as latency) varies widely between individuals, with JAK2 mutations detectable several decades before diagnosis and even from birth in some individuals. Here, we will review the current evidence on the biological factors, such as additional mutations and chronic inflammation, which influence clonal expansion and may determine why some JAK2-mutated individuals will progress to an overt neoplasm during their lifetime while others will not. We will also introduce several germline variants that predispose individuals to CHIP (as well as MPN) identified from genome-wide association studies. Finally, we will explore possible mutation screening or interventions that could help to minimize MPN-associated cardiovascular complications or even delay malignant progression.
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Affiliation(s)
- Ruth Stuckey
- Hematology Department, Hospital Universitario de Gran Canaria Dr. Negrín, 35019 Las Palmas de Gran Canaria, Spain; (R.S.); (C.B.-S.); (A.S.-D.)
| | - Cristina Bilbao-Sieyro
- Hematology Department, Hospital Universitario de Gran Canaria Dr. Negrín, 35019 Las Palmas de Gran Canaria, Spain; (R.S.); (C.B.-S.); (A.S.-D.)
- Morphology Department, Universidad de Las Palmas de Gran Canaria, 35016 Las Palmas de Gran Canaria, Spain
| | - Adrián Segura-Díaz
- Hematology Department, Hospital Universitario de Gran Canaria Dr. Negrín, 35019 Las Palmas de Gran Canaria, Spain; (R.S.); (C.B.-S.); (A.S.-D.)
| | - María Teresa Gómez-Casares
- Hematology Department, Hospital Universitario de Gran Canaria Dr. Negrín, 35019 Las Palmas de Gran Canaria, Spain; (R.S.); (C.B.-S.); (A.S.-D.)
- Department of Medical Sciences, Universidad de Las Palmas de Gran Canaria, 35016 Las Palmas de Gran Canaria, Spain
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Chen Z, Lau KS. Advances in Mapping Tumor Progression from Precancer Atlases. Cancer Prev Res (Phila) 2023; 16:439-447. [PMID: 37167978 PMCID: PMC10523872 DOI: 10.1158/1940-6207.capr-22-0473] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Revised: 03/22/2023] [Accepted: 04/11/2023] [Indexed: 05/13/2023]
Abstract
Tissue profiling technologies present opportunities for understanding transition from precancerous lesions to malignancy, which may impact risk stratification, prevention, and even cancer treatment. A human precancer atlas building effort is ongoing to tackle the significant challenge of decoding the heterogeneity among cells, specimens, and patients. Here, we discuss the findings resulting from atlases built across precancer types, including those found in colon, breast, lung, stomach, cervix, and skin, using bulk, single-cell, and spatial profiling strategies. We highlight two main themes that emerge across precancer types: the ordering of molecular events that occur during tumor progression and the fluctuation of microenvironmental response during precancer progression. We further highlight the key challenges of data integration across large cohorts of patients, and the need for computational tools to reliably annotate and quality control high-volume, high-dimensional data.
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Affiliation(s)
- Zhengyi Chen
- Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN, USA
- Program in Chemical and Physical Biology, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Ken S. Lau
- Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN, USA
- Program in Chemical and Physical Biology, Vanderbilt University School of Medicine, Nashville, TN, USA
- Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN, USA
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9
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Konig S, Strobel H, Grunert M, Lyszkiewicz M, Brühl O, Karpel-Massler G, Ziętara N, La Ferla-Brühl K, Siegelin MD, Debatin KM, Westhoff MA. Unblinding the watchmaker: cancer treatment and drug design in the face of evolutionary pressure. Expert Opin Drug Discov 2022; 17:1081-1094. [PMID: 35997138 DOI: 10.1080/17460441.2022.2114454] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
INTRODUCTION Death due to cancer is mostly associated with therapy ineffectiveness, i.e. tumor cells no longer responding to treatment. The underlying dynamics that facilitate this mutational escape from selective pressure are well studied in several other fields and several interesting approaches exist to combat this phenomenon, for example in the context of antibiotic-resistance in bacteria. AREAS COVERED Ninety percent of all cancer-related deaths are associated with treatment failure. Here, we discuss the common treatment modalities and prior attempts to overcome acquired resistance to therapy. The underlying molecular mechanisms are discussed and the implications of emerging resistance in other systems, such as bacteria, are discussed in the context of cancer. EXPERT OPINION Reevaluating emerging therapy resistance in tumors as an evolutionary mechanism to survive in a rapidly and drastically altering fitness landscape leads to novel treatment strategies and distinct requirements for new drugs. Here, we propose a scheme of considerations that need to be applied prior to the discovery of novel therapeutic drugs.
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Affiliation(s)
- Sophia Konig
- Department of Pediatrics and Adolescent Medicine, Ulm University Hospital, Ulm, Germany
| | - Hannah Strobel
- Department of Pediatrics and Adolescent Medicine, Ulm University Hospital, Ulm, Germany
| | - Michael Grunert
- Department of Nuclear Medicine, German Armed Forces Hospital of Ulm, Ulm, Germany
| | - Marcin Lyszkiewicz
- Department of Pediatrics and Adolescent Medicine, Ulm University Hospital, Ulm, Germany
| | - Oliver Brühl
- Laboratorio Analisi Sicilia, Catania, Lentini, Italy
| | | | - Natalia Ziętara
- Cancer Immunology and Immune Modulation, Boehringer Ingelheim Pharma GmbH & Co. KG, Germany
| | | | - Markus D Siegelin
- Department of Pathology and Cell Biology, Columbia University Medical Center, Albany, NY, USA
| | - Klaus-Michael Debatin
- Department of Pediatrics and Adolescent Medicine, Ulm University Hospital, Ulm, Germany
| | - Mike-Andrew Westhoff
- Department of Pediatrics and Adolescent Medicine, Ulm University Hospital, Ulm, Germany
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10
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Olive GN, Yang IA, Marshall H, Bowman RV, Fong KM. More than meets the eye. Eur Respir J 2022; 60:60/3/2200763. [PMID: 36109046 DOI: 10.1183/13993003.00763-2022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Accepted: 04/27/2022] [Indexed: 11/05/2022]
Affiliation(s)
- Gerard N Olive
- Thoracic Medicine, The Prince Charles Hospital, Brisbane, Australia.,UQ Thoracic Research Centre, Faculty of Medicine, The University of Queensland, Brisbane, Australia
| | - Ian A Yang
- Thoracic Medicine, The Prince Charles Hospital, Brisbane, Australia.,UQ Thoracic Research Centre, Faculty of Medicine, The University of Queensland, Brisbane, Australia
| | - Henry Marshall
- Thoracic Medicine, The Prince Charles Hospital, Brisbane, Australia.,UQ Thoracic Research Centre, Faculty of Medicine, The University of Queensland, Brisbane, Australia
| | - Rayleen V Bowman
- Thoracic Medicine, The Prince Charles Hospital, Brisbane, Australia.,UQ Thoracic Research Centre, Faculty of Medicine, The University of Queensland, Brisbane, Australia
| | - Kwun M Fong
- Thoracic Medicine, The Prince Charles Hospital, Brisbane, Australia .,UQ Thoracic Research Centre, Faculty of Medicine, The University of Queensland, Brisbane, Australia
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11
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Mai H, Rong Z, Zhao S, Cai R, Steinke H, Bechmann I, Ertürk A. Scalable tissue labeling and clearing of intact human organs. Nat Protoc 2022; 17:2188-2215. [PMID: 35859136 DOI: 10.1038/s41596-022-00712-8] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Accepted: 04/05/2022] [Indexed: 11/09/2022]
Abstract
Advances in tissue labeling and clearing methods include improvement of tissue transparency, better preservation of fluorescence signal, compatibility with immunostaining and large sample volumes. However, as existing methods share the common limitation that they can only be applied to human tissue slices, rendering intact human organs transparent remains a challenge. Here, we describe experimental details of the small-micelle-mediated human organ efficient clearing and labeling (SHANEL) pipeline, which can be applied for cellular mapping of intact human organs. We have successfully cleared multiple human organs, including kidney, pancreas, heart, lung, spleen and brain, as well as hard tissue like skull. We also describe an advanced volumetric imaging system using a commercial light-sheet fluorescence microscope that can accommodate most human organs and a pipeline for whole-organ imaging and visualization. The complete experimental process of labeling and clearing whole human organs takes months and the analysis process takes several weeks, depending on the organ types and sizes.
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Affiliation(s)
- Hongcheng Mai
- Institute for Tissue Engineering and Regenerative Medicine (iTERM), Helmholtz Center, Neuherberg, Munich, Germany.,Institute for Stroke and Dementia Research, University Hospital, Ludwig-Maximilians University Munich, Munich, Germany.,Munich Medical Research School (MMRS), Ludwig-Maximilians University Munich, Munich, Germany
| | - Zhouyi Rong
- Institute for Tissue Engineering and Regenerative Medicine (iTERM), Helmholtz Center, Neuherberg, Munich, Germany.,Institute for Stroke and Dementia Research, University Hospital, Ludwig-Maximilians University Munich, Munich, Germany.,Munich Medical Research School (MMRS), Ludwig-Maximilians University Munich, Munich, Germany
| | - Shan Zhao
- Institute for Tissue Engineering and Regenerative Medicine (iTERM), Helmholtz Center, Neuherberg, Munich, Germany.,Institute for Stroke and Dementia Research, University Hospital, Ludwig-Maximilians University Munich, Munich, Germany.,Munich Medical Research School (MMRS), Ludwig-Maximilians University Munich, Munich, Germany
| | - Ruiyao Cai
- Institute for Tissue Engineering and Regenerative Medicine (iTERM), Helmholtz Center, Neuherberg, Munich, Germany.,Institute for Stroke and Dementia Research, University Hospital, Ludwig-Maximilians University Munich, Munich, Germany
| | - Hanno Steinke
- Institute of Anatomy, University of Leipzig, Leipzig, Germany
| | - Ingo Bechmann
- Institute of Anatomy, University of Leipzig, Leipzig, Germany
| | - Ali Ertürk
- Institute for Tissue Engineering and Regenerative Medicine (iTERM), Helmholtz Center, Neuherberg, Munich, Germany. .,Institute for Stroke and Dementia Research, University Hospital, Ludwig-Maximilians University Munich, Munich, Germany. .,Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
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12
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Nevedomskaya E, Haendler B. From Omics to Multi-Omics Approaches for In-Depth Analysis of the Molecular Mechanisms of Prostate Cancer. Int J Mol Sci 2022; 23:6281. [PMID: 35682963 PMCID: PMC9181488 DOI: 10.3390/ijms23116281] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Revised: 05/24/2022] [Accepted: 06/01/2022] [Indexed: 02/01/2023] Open
Abstract
Cancer arises following alterations at different cellular levels, including genetic and epigenetic modifications, transcription and translation dysregulation, as well as metabolic variations. High-throughput omics technologies that allow one to identify and quantify processes involved in these changes are now available and have been instrumental in generating a wealth of steadily increasing data from patient tumors, liquid biopsies, and from tumor models. Extensive investigation and integration of these data have led to new biological insights into the origin and development of multiple cancer types and helped to unravel the molecular networks underlying this complex pathology. The comprehensive and quantitative analysis of a molecule class in a biological sample is named omics and large-scale omics studies addressing different prostate cancer stages have been performed in recent years. Prostate tumors represent the second leading cancer type and a prevalent cause of cancer death in men worldwide. It is a very heterogenous disease so that evaluating inter- and intra-tumor differences will be essential for a precise insight into disease development and plasticity, but also for the development of personalized therapies. There is ample evidence for the key role of the androgen receptor, a steroid hormone-activated transcription factor, in driving early and late stages of the disease, and this led to the development and approval of drugs addressing diverse targets along this pathway. Early genomic and transcriptomic studies have allowed one to determine the genes involved in prostate cancer and regulated by androgen signaling or other tumor-relevant signaling pathways. More recently, they have been supplemented by epigenomic, cistromic, proteomic and metabolomic analyses, thus, increasing our knowledge on the intricate mechanisms involved, the various levels of regulation and their interplay. The comprehensive investigation of these omics approaches and their integration into multi-omics analyses have led to a much deeper understanding of the molecular pathways involved in prostate cancer progression, and in response and resistance to therapies. This brings the hope that novel vulnerabilities will be identified, that existing therapies will be more beneficial by targeting the patient population likely to respond best, and that bespoke treatments with increased efficacy will be available soon.
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Affiliation(s)
| | - Bernard Haendler
- Research and Early Development, Pharmaceuticals, Bayer AG, Müllerstr. 178, 13353 Berlin, Germany;
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13
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Abstract
This overview of the molecular pathology of lung cancer includes a review of the most salient molecular alterations of the genome, transcriptome, and the epigenome. The insights provided by the growing use of next-generation sequencing (NGS) in lung cancer will be discussed, and interrelated concepts such as intertumor heterogeneity, intratumor heterogeneity, tumor mutational burden, and the advent of liquid biopsy will be explored. Moreover, this work describes how the evolving field of molecular pathology refines the understanding of different histologic phenotypes of non-small-cell lung cancer (NSCLC) and the underlying biology of small-cell lung cancer. This review will provide an appreciation for how ongoing scientific findings and technologic advances in molecular pathology are crucial for development of biomarkers, therapeutic agents, clinical trials, and ultimately improved patient care.
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Affiliation(s)
- James J Saller
- Departments of Pathology and Thoracic Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, USA
| | - Theresa A Boyle
- Departments of Pathology and Thoracic Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, USA
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14
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Marino N, German R, Podicheti R, Rockey P, Sandusky GE, Temm CJ, Nakshatri H, Addison RJ, Selman B, Althouse SK, Storniolo AMV. FAM83A is a potential biomarker for breast cancer initiation. Biomark Res 2022; 10:8. [PMID: 35183258 PMCID: PMC8858535 DOI: 10.1186/s40364-022-00353-9] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Accepted: 01/31/2022] [Indexed: 11/10/2022] Open
Abstract
Background Family with sequence similarity 83 member A (FAM83A) presents oncogenic properties in several cancers including breast cancer. Recently, we reported FAM83A overexpression in normal breast tissues from women at high risk of breast cancer. We now hypothesize that FAM83A is a key factor in breast cancer initiation. Methods Immunohistochemical staining was used to evaluate FAM83A protein levels in both a normal breast tissue microarray (TMA, N = 411) and a breast tumor TMA (N = 349). EGFR staining and its correlation with FAM83A expression were also assessed. Lentivirus-mediated manipulation of FAM83A expression in primary and hTERT-immortalized breast epithelial cells was employed. Biological and molecular alterations upon FAM83A overexpression/downregulation and FAM83A’s interaction partners were investigated. Results TMA analysis revealed a 1.5-fold increase in FAM83A expression level in breast cancer cases as compared with normal breast tissues (p < 0.0001). FAM83A protein expression was directly correlated with EGFR level in both normal and breast cancer tissues. In in vitro assays, exogenous expression of FAM83A in either primary or immortalized breast epithelial cells promoted cell viability and proliferation. Additionally, Ingenuity Pathway Analysis (IPA) revealed that FAM83A overexpression in primary cells affected the expression of genes involved in cellular morphology and metabolism. Mass spectrometry analysis identified DDX3X and LAMB3 as potential FAM83A interaction partners in primary cells, while we detected FAM83A interaction with cytoskeleton reorganization factors, including LIMA1, MYH10, PLEC, MYL6 in the immortalized cells. Conclusions This study shows that FAM83A promotes metabolic activation in primary breast epithelial cells and cell proliferation in both primary and immortalized cells. These findings support its role in early breast oncogenesis. Supplementary Information The online version contains supplementary material available at 10.1186/s40364-022-00353-9.
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15
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Radtke AJ, Chu CJ, Yaniv Z, Yao L, Marr J, Beuschel RT, Ichise H, Gola A, Kabat J, Lowekamp B, Speranza E, Croteau J, Thakur N, Jonigk D, Davis JL, Hernandez JM, Germain RN. IBEX: an iterative immunolabeling and chemical bleaching method for high-content imaging of diverse tissues. Nat Protoc 2022; 17:378-401. [PMID: 35022622 DOI: 10.1038/s41596-021-00644-9] [Citation(s) in RCA: 69] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Accepted: 10/05/2021] [Indexed: 01/02/2023]
Abstract
High-content imaging is needed to catalog the variety of cellular phenotypes and multicellular ecosystems present in metazoan tissues. We recently developed iterative bleaching extends multiplexity (IBEX), an iterative immunolabeling and chemical bleaching method that enables multiplexed imaging (>65 parameters) in diverse tissues, including human organs relevant for international consortia efforts. IBEX is compatible with >250 commercially available antibodies and 16 unique fluorophores, and can be easily adopted to different imaging platforms using slides and nonproprietary imaging chambers. The overall protocol consists of iterative cycles of antibody labeling, imaging and chemical bleaching that can be completed at relatively low cost in 2-5 d by biologists with basic laboratory skills. To support widespread adoption, we provide extensive details on tissue processing, curated lists of validated antibodies and tissue-specific panels for multiplex imaging. Furthermore, instructions are included on how to automate the method using competitively priced instruments and reagents. Finally, we present a software solution for image alignment that can be executed by individuals without programming experience using open-source software and freeware. In summary, IBEX is a noncommercial method that can be readily implemented by academic laboratories and scaled to achieve high-content mapping of diverse tissues in support of a Human Reference Atlas or other such applications.
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Affiliation(s)
- Andrea J Radtke
- Center for Advanced Tissue Imaging, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
| | - Colin J Chu
- Lymphocyte Biology Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
- Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
| | - Ziv Yaniv
- Bioinformatics and Computational Bioscience Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Li Yao
- Howard Hughes Medical Institute, Chevy Chase, MD, USA
| | - James Marr
- Leica Microsystems Inc., Wetzlar, Germany
| | - Rebecca T Beuschel
- Center for Advanced Tissue Imaging, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Hiroshi Ichise
- Lymphocyte Biology Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Anita Gola
- Lymphocyte Biology Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
- Howard Hughes Medical Institute, Robin Neustein Laboratory of Mammalian Cell Biology and Development, The Rockefeller University, New York, NY, USA
| | - Juraj Kabat
- Biological Imaging Section, Research Technologies Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Bradley Lowekamp
- Bioinformatics and Computational Bioscience Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Emily Speranza
- Lymphocyte Biology Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
- Innate Immunity and Pathogenesis Section, Laboratory of Virology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT, USA
| | - Joshua Croteau
- Department of Business Development, BioLegend, Inc, San Diego, CA, USA
| | - Nishant Thakur
- Lymphocyte Biology Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Danny Jonigk
- Institute of Pathology, Hannover Medical School, Member of the German Center for Lung Research (DZL), Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Hannover, Germany
| | - Jeremy L Davis
- Surgical Oncology Program, Metastasis Biology Section, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Jonathan M Hernandez
- Surgical Oncology Program, Metastasis Biology Section, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Ronald N Germain
- Center for Advanced Tissue Imaging, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
- Lymphocyte Biology Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
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16
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Neinavaie F, Ibrahim-Hashim A, Kramer AM, Brown JS, Richards CL. The Genomic Processes of Biological Invasions: From Invasive Species to Cancer Metastases and Back Again. Front Ecol Evol 2021. [DOI: 10.3389/fevo.2021.681100] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
The concept of invasion is useful across a broad range of contexts, spanning from the fine scale landscape of cancer tumors up to the broader landscape of ecosystems. Invasion biology provides extraordinary opportunities for studying the mechanistic basis of contemporary evolution at the molecular level. Although the field of invasion genetics was established in ecology and evolution more than 50 years ago, there is still a limited understanding of how genomic level processes translate into invasive phenotypes across different taxa in response to complex environmental conditions. This is largely because the study of most invasive species is limited by information about complex genome level processes. We lack good reference genomes for most species. Rigorous studies to examine genomic processes are generally too costly. On the contrary, cancer studies are fortified with extensive resources for studying genome level dynamics and the interactions among genetic and non-genetic mechanisms. Extensive analysis of primary tumors and metastatic samples have revealed the importance of several genomic mechanisms including higher mutation rates, specific types of mutations, aneuploidy or whole genome doubling and non-genetic effects. Metastatic sites can be directly compared to primary tumor cell counterparts. At the same time, clonal dynamics shape the genomics and evolution of metastatic cancers. Clonal diversity varies by cancer type, and the tumors’ donor and recipient tissues. Still, the cancer research community has been unable to identify any common events that provide a universal predictor of “metastatic potential” which parallels findings in evolutionary ecology. Instead, invasion in cancer studies depends strongly on context, including order of events and clonal composition. The detailed studies of the behavior of a variety of human cancers promises to inform our understanding of genome level dynamics in the diversity of invasive species and provide novel insights for management.
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17
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Lee KJ, Janda M, Stark MS, Sturm RA, Soyer HP. On Naevi and Melanomas: Two Sides of the Same Coin? Front Med (Lausanne) 2021; 8:635316. [PMID: 33681261 PMCID: PMC7933521 DOI: 10.3389/fmed.2021.635316] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Accepted: 02/01/2021] [Indexed: 12/13/2022] Open
Abstract
Benign naevi are closely linked to melanoma, as risk factors, simulators, or sites of melanoma formation. There is a heavy genetic overlap between the two lesions, a shared environmental influence of ultraviolet radiation, and many similar cellular features, yet naevi remain locally situated while melanomas spread from their primary site and may progress systemically to distal organs. Untangling the overlapping contributors and predictors of naevi and melanoma is an ongoing area of research and should eventually lead to more personalized prevention and treatment strategies, through the development of melanoma risk stratification tools and early detection of evolving melanomas. This will be achieved through a range of complementary strategies: risk-adjusted primary prevention counseling; the use of lesion imaging technologies such as sequential 3D total body photography and consumer-performed lesion imaging; artificial intelligence deep phenotyping and clinical assistance; a better understanding of genetic drivers of malignancy, risk variants, clinical genetics, and polygenic effects; and the interplay between genetics, phenotype and the environment.
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Affiliation(s)
- Katie J Lee
- Dermatology Research Centre, The University of Queensland Diamantina Institute, The University of Queensland, Brisbane, QLD, Australia
| | - Monika Janda
- Centre for Health Services Research, The University of Queensland, Brisbane, QLD, Australia
| | - Mitchell S Stark
- Dermatology Research Centre, The University of Queensland Diamantina Institute, The University of Queensland, Brisbane, QLD, Australia
| | - Richard A Sturm
- Dermatology Research Centre, The University of Queensland Diamantina Institute, The University of Queensland, Brisbane, QLD, Australia
| | - H Peter Soyer
- Dermatology Research Centre, The University of Queensland Diamantina Institute, The University of Queensland, Brisbane, QLD, Australia.,Department of Dermatology, Princess Alexandra Hospital, Brisbane, QLD, Australia
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18
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Kalinke L, Thakrar R, Janes SM. The promises and challenges of early non-small cell lung cancer detection: patient perceptions, low-dose CT screening, bronchoscopy and biomarkers. Mol Oncol 2020; 15:2544-2564. [PMID: 33252175 PMCID: PMC8486568 DOI: 10.1002/1878-0261.12864] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Revised: 11/04/2020] [Accepted: 11/26/2020] [Indexed: 12/14/2022] Open
Abstract
Lung cancer survival statistics are sobering with survival ranking among the poorest of all cancers despite the addition of targeted therapies and immunotherapies. However, improvements in tools for early detection hold promise. The Nederlands–Leuvens Longkanker Screenings Onderzoek (NELSON) trial recently corroborated the findings from the previous National Lung Screening Trial low‐dose Computerised Tomography (NLST) screening trial in reducing lung cancer mortality. Biomarker research and development is increasing at pace as the molecular life histories of lung cancers become further unravelled. Low‐dose CT screening (LDCT) is effective but targets only those at the highest risk and is burdensome on healthcare. An optimally designed CT screening programme at best will only detect a low proportion of overall lung cancers as only those at very high‐risk meet screening criteria. Biomarkers that help risk stratify suitable patients for LDCT screening, and those that assist in determining which LDCT detected nodules are likely to represent malignant disease are needed. Some biomarkers have been proposed as standalone lung cancer diagnosis tools. Bronchoscopy technology is improving, with better capacity to identify and obtain samples from early lung cancers. Clinicians need to be aware of each early lung cancer detection method’s inherent limitations. We anticipate that the future of early lung cancer diagnosis will involve a synergistic, multimodal approach, combining several early detection methods.
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Affiliation(s)
- Lukas Kalinke
- Lungs for Living Research Centre, University College London, UK
| | - Ricky Thakrar
- Lungs for Living Research Centre, University College London, UK
| | - Sam M Janes
- Lungs for Living Research Centre, University College London, UK
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19
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The 4-NQO mouse model: An update on a well-established in vivo model of oral carcinogenesis. Methods Cell Biol 2020; 163:197-229. [PMID: 33785166 DOI: 10.1016/bs.mcb.2020.09.004] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The early detection and management of oral premalignant lesions (OPMDs) improve their outcomes. Animal models that mimic histological and biological processes of human oral carcinogenesis may help to improve the identification of OPMD at-risk of progression into oral squamous cell carcinoma and to develop preventive strategies for the entire field of cancerization. No animal model is perfectly applicable for investigating human oral carcinogenesis. However, the 4-nitroquinoline 1-oxide (4-NQO) mouse model is well established and mimics several morphological, histological, genomic and molecular features of human oral carcinogenesis. Some of the reasons for the success of this model include its reproducible experimental conditions with limited variation, the possibility of realizing longitudinal studies with invasive intervention or gene manipulation, and sample availability for all stages of oral carcinogenesis, especially premalignant lesions. Moreover, the role of histological and molecular alterations in the field of cancerization (i.e., macroscopically healthy mucosa exposed to a carcinogen) during oral carcinogenesis can be easily explored using this model. In this review, we discuss the advantages and drawbacks of this model for studying human oral carcinogenesis. In summary, the 4-NQO-induced murine oral cancer model is relevant for investigating human oral carcinogenesis, including the immune microenvironment, and for evaluating therapeutic and chemoprevention agents.
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20
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Lim RJ, Liu B, Krysan K, Dubinett SM. Lung Cancer and Immunity Markers. Cancer Epidemiol Biomarkers Prev 2020; 29:2423-2430. [PMID: 32856614 DOI: 10.1158/1055-9965.epi-20-0716] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Revised: 08/01/2020] [Accepted: 08/03/2020] [Indexed: 12/17/2022] Open
Abstract
An in-depth understanding of lung cancer biology and mechanisms of tumor progression has facilitated significant advances in the treatment of lung cancer. There remains a pressing need for the development of innovative approaches to detect and intercept lung cancer at its earliest stage of development. Recent advances in genomics, computational biology, and innovative technologies offer unique opportunities to identify the immune landscape in the tumor microenvironment associated with early-stage lung carcinogenesis, and provide further insight in the mechanism of lung cancer evolution. This review will highlight the concept of immunoediting and focus on recent studies assessing immune changes and biomarkers in pulmonary premalignancy and early-stage non-small cell lung cancer. A protumor immune response hallmarked by an increase in checkpoint inhibition and inhibitory immune cells and a simultaneous reduction in antitumor immune response have been correlated with tumor progression. The potential systemic biomarkers associated with early lung cancer will be highlighted along with current clinical efforts for lung cancer interception. Research focusing on the development of novel strategies for cancer interception prior to the progression to advanced stages will potentially lead to a paradigm shift in the treatment of lung cancer and have a major impact on clinical outcomes.See all articles in this CEBP Focus section, "NCI Early Detection Research Network: Making Cancer Detection Possible."
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Affiliation(s)
- Raymond J Lim
- Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California.,Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, California
| | - Bin Liu
- Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California
| | - Kostyantyn Krysan
- Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California.,Department of Medicine, VA Greater Los Angeles Healthcare System, Los Angeles, California
| | - Steven M Dubinett
- Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California. .,Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, California.,Department of Medicine, VA Greater Los Angeles Healthcare System, Los Angeles, California.,Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California.,Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, California
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21
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Characterizing the ecological and evolutionary dynamics of cancer. Nat Genet 2020; 52:759-767. [DOI: 10.1038/s41588-020-0668-4] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2019] [Accepted: 06/22/2020] [Indexed: 12/14/2022]
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22
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Affiliation(s)
- Christina Curtis
- Departments of Medicine and Genetics, Stanford University School of Medicine, Lorry Lokey Stem Cell Research Building, Stanford, CA 94305, USA.
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23
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Fluorescence microscopy tensor imaging representations for large-scale dataset analysis. Sci Rep 2020; 10:5632. [PMID: 32221334 PMCID: PMC7101442 DOI: 10.1038/s41598-020-62233-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Accepted: 03/10/2020] [Indexed: 12/13/2022] Open
Abstract
Understanding complex biological systems requires the system-wide characterization of cellular and molecular features. Recent advances in optical imaging technologies and chemical tissue clearing have facilitated the acquisition of whole-organ imaging datasets, but automated tools for their quantitative analysis and visualization are still lacking. We have here developed a visualization technique capable of providing whole-organ tensor imaging representations of local regional descriptors based on fluorescence data acquisition. This method enables rapid, multiscale, analysis and virtualization of large-volume, high-resolution complex biological data while generating 3D tractographic representations. Using the murine heart as a model, our method allowed us to analyze and interrogate the cardiac microvasculature and the tissue resident macrophage distribution and better infer and delineate the underlying structural network in unprecedented detail.
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