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1
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Gaynor L, Singh H, Tie G, Badarinath K, Madha S, Mancini A, Bhattacharya S, Hoshino M, de Sauvage FJ, Murata K, Jadhav U, Shivdasani RA. Crypt density and recruited enhancers underlie intestinal tumour initiation. Nature 2025:10.1038/s41586-024-08573-9. [PMID: 39778708 DOI: 10.1038/s41586-024-08573-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Accepted: 12/23/2024] [Indexed: 01/11/2025]
Abstract
Oncogenic mutations that drive colorectal cancer can be present in healthy intestines for long periods without overt consequence1,2. Mutation of Apc, the most common initiating event in conventional adenomas3, activates Wnt signalling, thus conferring fitness on mutant intestinal stem cells (ISCs)4,5. Apc mutations may occur in ISCs that arise by routine self-renewal or by dedifferentiation of their progeny. Although ISCs of these different origins are fundamentally similar6,7, it is unclear whether both generate tumours equally well in uninjured intestines. It is also unknown whether cis-regulatory elements are substantively modulated upon Wnt hyperactivation or as a feature of subsequent tumours. Here we show in two mouse models that adenomas are not an obligatory outcome of Apc deletion in either ISC source, but require proximity of mutant intestinal crypts. Reduced crypt density abrogates, and aggregation of mutant colonic crypts augments, adenoma formation. Moreover, adenoma-resident ISCs open chromatin at thousands of enhancers that are inaccessible in Apc-null ISCs that are not associated with adenomas. These cis elements explain adenoma-selective gene activity and persist, with little further expansion of the repertoire, as other oncogenic mutations accumulate. Thus, cooperativity between neighbouring mutant crypts and new accessibility at specific enhancers are key steps early in intestinal tumorigenesis.
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Affiliation(s)
- Liam Gaynor
- Department of Medical Oncology and Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA
- Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA, USA
| | - Harshabad Singh
- Department of Medical Oncology and Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Guodong Tie
- Department of Medical Oncology and Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Krithika Badarinath
- Department of Medical Oncology and Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Shariq Madha
- Department of Medical Oncology and Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Andrew Mancini
- Department of Molecular Oncology, Genentech, South San Francisco, CA, USA
| | - Swarnabh Bhattacharya
- Department of Medical Oncology and Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Mikio Hoshino
- Department of Biochemistry and Cellular Biology, National Center of Neurology and Psychiatry, Tokyo, Japan
| | | | - Kazutaka Murata
- Department of Medical Oncology and Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Unmesh Jadhav
- Department of Medical Oncology and Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Ramesh A Shivdasani
- Department of Medical Oncology and Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA.
- Department of Medicine, Harvard Medical School, Boston, MA, USA.
- Harvard Stem Cell Institute, Cambridge, MA, USA.
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2
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Sadien ID, Adler S, Mehmed S, Bailey S, Sawle A, Couturier DL, Eldridge M, Adams DJ, Kemp R, Lourenço FC, Winton DJ. Polyclonality overcomes fitness barriers in Apc-driven tumorigenesis. Nature 2024; 634:1196-1203. [PMID: 39478206 PMCID: PMC11525183 DOI: 10.1038/s41586-024-08053-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2023] [Accepted: 09/16/2024] [Indexed: 11/02/2024]
Abstract
Loss-of-function mutations in the tumour suppressor APC are an initial step in intestinal tumorigenesis1,2. APC-mutant intestinal stem cells outcompete their wild-type neighbours through the secretion of Wnt antagonists, which accelerates the fixation and subsequent rapid clonal expansion of mutants3-5. Reports of polyclonal intestinal tumours in human patients and mouse models appear at odds with this process6,7. Here we combine multicolour lineage tracing with chemical mutagenesis in mice to show that a large proportion of intestinal tumours have a multiancestral origin. Polyclonal tumours retain a structure comprising subclones with distinct Apc mutations and transcriptional states, driven predominantly by differences in KRAS and MYC signalling. These pathway-level changes are accompanied by profound differences in cancer stem cell phenotypes. Of note, these findings are confirmed by introducing an oncogenic Kras mutation that results in predominantly monoclonal tumour formation. Further, polyclonal tumours have accelerated growth dynamics, suggesting a link between polyclonality and tumour progression. Together, these findings demonstrate the role of interclonal interactions in promoting tumorigenesis through non-cell autonomous pathways that are dependent on the differential activation of oncogenic pathways between clones.
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Affiliation(s)
- Iannish D Sadien
- Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Cambridge, UK
| | - Sam Adler
- Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Cambridge, UK
| | - Shenay Mehmed
- Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Cambridge, UK
| | - Sasha Bailey
- Tumour Cell Biology Laboratory, The Francis Crick Institute, London, UK
| | - Ashley Sawle
- Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Cambridge, UK
| | | | - Matthew Eldridge
- Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Cambridge, UK
| | - David J Adams
- Wellcome Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK
| | - Richard Kemp
- Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Cambridge, UK
| | - Filipe C Lourenço
- Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Cambridge, UK
| | - Douglas J Winton
- Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Cambridge, UK.
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3
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Islam M, Yang Y, Simmons AJ, Shah VM, Musale KP, Xu Y, Tasneem N, Chen Z, Trinh LT, Molina P, Ramirez-Solano MA, Sadien ID, Dou J, Rolong A, Chen K, Magnuson MA, Rathmell JC, Macara IG, Winton DJ, Liu Q, Zafar H, Kalhor R, Church GM, Shrubsole MJ, Coffey RJ, Lau KS. Temporal recording of mammalian development and precancer. Nature 2024; 634:1187-1195. [PMID: 39478207 PMCID: PMC11525190 DOI: 10.1038/s41586-024-07954-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Accepted: 08/15/2024] [Indexed: 11/02/2024]
Abstract
Temporal ordering of cellular events offers fundamental insights into biological phenomena. Although this is traditionally achieved through continuous direct observations1,2, an alternative solution leverages irreversible genetic changes, such as naturally occurring mutations, to create indelible marks that enables retrospective temporal ordering3-5. Using a multipurpose, single-cell CRISPR platform, we developed a molecular clock approach to record the timing of cellular events and clonality in vivo, with incorporation of cell state and lineage information. Using this approach, we uncovered precise timing of tissue-specific cell expansion during mouse embryonic development, unconventional developmental relationships between cell types and new epithelial progenitor states by their unique genetic histories. Analysis of mouse adenomas, coupled to multiomic and single-cell profiling of human precancers, with clonal analysis of 418 human polyps, demonstrated the occurrence of polyclonal initiation in 15-30% of colonic precancers, showing their origins from multiple normal founders. Our study presents a multimodal framework that lays the foundation for in vivo recording, integrating synthetic or natural indelible genetic changes with single-cell analyses, to explore the origins and timing of development and tumorigenesis in mammalian systems.
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Affiliation(s)
- Mirazul Islam
- Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN, USA
- Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, USA
| | - Yilin Yang
- Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN, USA
- Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, USA
| | - Alan J Simmons
- Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN, USA
- Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, USA
| | - Vishal M Shah
- Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN, USA
- Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, USA
| | - Krushna Pavan Musale
- Department of Computer Science and Engineering, Indian Institute of Technology Kanpur, Kanpur, India
| | - Yanwen Xu
- Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN, USA
- Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, USA
| | - Naila Tasneem
- Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN, USA
- Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, USA
| | - Zhengyi Chen
- Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN, USA
- Chemical and Physical Biology Program, Vanderbilt University, Nashville, TN, USA
| | - Linh T Trinh
- Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, USA
- Vanderbilt Center for Stem Cell Biology, Vanderbilt University, Nashville, TN, USA
| | - Paola Molina
- Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, USA
| | - Marisol A Ramirez-Solano
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA
- Center for Quantitative Sciences, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Iannish D Sadien
- Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK
| | - Jinzhuang Dou
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Andrea Rolong
- Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN, USA
- Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, USA
| | - Ken Chen
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Mark A Magnuson
- Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, USA
- Vanderbilt Center for Stem Cell Biology, Vanderbilt University, Nashville, TN, USA
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA
| | - Jeffrey C Rathmell
- Vanderbilt Center for Immunobiology, Vanderbilt University Medical Center, Nashville, TN, USA
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Ian G Macara
- Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN, USA
- Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, USA
| | - Douglas J Winton
- Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK
| | - Qi Liu
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA
- Center for Quantitative Sciences, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Hamim Zafar
- Department of Computer Science and Engineering, Indian Institute of Technology Kanpur, Kanpur, India
- Department of Biological Sciences and Bioengineering, Indian Institute of Technology Kanpur, Kanpur, India
| | - Reza Kalhor
- Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - George M Church
- Department of Genetics, Harvard Medical School, Boston, MA, USA
- Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA
| | - Martha J Shrubsole
- Department of Medicine, Division of Epidemiology, Vanderbilt University Medical Center, Nashville, TN, USA
- Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Robert J Coffey
- Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN, USA.
- Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, USA.
- Vanderbilt Center for Stem Cell Biology, Vanderbilt University, Nashville, TN, USA.
- Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA.
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Center, Nashville, TN, USA.
| | - Ken S Lau
- Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN, USA.
- Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, USA.
- Chemical and Physical Biology Program, Vanderbilt University, Nashville, TN, USA.
- Vanderbilt Center for Stem Cell Biology, Vanderbilt University, Nashville, TN, USA.
- Center for Quantitative Sciences, Vanderbilt University Medical Center, Nashville, TN, USA.
- Vanderbilt Center for Immunobiology, Vanderbilt University Medical Center, Nashville, TN, USA.
- Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA.
- Department of Surgery, Vanderbilt University Medical Center, Nashville, TN, USA.
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4
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Okuno K, Ikemura K, Okamoto R, Oki K, Watanabe A, Kuroda Y, Kidachi M, Fujino S, Nie Y, Higuchi T, Chuman M, Washio M, Sakuraya M, Niihara M, Kumagai K, Sangai T, Kumamoto Y, Naitoh T, Hiki N, Yamashita K. CAF-associated genes putatively representing distinct prognosis by in silico landscape of stromal components of colon cancer. PLoS One 2024; 19:e0299827. [PMID: 38557819 PMCID: PMC10984474 DOI: 10.1371/journal.pone.0299827] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Accepted: 02/15/2024] [Indexed: 04/04/2024] Open
Abstract
Comprehensive understanding prognostic relevance of distinct tumor microenvironment (TME) remained elusive in colon cancer. In this study, we performed in silico analysis of the stromal components of primary colon cancer, with a focus on the markers of cancer-associated fibroblasts (CAF) and tumor-associated endothelia (TAE), as well as immunological infiltrates like tumor-associated myeloid cells (TAMC) and cytotoxic T lymphocytes (CTL). The relevant CAF-associated genes (CAFG)(representing R index = 0.9 or beyond with SPARC) were selected based on stroma specificity (cancer stroma/epithelia, cS/E = 10 or beyond) and expression amounts, which were largely exhibited negative prognostic impacts. CAFG were partially shared with TAE-associated genes (TAEG)(PLAT, ANXA1, and PTRF) and TAMC-associated genes (TAMCG)(NNMT), but not with CTL-associated genes (CTLG). Intriguingly, CAFG were prognostically subclassified in order of fibrosis (representing COL5A2, COL5A1, and COL12A1) followed by exclusive TAEG and TAMCG. Prognosis was independently stratified by CD8A, a CTL marker, in the context of low expression of the strongest negative prognostic CAFG, COL8A1. CTLG were comprehensively identified as IFNG, B2M, and TLR4, in the group of low S/E, representing good prognosis. Our current in silico analysis of the micro-dissected stromal gene signatures with prognostic relevance clarified comprehensive understanding of clinical features of the TME and provides deep insights of the landscape.
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Affiliation(s)
- Kota Okuno
- Division of Advanced Surgical Oncology, Research and Development Center for New Medical Frontiers, Kitasato University School of Medicine, Sagamihara, Japan
| | - Kyonosuke Ikemura
- Division of Advanced Surgical Oncology, Research and Development Center for New Medical Frontiers, Kitasato University School of Medicine, Sagamihara, Japan
| | - Riku Okamoto
- Division of Advanced Surgical Oncology, Research and Development Center for New Medical Frontiers, Kitasato University School of Medicine, Sagamihara, Japan
| | - Keiko Oki
- Division of Advanced Surgical Oncology, Research and Development Center for New Medical Frontiers, Kitasato University School of Medicine, Sagamihara, Japan
| | - Akiko Watanabe
- Division of Advanced Surgical Oncology, Research and Development Center for New Medical Frontiers, Kitasato University School of Medicine, Sagamihara, Japan
| | - Yu Kuroda
- Division of Advanced Surgical Oncology, Research and Development Center for New Medical Frontiers, Kitasato University School of Medicine, Sagamihara, Japan
| | - Mikiko Kidachi
- Division of Advanced Surgical Oncology, Research and Development Center for New Medical Frontiers, Kitasato University School of Medicine, Sagamihara, Japan
| | - Shiori Fujino
- Division of Advanced Surgical Oncology, Research and Development Center for New Medical Frontiers, Kitasato University School of Medicine, Sagamihara, Japan
| | - Yusuke Nie
- Division of Advanced Surgical Oncology, Research and Development Center for New Medical Frontiers, Kitasato University School of Medicine, Sagamihara, Japan
| | - Tadashi Higuchi
- Department of Upper Gastrointestinal Surgery, Kitasato University School of Medicine, Sagamihara, Japan
| | - Motohiro Chuman
- Department of Upper Gastrointestinal Surgery, Kitasato University School of Medicine, Sagamihara, Japan
| | - Marie Washio
- Department of Upper Gastrointestinal Surgery, Kitasato University School of Medicine, Sagamihara, Japan
| | - Mikiko Sakuraya
- Department of Upper Gastrointestinal Surgery, Kitasato University School of Medicine, Sagamihara, Japan
| | - Masahiro Niihara
- Department of Upper Gastrointestinal Surgery, Kitasato University School of Medicine, Sagamihara, Japan
| | - Koshi Kumagai
- Department of Upper Gastrointestinal Surgery, Kitasato University School of Medicine, Sagamihara, Japan
| | - Takafumi Sangai
- Department of Breast and Thyroid Surgery, Kitasato University School of Medicine, Sagamihara, Japan
| | - Yusuke Kumamoto
- Department of General-Pediatric-Hepatobiliary Pancreatic Surgery, Kitasato University School of Medicine, Sagamihara, Japan
| | - Takeshi Naitoh
- Department of Lower Gastrointestinal Surgery, Kitasato University School of Medicine, Sagamihara, Japan
| | - Naoki Hiki
- Department of Upper Gastrointestinal Surgery, Kitasato University School of Medicine, Sagamihara, Japan
| | - Keishi Yamashita
- Division of Advanced Surgical Oncology, Research and Development Center for New Medical Frontiers, Kitasato University School of Medicine, Sagamihara, Japan
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5
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Islam M, Yang Y, Simmons AJ, Shah VM, Pavan MK, Xu Y, Tasneem N, Chen Z, Trinh LT, Molina P, Ramirez-Solano MA, Sadien I, Dou J, Chen K, Magnuson MA, Rathmell JC, Macara IG, Winton D, Liu Q, Zafar H, Kalhor R, Church GM, Shrubsole MJ, Coffey RJ, Lau KS. Temporal recording of mammalian development and precancer. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.12.18.572260. [PMID: 38187699 PMCID: PMC10769302 DOI: 10.1101/2023.12.18.572260] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/09/2024]
Abstract
Key to understanding many biological phenomena is knowing the temporal ordering of cellular events, which often require continuous direct observations [1, 2]. An alternative solution involves the utilization of irreversible genetic changes, such as naturally occurring mutations, to create indelible markers that enables retrospective temporal ordering [3-8]. Using NSC-seq, a newly designed and validated multi-purpose single-cell CRISPR platform, we developed a molecular clock approach to record the timing of cellular events and clonality in vivo , while incorporating assigned cell state and lineage information. Using this approach, we uncovered precise timing of tissue-specific cell expansion during murine embryonic development and identified new intestinal epithelial progenitor states by their unique genetic histories. NSC-seq analysis of murine adenomas and single-cell multi-omic profiling of human precancers as part of the Human Tumor Atlas Network (HTAN), including 116 scRNA-seq datasets and clonal analysis of 418 human polyps, demonstrated the occurrence of polyancestral initiation in 15-30% of colonic precancers, revealing their origins from multiple normal founders. Thus, our multimodal framework augments existing single-cell analyses and lays the foundation for in vivo multimodal recording, enabling the tracking of lineage and temporal events during development and tumorigenesis.
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6
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Boland CR, Koi M, Hawn MT, Carethers JM, Yurgelun MB. Serendipity Strikes: How Pursuing Novel Hypotheses Shifted the Paradigm Regarding the Genetic Basis of Colorectal Cancer and Changed Cancer Therapy. Dig Dis Sci 2023; 68:3504-3513. [PMID: 37402979 PMCID: PMC11262588 DOI: 10.1007/s10620-023-08006-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/19/2023] [Indexed: 07/06/2023]
Abstract
In this installment of the "Paradigm Shifts in Perspective" series, the authors, all scientists who have been involved in colorectal cancer (CRC) research for most or all of their careers, have watched the field develop from early pathological descriptions of tumor formation to the current understanding of tumor pathogenesis that informs personalized therapies. We outline how our understanding of the pathogenetic basis of CRC began with seemingly isolated discoveries-initially with the mutations in RAS and the APC gene, the latter of which was initially found in the context of intestinal polyposis, to the more complex process of multistep carcinogenesis, to the chase for tumor suppressor genes, which led to the unexpected discovery of microsatellite instability (MSI). These discoveries enabled the authors to better understand how the DNA mismatch repair (MMR) system not only recognizes DNA damage but also responds to damage by DNA repair or by triggering apoptosis in the injured cell. This work served, in part, to link the earlier findings on the pathogenesis of CRC to the development of immune checkpoint inhibitors, which has been transformative-and curative-for certain types of CRCs and other cancers as well. These discoveries also highlight the circuitous routes that scientific progress takes, which can include thoughtful hypothesis testing and at other times recognizing the importance of seemingly serendipitous observations that substantially change the flow and direction of the discovery process. What has happened over the past 37 years was not predictable when this journey began, but it does speak to the power of careful scientific experimentation, following the facts, perseverance in the face of opposition, and the willingness to think outside of established paradigms.
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Affiliation(s)
| | | | - Mary T Hawn
- Department of Surgery, Stanford University School of Medicine, CJ Huang Bldg, Palo Alto, CA, 94306, USA
| | | | - Matthew B Yurgelun
- Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA
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7
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Li X, Liu D, Wang Y, Chen Y, Wang C, Lin Z, Tian L. PHF5A as a new OncoTarget and therapeutic prospects. Heliyon 2023; 9:e18010. [PMID: 37483794 PMCID: PMC10362332 DOI: 10.1016/j.heliyon.2023.e18010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Revised: 06/24/2023] [Accepted: 07/05/2023] [Indexed: 07/25/2023] Open
Abstract
PHF5A (PHD-finger domain protein 5A) is a highly conserved protein comprised of 110 amino acids that belong to PHD zinc finger proteins and is ubiquitously expressed in entire eukaryotic nuclei from yeast to man. PHF5A is an essential component of the SF3B splicing complex regulating protein-protein or protein-DNA interactions; particularly involved in pre-mRNA splicing. Besides its basic spliceosome-associated attributes encompassing the regulation of alternative splicing of specific genes, PHF5A also plays a pivotal role in cell cycle regulation and morphological development of cells along with their differentiation into particular tissues/organs, DNA damage repair, maintenance of pluripotent embryonic stem cells (CSCs) embryogenesis and regulation of chromatin-mediated transcription. Presently identification of spliceosome and non-spliceosome-associated attributes of PHF5A needs great attention based on its key involvement in the pathogenesis of cancer malignancies including the prognosis of lung adenocarcinoma, endometrial adenocarcinoma, breast, and colorectal cancer. PHF5A is an essential splicing factor or cofactor actively participating as an oncogenic protein in tumorigenesis via activation of downstream signaling pathway attributed to its regulation of dysregulated splicing or abnormal alternative splicing of targeted genes. Further, the participation of PHF5A in regulating the growth of cancer stem cells might not be ignored. The current review briefly overviews the structural and functional attributes of PHF5A along with its hitherto described role in the propagation of cancer malignancies and its future concern as a potential therapeutic target for cancer management/treatment.
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Affiliation(s)
- Xiaojiang Li
- Department of Orthopedics, Affiliated Hospital of Changchun University of Traditional Chinese Medicine, Changchun, 130000, China
| | - Dalong Liu
- Department of Orthopedics, Affiliated Hospital of Changchun University of Traditional Chinese Medicine, Changchun, 130000, China
| | - Yun Wang
- Department of Thoracic Surgery, Affiliated Hospital of Changchun University of Traditional Chinese Medicine, Changchun, 130000, China
| | - Yu Chen
- Department of Orthopedics, LiaoYuanCity TCM Hospital, LiaoYuan, 136200, China
| | - Chenyang Wang
- Department of Orthopedics, LiaoYuanCity TCM Hospital, LiaoYuan, 136200, China
| | - Zhicheng Lin
- Department of Internal Medicine, Baishan Hospital of Traditional Chinese Medicine, Baishan, 134300, China
| | - Lin Tian
- Department of Lung Oncology, Affiliated Hospital of Changchun University of Traditional Chinese Medicine, Changchun, 130000, China
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8
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Paterson C, Bozic I, Smith MJ, Hoad X, Evans DGR. A mechanistic mathematical model of initiation and malignant transformation in sporadic vestibular schwannoma. Br J Cancer 2022; 127:1843-1857. [PMID: 36097176 PMCID: PMC9643471 DOI: 10.1038/s41416-022-01955-8] [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: 10/28/2021] [Revised: 07/13/2022] [Accepted: 08/08/2022] [Indexed: 11/08/2022] Open
Abstract
BACKGROUND A vestibular schwannoma (VS) is a relatively rare, benign tumour of the eighth cranial nerve, often involving alterations to the gene NF2. Previous mathematical models of schwannoma incidence have not attempted to account for alterations in specific genes, and could not distinguish between nonsense mutations and loss of heterozygosity (LOH). METHODS Here, we present a mechanistic approach to modelling initiation and malignant transformation in schwannoma. Each parameter is associated with a specific gene or mechanism operative in Schwann cells, and can be determined by combining incidence data with empirical frequencies of pathogenic variants and LOH. RESULTS This results in new estimates for the base-pair mutation rate u = 4.48 × 10-10 and the rate of LOH = 2.03 × 10-6/yr in Schwann cells. In addition to new parameter estimates, we extend the approach to estimate the risk of both spontaneous and radiation-induced malignant transformation. DISCUSSION We conclude that radiotherapy is likely to have a negligible excess risk of malignancy for sporadic VS, with a possible exception of rapidly growing tumours.
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Affiliation(s)
- Chay Paterson
- Division of Evolution, Infection and Genomics, School of Biological Sciences, University of Manchester, Manchester, UK.
| | - Ivana Bozic
- Department of Applied Mathematics, University of Washington, Seattle, WA, USA
| | - Miriam J Smith
- Division of Evolution, Infection and Genomics, School of Biological Sciences, University of Manchester, Manchester, UK
- Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester, UK
| | - Xanthe Hoad
- Radiation Protection Group, Medical Physics, University Hospital Southampton NHS Foundation Trust, Southampton, UK
| | - D Gareth R Evans
- Division of Evolution, Infection and Genomics, School of Biological Sciences, University of Manchester, Manchester, UK
- Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester, UK
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9
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Lange S, Mogwitz R, Hünniger D, Voß-Böhme A. Modeling age-specific incidence of colon cancer via niche competition. PLoS Comput Biol 2022; 18:e1010403. [PMID: 35984850 PMCID: PMC9432715 DOI: 10.1371/journal.pcbi.1010403] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Revised: 08/31/2022] [Accepted: 07/18/2022] [Indexed: 11/23/2022] Open
Abstract
Cancer development is a multistep process often starting with a single cell in which a number of epigenetic and genetic alterations have accumulated thus transforming it into a tumor cell. The progeny of such a single benign tumor cell expands in the tissue and can at some point progress to malignant tumor cells until a detectable tumor is formed. The dynamics from the early phase of a single cell to a detectable tumor with billions of tumor cells are complex and still not fully resolved, not even for the well-known prototype of multistage carcinogenesis, the adenoma-adenocarcinoma sequence of colorectal cancer. Mathematical models of such carcinogenesis are frequently tested and calibrated based on reported age-specific incidence rates of cancer, but they usually require calibration of four or more parameters due to the wide range of processes these models aim to reflect. We present a cell-based model, which focuses on the competition between wild-type and tumor cells in colonic crypts, with which we are able reproduce epidemiological incidence rates of colon cancer. Additionally, the fraction of cancerous tumors with precancerous lesions predicted by the model agree with clinical estimates. The correspondence between model and reported data suggests that the fate of tumor development is majorly determined by the early phase of tumor growth and progression long before a tumor becomes detectable. Due to the focus on the early phase of tumor development, the model has only a single fit parameter, the time scale set by an effective replacement rate of stem cells in the crypt. We find this effective rate to be considerable smaller than the actual replacement rate, which implies that the time scale is limited by the processes succeeding clonal conversion of crypts. Cancer development is a multistep process often starting with a single cell turning into a tumor cell whose progeny growths via clonal expansion into a macroscopic tumor with billions of cells. While experimental insight exists on the cellular scale and cancer registries provide statistics on detectable tumors, the complex dynamics leading from the microscopic cellular scale to a macroscopic tumor is still not fully resolved. Models of cancer biology are commonly used to explain incidence rates but usually require the fit of several biological parameters due to the complexity of the incorporated processes. We employ a cell-based model based on the competition in colonic crypts, to reproduce epidemiological age-specific incidence rates of colon cancer. Due to the focus on the early stage of tumor development, only the time scale in the model has to be calibrated. The agreement between theoretical prediction and epidemiological observation suggests that the fate of tumor development is dominated by the early phase of tumor development long before a tumor becomes detectable.
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Affiliation(s)
- Steffen Lange
- DataMedAssist, HTW Dresden - University of Applied Sciences, Dresden, Germany
- Faculty of Informatics/Mathematics, HTW Dresden - University of Applied Sciences, Dresden, Germany
- * E-mail:
| | - Richard Mogwitz
- Faculty of Informatics/Mathematics, HTW Dresden - University of Applied Sciences, Dresden, Germany
| | - Denis Hünniger
- DataMedAssist, HTW Dresden - University of Applied Sciences, Dresden, Germany
- Faculty of Informatics/Mathematics, HTW Dresden - University of Applied Sciences, Dresden, Germany
| | - Anja Voß-Böhme
- DataMedAssist, HTW Dresden - University of Applied Sciences, Dresden, Germany
- Faculty of Informatics/Mathematics, HTW Dresden - University of Applied Sciences, Dresden, Germany
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10
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Pagano E, Elias JE, Schneditz G, Saveljeva S, Holland LM, Borrelli F, Karlsen TH, Kaser A, Kaneider NC. Activation of the GPR35 pathway drives angiogenesis in the tumour microenvironment. Gut 2022; 71:509-520. [PMID: 33758004 PMCID: PMC8862021 DOI: 10.1136/gutjnl-2020-323363] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Revised: 03/10/2021] [Accepted: 03/11/2021] [Indexed: 12/11/2022]
Abstract
OBJECTIVE Primary sclerosing cholangitis (PSC) is in 70% of cases associated with inflammatory bowel disease. The hypermorphic T108M variant of the orphan G protein-coupled receptor GPR35 increases risk for PSC and ulcerative colitis (UC), conditions strongly predisposing for inflammation-associated liver and colon cancer. Lack of GPR35 reduces tumour numbers in mouse models of spontaneous and colitis associated cancer. The tumour microenvironment substantially determines tumour growth, and tumour-associated macrophages are crucial for neovascularisation. We aim to understand the role of the GPR35 pathway in the tumour microenvironment of spontaneous and colitis-associated colon cancers. DESIGN Mice lacking GPR35 on their macrophages underwent models of spontaneous colon cancer or colitis-associated cancer. The role of tumour-associated macrophages was then assessed in biochemical and functional assays. RESULTS Here, we show that GPR35 on macrophages is a potent amplifier of tumour growth by stimulating neoangiogenesis and tumour tissue remodelling. Deletion of Gpr35 in macrophages profoundly reduces tumour growth in inflammation-associated and spontaneous tumour models caused by mutant tumour suppressor adenomatous polyposis coli. Neoangiogenesis and matrix metalloproteinase activity is promoted by GPR35 via Na/K-ATPase-dependent ion pumping and Src activation, and is selectively inhibited by a GPR35-specific pepducin. Supernatants from human inducible-pluripotent-stem-cell derived macrophages carrying the UC and PSC risk variant stimulate tube formation by enhancing the release of angiogenic factors. CONCLUSIONS Activation of the GPR35 pathway promotes tumour growth via two separate routes, by directly augmenting proliferation in epithelial cells that express the receptor, and by coordinating macrophages' ability to create a tumour-permissive environment.
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Affiliation(s)
- Ester Pagano
- Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, University of Cambridge, Cambridge, UK,Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Joshua E Elias
- Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, University of Cambridge, Cambridge, UK,Division of Gastroenterology and Hepatology, Department of Medicine, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK
| | - Georg Schneditz
- Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, University of Cambridge, Cambridge, UK,Norwegian PSC Research Center, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Svetlana Saveljeva
- Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, University of Cambridge, Cambridge, UK
| | - Lorraine M Holland
- Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, University of Cambridge, Cambridge, UK
| | - Francesca Borrelli
- Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Tom H Karlsen
- Norwegian PSC Research Center, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Arthur Kaser
- Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, University of Cambridge, Cambridge, UK,Division of Gastroenterology and Hepatology, Department of Medicine, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK
| | - Nicole C Kaneider
- Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, University of Cambridge, Cambridge, UK .,Division of Gastroenterology and Hepatology, Department of Medicine, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK
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11
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Kester L, de Barbanson B, Lyubimova A, Chen LT, van der Schrier V, Alemany A, Mooijman D, Peterson-Maduro J, Drost J, de Ridder J, van Oudenaarden A. Integration of multiple lineage measurements from the same cell reconstructs parallel tumor evolution. CELL GENOMICS 2022; 2:100096. [PMID: 36778661 PMCID: PMC9903660 DOI: 10.1016/j.xgen.2022.100096] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Revised: 05/23/2021] [Accepted: 01/19/2022] [Indexed: 12/30/2022]
Abstract
Organoid evolution models complemented with integrated single-cell sequencing technology provide a powerful platform to characterize intra-tumor heterogeneity (ITH) and tumor evolution. Here, we conduct a parallel evolution experiment to mimic the tumor evolution process by evolving a colon cancer organoid model over 100 generations, spanning 6 months in time. We use single-cell whole-genome sequencing (WGS) in combination with viral lineage tracing at 12 time points to simultaneously monitor clone size, CNV states, SNV states, and viral lineage barcodes for 1,641 single cells. We integrate these measurements to construct clonal evolution trees with high resolution. We characterize the order of events in which chromosomal aberrations occur and identify aberrations that recur multiple times within the same tumor sub-population. We observe recurrent sequential loss of chromosome 4 after loss of chromosome 18 in four unique tumor clones. SNVs and CNVs identified in our organoid experiments are also frequently reported in colorectal carcinoma samples, and out of 334 patients with chromosome 18 loss in a Memorial Sloan Kettering colorectal cancer cohort, 99 (29.6%) also harbor chromosome 4 loss. Our study reconstructs tumor evolution in a colon cancer organoid model at high resolution, demonstrating an approach to identify potentially clinically relevant genomic aberrations in tumor evolution.
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Affiliation(s)
- Lennart Kester
- Oncode Institute, Hubrecht Institute-KNAW (Royal Netherlands Academy of Arts and Sciences), 3584 CT Utrecht, the Netherlands
| | - Buys de Barbanson
- Oncode Institute, Hubrecht Institute-KNAW (Royal Netherlands Academy of Arts and Sciences), 3584 CT Utrecht, the Netherlands,Oncode Institute, Center for Molecular Medicine, University Medical Center Utrecht, 3584 CX Utrecht, the Netherlands
| | - Anna Lyubimova
- Oncode Institute, Hubrecht Institute-KNAW (Royal Netherlands Academy of Arts and Sciences), 3584 CT Utrecht, the Netherlands
| | - Li-Ting Chen
- Oncode Institute, Hubrecht Institute-KNAW (Royal Netherlands Academy of Arts and Sciences), 3584 CT Utrecht, the Netherlands,Oncode Institute, Center for Molecular Medicine, University Medical Center Utrecht, 3584 CX Utrecht, the Netherlands
| | - Valérie van der Schrier
- Oncode Institute, Hubrecht Institute-KNAW (Royal Netherlands Academy of Arts and Sciences), 3584 CT Utrecht, the Netherlands
| | - Anna Alemany
- Oncode Institute, Hubrecht Institute-KNAW (Royal Netherlands Academy of Arts and Sciences), 3584 CT Utrecht, the Netherlands
| | - Dylan Mooijman
- Oncode Institute, Hubrecht Institute-KNAW (Royal Netherlands Academy of Arts and Sciences), 3584 CT Utrecht, the Netherlands
| | - Josi Peterson-Maduro
- Oncode Institute, Hubrecht Institute-KNAW (Royal Netherlands Academy of Arts and Sciences), 3584 CT Utrecht, the Netherlands
| | - Jarno Drost
- Oncode Institute, Princess Máxima Center for Pediatric Oncology, 3584 CS Utrecht, the Netherlands
| | - Jeroen de Ridder
- Oncode Institute, Center for Molecular Medicine, University Medical Center Utrecht, 3584 CX Utrecht, the Netherlands,Corresponding author
| | - Alexander van Oudenaarden
- Oncode Institute, Hubrecht Institute-KNAW (Royal Netherlands Academy of Arts and Sciences), 3584 CT Utrecht, the Netherlands,Corresponding author
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12
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Gaiani F, Marchesi F, Negri F, Greco L, Malesci A, de’Angelis GL, Laghi L. Heterogeneity of Colorectal Cancer Progression: Molecular Gas and Brakes. Int J Mol Sci 2021; 22:ijms22105246. [PMID: 34063506 PMCID: PMC8156342 DOI: 10.3390/ijms22105246] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Revised: 05/11/2021] [Accepted: 05/13/2021] [Indexed: 02/06/2023] Open
Abstract
The review begins with molecular genetics, which hit the field unveiling the involvement of oncogenes and tumor suppressor genes in the pathogenesis of colorectal cancer (CRC) and uncovering genetic predispositions. Then the notion of molecular phenotypes with different clinical behaviors was introduced and translated in the clinical arena, paving the way to next-generation sequencing that captured previously unrecognized heterogeneity. Among other molecular regulators of CRC progression, the extent of host immune response within the tumor micro-environment has a critical position. Translational sciences deeply investigated the field, accelerating the pace toward clinical transition, due to its strong association with outcomes. While the perturbation of gut homeostasis occurring in inflammatory bowel diseases can fuel carcinogenesis, micronutrients like vitamin D and calcium can act as brakes, and we discuss underlying molecular mechanisms. Among the components of gut microbiota, Fusobacterium nucleatum is over-represented in CRC, and may worsen patient outcome. However, any translational knowledge tracing the multifaceted evolution of CRC should be interpreted according to the prognostic and predictive frame of the TNM-staging system in a perspective of clinical actionability. Eventually, we examine challenges and promises of pharmacological interventions aimed to restrain disease progression at different disease stages.
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Affiliation(s)
- Federica Gaiani
- Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy; (F.G.); (G.L.d.)
- Gastroenterology and Endoscopy Unit, University-Hospital of Parma, via Gramsci 14, 43126 Parma, Italy
| | - Federica Marchesi
- IRCCS Humanitas Research Hospital, via Manzoni 56, 20089 Rozzano, Italy; (F.M.); (A.M.)
- Department of Medical Biotechnology and Translational Medicine, University of Milan, 20132 Milan, Italy
| | - Francesca Negri
- Medical Oncology Unit, University Hospital of Parma, 43126 Parma, Italy;
| | - Luana Greco
- Laboratory of Molecular Gastroenterology, IRCCS Humanitas Research Hospital, via Manzoni 56, 20089 Rozzano, Italy;
| | - Alberto Malesci
- IRCCS Humanitas Research Hospital, via Manzoni 56, 20089 Rozzano, Italy; (F.M.); (A.M.)
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Italy
| | - Gian Luigi de’Angelis
- Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy; (F.G.); (G.L.d.)
- Gastroenterology and Endoscopy Unit, University-Hospital of Parma, via Gramsci 14, 43126 Parma, Italy
| | - Luigi Laghi
- Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy; (F.G.); (G.L.d.)
- Laboratory of Molecular Gastroenterology, IRCCS Humanitas Research Hospital, via Manzoni 56, 20089 Rozzano, Italy;
- Correspondence:
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13
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Germline genomes have a dominant-heritable contribution to cancer immune evasion and immunotherapy response. QUANTITATIVE BIOLOGY 2020. [DOI: 10.1007/s40484-020-0212-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
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14
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Signalling input from divergent pathways subverts B cell transformation. Nature 2020; 583:845-851. [PMID: 32699415 PMCID: PMC7394729 DOI: 10.1038/s41586-020-2513-4] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2019] [Accepted: 04/28/2020] [Indexed: 01/29/2023]
Abstract
Malignant transformation typically involves multiple genetic lesions whose combined activity gives rise to cancer1. Our analysis of 1,148 patient-derived B-cell leukemia (B-ALL) samples revealed that individual mutations did not promote leukemogenesis unless they converged on one single oncogenic pathway characteristic for the differentiation stage of transformed B cells. Mutations not aligned with the central oncogenic driver activated divergent pathways and subverted transformation. Oncogenic lesions in B-ALL frequently mimic cytokine receptor signaling at the pro-B cell stage (through activation of STAT5)2–4 or the pre-B cell receptor in more mature cells (through activation of ERK)5–8. STAT5- and ERK-activating lesions were frequently found but only co-occurred in ~3% of cases (P=2.2E-16). Single-cell mutation and phosphoprotein analyses revealed the segregation of oncogenic STAT5- or ERK-activation to competing clones. STAT5 and ERK engaged opposing biochemical and transcriptional programs orchestrated by MYC and BCL6, respectively. Genetic reactivation of the divergent (suppressed) pathway came at the expense of the principal oncogenic driver and reversed transformation. Conversely, deletion of divergent pathway components accelerated leukemogenesis. Thus, persistence of divergent signaling pathways represents a powerful barrier to transformation while convergence on one principal driver defines a central event in leukemia-initiation. Pharmacological reactivation of suppressed divergent circuits strongly synergized with inhibition of the principal oncogenic driver. Hence, reactivation of divergent pathways can be leveraged as a previously unrecognized strategy to deepen treatment responses.
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15
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Baker SJ, Vogelstein B. p53: a tumor suppressor hiding in plain sight. J Mol Cell Biol 2020; 11:536-538. [PMID: 31276589 PMCID: PMC6736432 DOI: 10.1093/jmcb/mjz068] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2019] [Accepted: 06/25/2019] [Indexed: 12/12/2022] Open
Affiliation(s)
- Suzanne J Baker
- St Jude Children's Research Hospital, Department of Developmental Neurobiology, 262 Danny Thomas Place, Memphis, TN 38105, USA
| | - Bert Vogelstein
- Ludwig Center & Howard Hughes Medical Institute, Johns Hopkins Kimmel Cancer Center, 1650 Orleans Street St, Baltimore, MD 21205, USA
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16
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Guan Y, Wang G, Fails D, Nagarajan P, Ge Y. Unraveling cancer lineage drivers in squamous cell carcinomas. Pharmacol Ther 2020; 206:107448. [PMID: 31836455 PMCID: PMC6995404 DOI: 10.1016/j.pharmthera.2019.107448] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Accepted: 12/03/2019] [Indexed: 12/12/2022]
Abstract
Cancer hijacks embryonic development and adult wound repair mechanisms to fuel malignancy. Cancer frequently originates from de-regulated adult stem cells or progenitors, which are otherwise essential units for postnatal tissue remodeling and repair. Cancer genomics studies have revealed convergence of multiple cancers across organ sites, including squamous cell carcinomas (SCCs), a common group of cancers arising from the head and neck, esophagus, lung, cervix and skin. In this review, we summarize our current knowledge on the molecular drivers of SCCs, including these five major organ sites. We especially focus our discussion on lineage dependent driver genes and pathways, in the context of squamous development and stratification. We then use skin as a model to discuss the notion of field cancerization during SCC carcinogenesis, and cancer as a wound that never heals. Finally, we turn to the idea of context dependency widely observed in cancer driver genes, and outline literature support and possible explanations for their lineage specific functions. Through these discussions, we aim to provide an up-to-date summary of molecular mechanisms driving tumor plasticity in squamous cancers. Such basic knowledge will be helpful to inform the clinics for better stratifying cancer patients, revealing novel drug targets and providing effective treatment options.
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Affiliation(s)
- Yinglu Guan
- Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
| | - Guan Wang
- Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
| | - Danielle Fails
- Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
| | - Priyadharsini Nagarajan
- Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
| | - Yejing Ge
- Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
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17
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Harris KL, Myers MB, McKim KL, Elespuru RK, Parsons BL. Rationale and Roadmap for Developing Panels of Hotspot Cancer Driver Gene Mutations as Biomarkers of Cancer Risk. ENVIRONMENTAL AND MOLECULAR MUTAGENESIS 2020; 61:152-175. [PMID: 31469467 PMCID: PMC6973253 DOI: 10.1002/em.22326] [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: 06/20/2019] [Revised: 08/23/2019] [Accepted: 08/26/2019] [Indexed: 05/24/2023]
Abstract
Cancer driver mutations (CDMs) are necessary and causal for carcinogenesis and have advantages as reporters of carcinogenic risk. However, little progress has been made toward developing measurements of CDMs as biomarkers for use in cancer risk assessment. Impediments for using a CDM-based metric to inform cancer risk include the complexity and stochastic nature of carcinogenesis, technical difficulty in quantifying low-frequency CDMs, and lack of established relationships between cancer driver mutant fractions and tumor incidence. Through literature review and database analyses, this review identifies the most promising targets to investigate as biomarkers of cancer risk. Mutational hotspots were discerned within the 20 most mutated genes across the 10 deadliest cancers. Forty genes were identified that encompass 108 mutational hotspot codons overrepresented in the COSMIC database; 424 different mutations within these hotspot codons account for approximately 63,000 tumors and their prevalence across tumor types is described. The review summarizes literature on the prevalence of CDMs in normal tissues and suggests such mutations are direct and indirect substrates for chemical carcinogenesis, which occurs in a spatially stochastic manner. Evidence that hotspot CDMs (hCDMs) frequently occur as tumor subpopulations is presented, indicating COSMIC data may underestimate mutation prevalence. Analyses of online databases show that genes containing hCDMs are enriched in functions related to intercellular communication. In its totality, the review provides a roadmap for the development of tissue-specific, CDM-based biomarkers of carcinogenic potential, comprised of batteries of hCDMs and can be measured by error-correct next-generation sequencing. Environ. Mol. Mutagen. 61:152-175, 2020. Published 2019. This article is a U.S. Government work and is in the public domain in the USA. Environmental and Molecular Mutagenesis published by Wiley Periodicals, Inc. on behalf of Environmental Mutagen Society.
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Affiliation(s)
- Kelly L. Harris
- Division of Genetic and Molecular ToxicologyNational Center for Toxicological Research, US Food and Drug AdministrationJeffersonArkansas
| | - Meagan B. Myers
- Division of Genetic and Molecular ToxicologyNational Center for Toxicological Research, US Food and Drug AdministrationJeffersonArkansas
| | - Karen L. McKim
- Division of Genetic and Molecular ToxicologyNational Center for Toxicological Research, US Food and Drug AdministrationJeffersonArkansas
| | - Rosalie K. Elespuru
- Division of Biology, Chemistry and Materials ScienceCDRH/OSEL, US Food and Drug AdministrationSilver SpringMaryland
| | - Barbara L. Parsons
- Division of Genetic and Molecular ToxicologyNational Center for Toxicological Research, US Food and Drug AdministrationJeffersonArkansas
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18
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Park S, Ahn HK, Lee DH, Jung Y, Jeong JW, Nam S, Lee WS. Systematic mutation analysis in rare colorectal cancer presenting ovarian metastases. Sci Rep 2019; 9:16990. [PMID: 31740709 PMCID: PMC6861287 DOI: 10.1038/s41598-019-53182-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2018] [Accepted: 10/24/2019] [Indexed: 12/14/2022] Open
Abstract
Although colorectal cancer is one of the most lethal cancer types in the world, its metastasis to the ovary is rare, compared to metastasis to other organs. Consequently, the genomic basis for colon-to-ovary metastasis remains unstudied, due to limited available patients, and thus there have been no attempts to construct individual-specific networks. Due to its rarity, the small sample size makes common mutations difficult to find. To overcome this problem, we herein attempted to apply a biological connectivity map called a sample-specific network (SSN), to reveal common biological functions in three samples. Our three samples were compared to a clinical dataset contained in The Cancer Genome Atlas (TCGA) Colorectal Adenocarcinoma (COAD), showing different mutational spectra, compared to matched samples based on age, gender, microsatellite instability (MSI) status, and tumor, node, metastasis (TNM) stage. The SSNs for the three samples revealed significant correlations of the mutation statuses of several apoptosis genes, in contrast to the TCGA-matched samples. Further analysis of a targeted-gene panel sequencing dataset for colon-to-ovary metastasis of primary tumor samples also confirmed significant correlations of the mutational statuses among apoptosis genes. In summary, using SSN, we successfully identified a common function (apoptosis) among our three patients having colon-to-ovary metastasis, despite no common mutations in the three patients. Such computational analyses could facilitate productive study of rare cancers and other diseases.
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Affiliation(s)
- Sungjin Park
- College of Medicine, Gachon University, Incheon, Korea
- Gachon Institute of Genome Medicine and Science, Gachon University Gil Medical Center, Incheon, Korea
| | - Hee Kyung Ahn
- Department of Medical Oncology, Gachon University Gil Medical Center, Incheon, Korea
| | - Dae Ho Lee
- College of Medicine, Gachon University, Incheon, Korea
- Gachon Advanced Institute of Health Sciences & Technology, Gachon University, Incheon, Korea
- Department of Internal Medicine, Gachon University Gil Medical Center, Incheon, Korea
| | - YunJae Jung
- Department of Microbiology, College of Medicine, Gachon University, Incheon, Korea
| | - Joo-Won Jeong
- Department of Anatomy and Neurobiology, College of Medicine, Kyung Hee University, Seoul, Korea
| | - Seungyoon Nam
- College of Medicine, Gachon University, Incheon, Korea.
- Gachon Institute of Genome Medicine and Science, Gachon University Gil Medical Center, Incheon, Korea.
- Department of Medical Oncology, Gachon University Gil Medical Center, Incheon, Korea.
- Department of Life Sciences, Gachon University, Seongnam, Gyeonggi-do, Korea.
| | - Won-Suk Lee
- College of Medicine, Gachon University, Incheon, Korea.
- Department of Surgery, Gachon University Gil Medical Center, Incheon, Korea.
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19
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Loponte S, Lovisa S, Deem AK, Carugo A, Viale A. The Many Facets of Tumor Heterogeneity: Is Metabolism Lagging Behind? Cancers (Basel) 2019; 11:E1574. [PMID: 31623133 PMCID: PMC6826850 DOI: 10.3390/cancers11101574] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2019] [Revised: 10/03/2019] [Accepted: 10/09/2019] [Indexed: 12/13/2022] Open
Abstract
Tumor functional heterogeneity has been recognized for decades, and technological advancements are fueling renewed interest in uncovering the cell-intrinsic and extrinsic factors that influence tumor development and therapeutic response. Intratumoral heterogeneity is now arguably one of the most-studied topics in tumor biology, leading to the discovery of new paradigms and reinterpretation of old ones, as we aim to understand the profound implications that genomic, epigenomic, and functional heterogeneity hold with regard to clinical outcomes. In spite of our improved understanding of the biological complexity of cancer, characterization of tumor metabolic heterogeneity has lagged behind, lost in a century-old controversy debating whether glycolysis or mitochondrial respiration is more influential. But is tumor metabolism really so simple? Here, we review historical and current views of intratumoral heterogeneity, with an emphasis on summarizing the emerging data that begin to illuminate just how vast the spectrum of metabolic strategies a tumor can employ may be, and what this means for how we might interpret other tumor characteristics, such as mutational landscape, contribution of microenvironmental influences, and treatment resistance.
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Affiliation(s)
- Sara Loponte
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
| | - Sara Lovisa
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
| | - Angela K Deem
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
| | - Alessandro Carugo
- TRACTION platform, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
| | - Andrea Viale
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
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20
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Jin Y, Liu Y, Zhao L, Zhao F, Feng J, Li S, Chen H, Sun J, Zhu B, Geng R, Wei Y. Gut microbiota in patients after surgical treatment for colorectal cancer. Environ Microbiol 2018; 21:772-783. [PMID: 30548192 PMCID: PMC7379540 DOI: 10.1111/1462-2920.14498] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2018] [Accepted: 11/30/2018] [Indexed: 01/05/2023]
Abstract
Colorectal cancer (CRC) is a common disease worldwide that is strongly associated with the gut microbiota. However, little is known regarding the gut microbiota after surgical treatment. 16S rRNA gene sequencing was used to evaluate differences in gut microbiota among colorectal adenoma patients, CRC patients, CRC postoperative patients and healthy controls by comparing gut microbiota diversity, overall composition and taxonomic signature abundance. The gut microbiota of CRC patients, adenoma patients and healthy controls developed in accordance with the adenoma‐carcinoma sequence, with impressive shifts in the gut microbiota before or during the development of CRC. The gut microbiota of postoperative patients and CRC patients differed significantly. Subdividing CRC postoperative patients according to the presence or absence of newly developed adenoma which based on the colonoscopy findings revealed that the gut microbiota of newly developed adenoma patients differed significantly from that of clean intestine patients and was more similar to the gut microbiota of carcinoma patients than to the gut microbiota of healthy controls. The alterations of the gut microbiota between the two groups of postoperative patients corresponded to CRC prognosis. More importantly, we used the different gut microbiota as biomarkers to distinguish postoperative patients with or without newly developed adenoma, achieving an AUC value of 0.72. These insights on the changes in the gut microbiota of CRC patients after surgical treatment may allow the use of the microbiota as non‐invasive biomarkers for the diagnosis of newly developed adenomas and to help prevent cancer recurrence in postoperative patients.
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Affiliation(s)
- Ye Jin
- Department of Oncological and Laparoscopic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China 150001
| | - Yang Liu
- Department of Oncological and Laparoscopic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China 150001
| | - Lei Zhao
- Department of Oncological and Laparoscopic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China 150001
| | - Fuya Zhao
- Department of Oncological and Laparoscopic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China 150001
| | - Jing Feng
- Department of Oncological and Laparoscopic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China 150001
| | - Shengda Li
- Department of Oncological and Laparoscopic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China 150001
| | - Huinan Chen
- Department of Oncological and Laparoscopic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China 150001
| | - Jiayu Sun
- Department of Oncological and Laparoscopic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China 150001
| | - Biqiang Zhu
- Department of Oncological and Laparoscopic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China 150001
| | - Rui Geng
- Department of Oncological and Laparoscopic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China 150001
| | - Yunwei Wei
- Department of Oncological and Laparoscopic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China 150001
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21
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Shibata H, Komura S, Yamada Y, Sankoda N, Tanaka A, Ukai T, Kabata M, Sakurai S, Kuze B, Woltjen K, Haga H, Ito Y, Kawaguchi Y, Yamamoto T, Yamada Y. In vivo reprogramming drives Kras-induced cancer development. Nat Commun 2018; 9:2081. [PMID: 29802314 PMCID: PMC5970190 DOI: 10.1038/s41467-018-04449-5] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2018] [Accepted: 05/01/2018] [Indexed: 12/15/2022] Open
Abstract
The faithful shutdown of the somatic program occurs in the early stage of reprogramming. Here, we examined the effect of in vivo reprogramming on Kras-induced cancer development. We show that the transient expression of reprogramming factors (1-3 days) in pancreatic acinar cells results in the transient repression of acinar cell enhancers, which are similarly observed in pancreatitis. We next demonstrate that Kras and p53 mutations are insufficient to induce ERK signaling in the pancreas. Notably, the transient expression of reprogramming factors in Kras mutant mice is sufficient to induce the robust and persistent activation of ERK signaling in acinar cells and rapid formation of pancreatic ductal adenocarcinoma. In contrast, the forced expression of acinar cell-related transcription factors inhibits the pancreatitis-induced activation of ERK signaling and development of precancerous lesions in Kras-mutated acinar cells. These results underscore a crucial role of dedifferentiation-associated epigenetic regulations in the initiation of pancreatic cancers.
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Affiliation(s)
- Hirofumi Shibata
- Department of Life Science Frontiers, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, 606-8507, Japan.,Department of Otolaryngology, Gifu University Graduate School of Medicine, Gifu, 501-1194, Japan
| | - Shingo Komura
- Department of Life Science Frontiers, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, 606-8507, Japan
| | - Yosuke Yamada
- Department of Life Science Frontiers, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, 606-8507, Japan.,Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, 606-8507, Japan
| | - Nao Sankoda
- Department of Clinical Application, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, 606-8507, Japan
| | - Akito Tanaka
- Department of Life Science Frontiers, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, 606-8507, Japan
| | - Tomoyo Ukai
- Department of Life Science Frontiers, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, 606-8507, Japan
| | - Mio Kabata
- Department of Life Science Frontiers, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, 606-8507, Japan
| | - Satoko Sakurai
- Department of Life Science Frontiers, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, 606-8507, Japan
| | - Bunya Kuze
- Department of Otolaryngology, Gifu University Graduate School of Medicine, Gifu, 501-1194, Japan
| | - Knut Woltjen
- Department of Life Science Frontiers, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, 606-8507, Japan.,Hakubi Center for Advanced Research, Kyoto University, Kyoto, 606-8501, Japan
| | - Hironori Haga
- Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, 606-8507, Japan
| | - Yatsuji Ito
- Department of Otolaryngology, Gifu University Graduate School of Medicine, Gifu, 501-1194, Japan
| | - Yoshiya Kawaguchi
- Department of Clinical Application, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, 606-8507, Japan
| | - Takuya Yamamoto
- Department of Life Science Frontiers, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, 606-8507, Japan.,AMED-CREST, AMED, 1-7-1 Otemachi, Chiyodaku, Tokyo, 100-0004, Japan
| | - Yasuhiro Yamada
- Department of Life Science Frontiers, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, 606-8507, Japan. .,AMED-CREST, AMED, 1-7-1 Otemachi, Chiyodaku, Tokyo, 100-0004, Japan. .,Division of Stem Cell Pathology, Center for Experimental Medicine and Systems Biology, Institute of Medical Science, University of Tokyo, Tokyo, 108-8639, Japan.
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22
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Parsons BL. Multiclonal tumor origin: Evidence and implications. MUTATION RESEARCH-REVIEWS IN MUTATION RESEARCH 2018; 777:1-18. [PMID: 30115427 DOI: 10.1016/j.mrrev.2018.05.001] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/27/2018] [Revised: 04/11/2018] [Accepted: 05/05/2018] [Indexed: 12/31/2022]
Abstract
An accurate understanding of the clonal origins of tumors is critical for designing effective strategies to treat or prevent cancer and for guiding the field of cancer risk assessment. The intent of this review is to summarize evidence of multiclonal tumor origin and, thereby, contest the commonly held assumption of monoclonal tumor origin. This review describes relevant studies of X chromosome inactivation, analyses of tumor heterogeneity using other markers, single cell sequencing, and lineage tracing studies in aggregation chimeras and engineered rodent models. Methods for investigating tumor clonality have an inherent bias against detecting multiclonality. Despite this, multiclonality has been observed within all tumor stages and within 53 different types of tumors. For myeloid tumors, monoclonal tumor origin may be the predominant path to cancer and a monoclonal tumor origin cannot be ruled out for a fraction of other cancer types. Nevertheless, a large body of evidence supports the conclusion that most cancers are multiclonal in origin. Cooperation between different cell types and between clones of cells carrying different genetic and/or epigenetic lesions is discussed, along with how polyclonal tumor origin can be integrated with current perspectives on the genesis of tumors. In order to develop biologically sound and useful approaches to cancer risk assessment and precision medicine, mathematical models of carcinogenesis are needed, which incorporate multiclonal tumor origin and the contributions of spontaneous mutations in conjunction with the selective advantages conferred by particular mutations and combinations of mutations. Adherence to the idea that a growth must develop from a single progenitor cell to be considered neoplastic has outlived its usefulness. Moving forward, explicit examination of tumor clonality, using advanced tools, like lineage tracing models, will provide a strong foundation for future advances in clinical oncology and better training for the next generation of oncologists and pathologists.
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Affiliation(s)
- Barbara L Parsons
- US Food and Drug Administration, National Center for Toxicological Research, Division of Genetic and Molecular Toxicology, 3900 NCTR Rd., Jefferson, AR 72079, United States.
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23
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Abstract
Our understanding of the genetics of colorectal cancer has changed dramatically over recent years. Colorectal cancer can be classified in multiple different ways. Along with the advent of whole-exome sequencing, we have gained an understanding of the scale of the genetic changes found in sporadic colorectal cancer. We now know that there are multiple pathways that are commonly involved in the evolution of colorectal cancer including Wnt/β-catenin, RAS, EGFR, and PIK3 kinase. Another recent leap in our understanding of colorectal cancer genetics is the recognition that many, if not all tumors, are actually genetically heterogeneous within individual tumors and also between tumors. Recent research has revealed the prognostic and possibly therapeutic implications of various specific mutations, including specific mutations in BRAF and KRAS . There is increasing interest in the use of mutation testing for screening and surveillance through stool and circulating DNA testing. Recent advances in translational research in colorectal cancer genetics are dramatically changing our understanding of colorectal cancer and will likely change therapy and surveillance in the near future.
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Affiliation(s)
- Karin M Hardiman
- Division of Colon and Rectal Surgery, Department of Surgery, University of Michigan, Ann Arbor, Michigan
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24
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Sayagués JM, Corchete LA, Gutiérrez ML, Sarasquete ME, Del Mar Abad M, Bengoechea O, Fermiñán E, Anduaga MF, Del Carmen S, Iglesias M, Esteban C, Angoso M, Alcazar JA, García J, Orfao A, Muñoz-Bellvis L. Genomic characterization of liver metastases from colorectal cancer patients. Oncotarget 2018; 7:72908-72922. [PMID: 27662660 PMCID: PMC5341953 DOI: 10.18632/oncotarget.12140] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2016] [Accepted: 09/13/2016] [Indexed: 01/09/2023] Open
Abstract
Metastatic dissemination is the most frequent cause of death of sporadic colorectal cancer (sCRC) patients. Genomic abnormalities which are potentially characteristic of such advanced stages of the disease are complex and so far, they have been poorly described and only partially understood. We evaluated the molecular heterogeneity of sCRC tumors based on simultaneous assessment of the overall GEP of both coding mRNA and non-coding RNA genes in primary sCRC tumor samples from 23 consecutive patients and their paired liver metastases. Liver metastases from the sCRC patients analyzed, systematically showed deregulated transcripts of those genes identified as also deregulated in their paired primary colorectal carcinomas. However, some transcripts were found to be specifically deregulated in liver metastases (vs. non-tumoral colorectal tissues) while expressed at normal levels in their primary tumors, reflecting either an increased genomic instability of metastatic cells or theiradaption to the liver microenvironment. Newly deregulated metastatic transcripts included overexpression of APOA1, HRG, UGT2B4, RBP4 and ADH4 mRNAS and the miR-3180-3p, miR-3197, miR-3178, miR-4793 and miR-4440 miRNAs, together with decreased expression of the IGKV1-39, IGKC, IGKV1-27, FABP4 and MYLK mRNAS and the miR-363, miR-1, miR-143, miR-27b and miR-28-5p miRNAs. Canonical pathways found to be specifically deregulated in liver metastatic samples included multiple genes related with intercellular adhesion and the metastatic processes (e.g., IGF1R, PIK3CA, PTEN and EGFR), endocytosis (e.g., the PDGFRA, SMAD2, ERBB3, PML and FGFR2), and the cell cycle (e.g., SMAD2, CCND2, E2F5 and MYC). Our results also highlighted the activation of genes associated with the TGFβ signaling pathway, -e.g. RHOA, SMAD2, SMAD4, SMAD5, SMAD6, BMPR1A, SMAD7 and MYC-, which thereby emerge as candidate genes to play an important role in CRC tumor metastasis.
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Affiliation(s)
- José María Sayagués
- Cytometry Service-NUCLEUS, Department of Medicine, Cancer Research Center, IBMCC-CSIC/USAL and IBSAL, University of Salamanca, Salamanca, Spain
| | - Luís Antonio Corchete
- Cáncer Research Center and Service of Hematology, University Hospital of Salamanca, Salamanca, Spain
| | - María Laura Gutiérrez
- Cytometry Service-NUCLEUS, Department of Medicine, Cancer Research Center, IBMCC-CSIC/USAL and IBSAL, University of Salamanca, Salamanca, Spain
| | - Maria Eugenia Sarasquete
- Cáncer Research Center and Service of Hematology, University Hospital of Salamanca, Salamanca, Spain
| | - María Del Mar Abad
- Department of Pathology, University Hospital of Salamanca, Salamanca, Spain
| | - Oscar Bengoechea
- Department of Pathology, University Hospital of Salamanca, Salamanca, Spain
| | - Encarna Fermiñán
- Genomics Unit, Cancer Research Center, IBMCC-CSIC/USAL, Salamanca, Spain
| | - María Fernanda Anduaga
- Service of General and Gastrointestinal Surgery and IBSAL, University Hospital of Salamanca, Salamanca, Spain
| | - Sofia Del Carmen
- Department of Pathology, University Hospital of Salamanca, Salamanca, Spain
| | - Manuel Iglesias
- Service of General and Gastrointestinal Surgery and IBSAL, University Hospital of Salamanca, Salamanca, Spain
| | - Carmen Esteban
- Service of General and Gastrointestinal Surgery and IBSAL, University Hospital of Salamanca, Salamanca, Spain
| | - María Angoso
- Service of General and Gastrointestinal Surgery and IBSAL, University Hospital of Salamanca, Salamanca, Spain
| | - Jose Antonio Alcazar
- Service of General and Gastrointestinal Surgery and IBSAL, University Hospital of Salamanca, Salamanca, Spain
| | - Jacinto García
- Service of General and Gastrointestinal Surgery and IBSAL, University Hospital of Salamanca, Salamanca, Spain
| | - Alberto Orfao
- Cytometry Service-NUCLEUS, Department of Medicine, Cancer Research Center, IBMCC-CSIC/USAL and IBSAL, University of Salamanca, Salamanca, Spain
| | - Luís Muñoz-Bellvis
- Service of General and Gastrointestinal Surgery and IBSAL, University Hospital of Salamanca, Salamanca, Spain
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25
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CYB5R1 links epithelial-mesenchymal transition and poor prognosis in colorectal cancer. Oncotarget 2017; 7:31350-60. [PMID: 27120783 PMCID: PMC5058761 DOI: 10.18632/oncotarget.8912] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2015] [Accepted: 04/10/2016] [Indexed: 12/16/2022] Open
Abstract
Colorectal cancers show significant tumor cell heterogeneity within the same core genetic background. Epithelial-mesenchymal transition (EMT) is an important functional aspect of this heterogeneity and hallmark of colorectal cancer progression. Here, we identify CYB5R1, an enzyme involved in oxidative stress protection and drug metabolism, as an indicator of EMT in colon cancer. We demonstrate high CYB5R1 expression in colorectal cancer cells undergoing EMT at the infiltrative tumor edge and reveal an extraordinarily strong association of CYB5R1 expression with two core EMT gene expression signatures in a large independent colon cancer data set from The Cancer Genome Atlas (TCGA). Furthermore, we demonstrate that CYB5R1 is required for an infiltrative tumor cell phenotype, and robustly linked with poor prognosis in colorectal cancer. Our findings have important implications for colon cancer cells undergoing EMT and may be exploited for diagnostic and therapeutic purposes.
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26
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Linhart H, Bormann F, Hutter B, Brors B, Lyko F. Genetic and epigenetic profiling of a solitary Peutz-Jeghers colon polyp. Cold Spring Harb Mol Case Stud 2017; 3:a001610. [PMID: 28487883 PMCID: PMC5411691 DOI: 10.1101/mcs.a001610] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Colon polyps represent precursor lesions of colon cancers and their malignant potential varies according to histological subtype. A rare subtype of colon polyps is the Peutz–Jeghers (PJ) polyp. PJ polyps mostly occur in the context of Peutz–Jeghers syndrome, which is characterized by the development of multiple polyps in the intestinal tract and hyperpigmentation of oral mucosa and lips. Peutz–Jeghers is an autosomal dominant disorder caused by pathogenic variants of the serine threonine kinase STK11. PJ polyps very rarely occur outside of the syndrome and are then referred to as solitary PJ polyps. Contrary to the situation in Peutz–Jeghers, the genetic basis and the malignant potential of solitary PJ polyps are currently unknown. Here we describe a detailed and comprehensive genetic profile of a solitary PJ polyp. Pathological examination revealed a high tissue homogeneity with >80% epithelial cells. Whole-genome sequencing failed to identify any clonal mutations but demonstrated a significant number of subclonal mutations. No somatic or germline mutations were found at the STK11 locus, suggesting that solitary PJ polyps are genetically distinct from Peutz–Jeghers polyps. In addition, methylome analysis revealed global hypomethylation and CpG island hypermethylation, two features that have been described as hallmarks of the colorectal cancer epigenome. These results provide an example of a premalignant lesion that is defined by epigenetic, rather than genetic changes. Furthermore, our findings support the notion that solitary PJ polyps constitute neoplastic tissue with malignant potential that should be removed for cancer prevention.
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Affiliation(s)
- Heinz Linhart
- Division of Epigenetics, DKFZ-ZMBH Alliance, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.,Asklepios Klinik Lindau, 88131 Lindau, Germany
| | - Felix Bormann
- Division of Epigenetics, DKFZ-ZMBH Alliance, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Barbara Hutter
- Division of Applied Bioinformatics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Benedikt Brors
- Division of Applied Bioinformatics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Frank Lyko
- Division of Epigenetics, DKFZ-ZMBH Alliance, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
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27
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Gupta RG, Somer RA. Intratumor Heterogeneity: Novel Approaches for Resolving Genomic Architecture and Clonal Evolution. Mol Cancer Res 2017; 15:1127-1137. [DOI: 10.1158/1541-7786.mcr-17-0070] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2017] [Revised: 03/29/2017] [Accepted: 06/05/2017] [Indexed: 11/16/2022]
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28
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López-Posadas R, Neurath MF, Atreya I. Molecular pathways driving disease-specific alterations of intestinal epithelial cells. Cell Mol Life Sci 2017; 74:803-826. [PMID: 27624395 PMCID: PMC11107577 DOI: 10.1007/s00018-016-2363-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2016] [Revised: 09/06/2016] [Accepted: 09/08/2016] [Indexed: 12/22/2022]
Abstract
Due to the fact that chronic inflammation as well as tumorigenesis in the gut is crucially impacted by the fate of intestinal epithelial cells, our article provides a comprehensive overview of the composition, function, regulation and homeostasis of the gut epithelium. In particular, we focus on those aspects which were found to be altered in the context of inflammatory bowel diseases or colorectal cancer and also discuss potential molecular targets for a disease-specific therapeutic intervention.
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Affiliation(s)
- Rocío López-Posadas
- Department of Medicine 1, Friedrich-Alexander-University Erlangen-Nuremberg, Ulmenweg 18, 91054, Erlangen, Germany
| | - Markus F Neurath
- Department of Medicine 1, Friedrich-Alexander-University Erlangen-Nuremberg, Ulmenweg 18, 91054, Erlangen, Germany
| | - Imke Atreya
- Department of Medicine 1, Friedrich-Alexander-University Erlangen-Nuremberg, Ulmenweg 18, 91054, Erlangen, Germany.
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29
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Blaj C, Schmidt EM, Lamprecht S, Hermeking H, Jung A, Kirchner T, Horst D. Oncogenic Effects of High MAPK Activity in Colorectal Cancer Mark Progenitor Cells and Persist Irrespective of RAS Mutations. Cancer Res 2017; 77:1763-1774. [PMID: 28202525 DOI: 10.1158/0008-5472.can-16-2821] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2016] [Revised: 12/16/2016] [Accepted: 01/10/2017] [Indexed: 12/28/2022]
Abstract
About 40% of colorectal cancers have mutations in KRAS accompanied by downstream activation of MAPK signaling, which promotes tumor invasion and progression. Here, we report that MAPK signaling shows strong intratumoral heterogeneity and unexpectedly remains regulated in colorectal cancer irrespective of KRAS mutation status. Using primary colorectal cancer tissues, xenograft models, and MAPK reporter constructs, we showed that tumor cells with high MAPK activity resided specifically at the leading tumor edge, ceased to proliferate, underwent epithelial-mesenchymal transition (EMT), and expressed markers related to colon cancer stem cells. In KRAS-mutant colon cancer, regulation of MAPK signaling was preserved through remaining wild-type RAS isoforms. Moreover, using a lineage tracing strategy, we provide evidence that high MAPK activity marked a progenitor cell compartment of growth-fueling colon cancer cells in vivo Our results imply that differential MAPK signaling balances EMT, cancer stem cell potential, and tumor growth in colorectal cancer. Cancer Res; 77(7); 1763-74. ©2017 AACR.
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Affiliation(s)
- Cristina Blaj
- Pathologisches Institut, Ludwig-Maximilians-Universität München, München, Germany
| | - Eva Marina Schmidt
- Pathologisches Institut, Ludwig-Maximilians-Universität München, München, Germany
| | - Sebastian Lamprecht
- Pathologisches Institut, Ludwig-Maximilians-Universität München, München, Germany
| | - Heiko Hermeking
- Pathologisches Institut, Ludwig-Maximilians-Universität München, München, Germany.,German Cancer Consortium (DKTK), Heidelberg, Germany.,German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Andreas Jung
- Pathologisches Institut, Ludwig-Maximilians-Universität München, München, Germany.,German Cancer Consortium (DKTK), Heidelberg, Germany.,German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Thomas Kirchner
- Pathologisches Institut, Ludwig-Maximilians-Universität München, München, Germany.,German Cancer Consortium (DKTK), Heidelberg, Germany.,German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - David Horst
- Pathologisches Institut, Ludwig-Maximilians-Universität München, München, Germany. .,German Cancer Consortium (DKTK), Heidelberg, Germany.,German Cancer Research Center (DKFZ), Heidelberg, Germany
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30
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Pullamsetti SS, Savai R, Seeger W, Goncharova EA. Translational Advances in the Field of Pulmonary Hypertension. From Cancer Biology to New Pulmonary Arterial Hypertension Therapeutics. Targeting Cell Growth and Proliferation Signaling Hubs. Am J Respir Crit Care Med 2017; 195:425-437. [PMID: 27627135 PMCID: PMC5803657 DOI: 10.1164/rccm.201606-1226pp] [Citation(s) in RCA: 123] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2016] [Accepted: 09/08/2016] [Indexed: 12/21/2022] Open
Affiliation(s)
- Soni Savai Pullamsetti
- Department of Lung Development and Remodeling, Max Planck Institute for Heart and Lung Research, member of the German Center for Lung Research (DZL), Bad Nauheim, Germany
- Department of Internal Medicine, Universities of Giessen and Marburg Lung Center, member of the DZL, Giessen, Germany
- Justus Liebig University, Giessen, Germany; and
| | - Rajkumar Savai
- Department of Lung Development and Remodeling, Max Planck Institute for Heart and Lung Research, member of the German Center for Lung Research (DZL), Bad Nauheim, Germany
- Department of Internal Medicine, Universities of Giessen and Marburg Lung Center, member of the DZL, Giessen, Germany
- Justus Liebig University, Giessen, Germany; and
| | - Werner Seeger
- Department of Lung Development and Remodeling, Max Planck Institute for Heart and Lung Research, member of the German Center for Lung Research (DZL), Bad Nauheim, Germany
- Department of Internal Medicine, Universities of Giessen and Marburg Lung Center, member of the DZL, Giessen, Germany
- Justus Liebig University, Giessen, Germany; and
| | - Elena A. Goncharova
- Pittsburgh Heart, Lung, and Blood Vascular Medicine Institute, Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
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31
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Kim KJ, Chei S, Choi SY, Lee OH, Lee BY. Pterostilbene activates the GRP78–elF2α–ATF3 cascade of ER stress and subsequently induces apoptosis in human colon cancer cells. J Funct Foods 2016. [DOI: 10.1016/j.jff.2016.08.027] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
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32
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Dai D, Thiel KW, Salinas EA, Goodheart MJ, Leslie KK, Gonzalez Bosquet J. Stratification of endometrioid endometrial cancer patients into risk levels using somatic mutations. Gynecol Oncol 2016; 142:150-157. [PMID: 27181389 PMCID: PMC5257080 DOI: 10.1016/j.ygyno.2016.05.012] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2016] [Revised: 05/09/2016] [Accepted: 05/11/2016] [Indexed: 10/21/2022]
Abstract
OBJECTIVE Patients with endometrioid endometrial cancer are stratified as high risk and low risk for extrauterine disease by surgical staging. Since patients with low-grade, minimally invasive disease do not benefit from comprehensive staging, pre-surgery stratification into a risk category may prevent unnecessary surgical staging in low risk patients. Our objective was to develop a predictive model to identify risk levels using somatic mutations that could be used preoperatively. METHODS We classified endometrioid endometrial cancer patients in The Cancer Genome Atlas (TCGA) dataset into high risk and low risk categories: high risk patients presented with stage II, III or IV disease or stage I with high-intermediate risk features, whereas low risk patients consisted of the remaining stage I patients with either no myometrial invasion or low-intermediate risk features. Three strategies were used to build the prediction model: 1) mutational status for each gene; 2) number of somatic mutations for each gene; and 3) variant allele frequencies for each somatic mutation for each gene. RESULTS Each prediction strategy had a good performance, with an area under the curve (or AUC) between 61% and 80%. Analysis of variant allele frequency produced a superior prediction model for risk levels of endometrial cancer as compared to the other two strategies, with an AUC=91%. Lasso and Ridge methods identified 53 mutations that together had the highest predictability for high risk endometrioid endometrial cancer. CONCLUSIONS This prediction model will assist future retrospective and prospective studies to categorize endometrial cancer patients into high risk and low risk in the preoperative setting.
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Affiliation(s)
- Donghai Dai
- Department of Obstetrics and Gynecology, University of Iowa, Iowa City, IA, United States
| | - Kristina W Thiel
- Department of Obstetrics and Gynecology, University of Iowa, Iowa City, IA, United States
| | - Erin A Salinas
- Department of Obstetrics and Gynecology, University of Iowa, Iowa City, IA, United States
| | - Michael J Goodheart
- Department of Obstetrics and Gynecology, University of Iowa, Iowa City, IA, United States; Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, United States
| | - Kimberly K Leslie
- Department of Obstetrics and Gynecology, University of Iowa, Iowa City, IA, United States; Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, United States
| | - Jesus Gonzalez Bosquet
- Department of Obstetrics and Gynecology, University of Iowa, Iowa City, IA, United States.
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Hait WN, Lebowitz PF. Disease Interception: Myths, Mountains, and Mole Hills. Cancer Prev Res (Phila) 2016; 9:635-7. [PMID: 27138792 DOI: 10.1158/1940-6207.capr-16-0049] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2016] [Accepted: 04/14/2016] [Indexed: 11/16/2022]
Abstract
Malignant diseases develop slowly over time and are often preceded by identifiable premalignancies. As malignancy progresses, so does genomic complexity and the ability of cancers to evade most therapeutic interventions. Accordingly, with some notable exceptions, a relatively low percentage of advanced cancers are effectively treated and even fewer are cured. Despite this appreciation, much less attention has been paid to intercepting the disease process compared with that of treating well-established and refractory disease. One frequently cited reason is that the pharmaceutical industry is not interested in these pursuits. In this commentary, we attempt to define the true hurdles, the degree of difficulty inherent in each, and some important approaches to be considered. Cancer Prev Res; 9(8); 635-7. ©2016 AACR.
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Affiliation(s)
- William N Hait
- Janssen Research and Development LLC., Raritan, New Jersey.
| | - Peter F Lebowitz
- Janssen Research and Development LLC., Spring House, Pennsylvania
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Eo HJ, Park GH, Jeong JB. Inhibition of Wnt Signaling by Silymarin in Human Colorectal Cancer Cells. Biomol Ther (Seoul) 2016; 24:380-6. [PMID: 27068260 PMCID: PMC4930281 DOI: 10.4062/biomolther.2015.154] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2015] [Revised: 11/22/2015] [Accepted: 12/11/2015] [Indexed: 11/12/2022] Open
Abstract
Silymarin from milk thistle (Silybum marianum) has been reported to show an anti-cancer activity. In previous study, we reported that silymarin induces cyclin D1 proteasomal degradation through NF-κB-mediated threonine-286 phosphorylation. However, mechanism for the inhibition of Wnt signaling by silymarin still remains unanswered. Thus, we investigated whether silymarin affects Wnt signaling in human colorectal cancer cells to elucidate the additional anti-cancer mechanism of silymarin. Transient transfection with a TOP and FOP FLASH luciferase construct indicated that silymarin suppressed the transcriptional activity of β-catenin/TCF. Silymarin treatment resulted in a decrease of intracellular β-catenin protein but not mRNA. The inhibition of proteasome by MG132 and GSK3β inhibition by SB216763 blocked silymarin-mediated downregulation of β-catenin. In addition, silymarin increased phosphorylation of β-catenin and a point mutation of S33Y attenuated silymarin-mediated β-catenin downregulation. In addition, silymarin decreased TCF4 and increased Axin expression in both protein and mRNA level. From these results, we suggest that silymarin-mediated downregulation of β-catenin and TCF4 may result in the inhibition of Wnt signaling in human colorectal cancer cells.
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Affiliation(s)
- Hyun Ji Eo
- Department of Bioresource Sciences, Andong National University, Andong 36729, Republic of Korea
| | - Gwang Hun Park
- Department of Bioresource Sciences, Andong National University, Andong 36729, Republic of Korea
| | - Jin Boo Jeong
- Department of Bioresource Sciences, Andong National University, Andong 36729, Republic of Korea
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Sato KA, Hachiya T, Iwaya T, Kume K, Matsuo T, Kawasaki K, Abiko Y, Akasaka R, Matsumoto T, Otsuka K, Nishizuka SS. Individualized Mutation Detection in Circulating Tumor DNA for Monitoring Colorectal Tumor Burden Using a Cancer-Associated Gene Sequencing Panel. PLoS One 2016; 11:e0146275. [PMID: 26727500 PMCID: PMC4699643 DOI: 10.1371/journal.pone.0146275] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2015] [Accepted: 12/15/2015] [Indexed: 01/06/2023] Open
Abstract
BACKGROUND Circulating tumor DNA (ctDNA) carries information on tumor burden. However, the mutation spectrum is different among tumors. This study was designed to examine the utility of ctDNA for monitoring tumor burden based on an individual mutation profile. METHODOLOGY DNA was extracted from a total of 176 samples, including pre- and post-operational plasma, primary tumors, and peripheral blood mononuclear cells (PBMC), from 44 individuals with colorectal tumor who underwent curative resection of colorectal tumors, as well as nine healthy individuals. Using a panel of 50 cancer-associated genes, tumor-unique mutations were identified by comparing the single nucleotide variants (SNVs) from tumors and PBMCs with an Ion PGM sequencer. A group of the tumor-unique mutations from individual tumors were designated as individual marker mutations (MMs) to trace tumor burden by ctDNA using droplet digital PCR (ddPCR). From these experiments, three major objectives were assessed: (a) Tumor-unique mutations; (b) mutation spectrum of a tumor; and (c) changes in allele frequency of the MMs in ctDNA after curative resection of the tumor. RESULTS A total of 128 gene point mutations were identified in 27 colorectal tumors. Twenty-six genes were mutated in at least 1 sample, while 14 genes were found to be mutated in only 1 sample, respectively. An average of 2.7 genes were mutated per tumor. Subsequently, 24 MMs were selected from SNVs for tumor burden monitoring. Among the MMs found by ddPCR with > 0.1% variant allele frequency in plasma DNA, 100% (8 out of 8) exhibited a decrease in post-operation ctDNA, whereas none of the 16 MMs found by ddPCR with < 0.1% variant allele frequency in plasma DNA showed a decrease. CONCLUSIONS This panel of 50 cancer-associated genes appeared to be sufficient to identify individual, tumor-unique, mutated ctDNA markers in cancer patients. The MMs showed the clinical utility in monitoring curatively-treated colorectal tumor burden if the allele frequency of MMs in plasma DNA is above 0.1%.
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Affiliation(s)
- Kei A. Sato
- Molecular Therapeutics Laboratory, Department of Surgery, Iwate Medical University School of Medicine, Morioka, Japan
- Department of Surgery, Iwate medical University School of Medicine, Morioka, Japan
| | - Tsuyoshi Hachiya
- Division of Biomedical Information Analysis, Iwate Tohoku Medical Megabank Organization, Iwate Medical University, Yahaba, Japan
| | - Takeshi Iwaya
- Department of Surgery, Iwate medical University School of Medicine, Morioka, Japan
| | - Kohei Kume
- Molecular Therapeutics Laboratory, Department of Surgery, Iwate Medical University School of Medicine, Morioka, Japan
- Department of Surgery, Iwate medical University School of Medicine, Morioka, Japan
- MIAST (Medical Innovation by Advanced Science and Technology) Project, Iwate Medical University School, Morioka, Japan
- Institute of Biomedical Science, Iwate Medical University, Yahaba, Japan
| | - Teppei Matsuo
- Department of Surgery, Iwate medical University School of Medicine, Morioka, Japan
| | - Keisuke Kawasaki
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Iwate Medical University School of Medicine, Morioka, Japan
| | - Yukito Abiko
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Iwate Medical University School of Medicine, Morioka, Japan
| | - Risaburo Akasaka
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Iwate Medical University School of Medicine, Morioka, Japan
| | - Takayuki Matsumoto
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Iwate Medical University School of Medicine, Morioka, Japan
| | - Koki Otsuka
- Department of Surgery, Iwate medical University School of Medicine, Morioka, Japan
| | - Satoshi S. Nishizuka
- Molecular Therapeutics Laboratory, Department of Surgery, Iwate Medical University School of Medicine, Morioka, Japan
- Department of Surgery, Iwate medical University School of Medicine, Morioka, Japan
- MIAST (Medical Innovation by Advanced Science and Technology) Project, Iwate Medical University School, Morioka, Japan
- Institute of Biomedical Science, Iwate Medical University, Yahaba, Japan
- Department of Surgery, Iwate Medical University School of Dentistry, Morioka, Japan
- * E-mail:
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Dickinson BT, Kisiel J, Ahlquist DA, Grady WM. Molecular markers for colorectal cancer screening. Gut 2015; 64:1485-94. [PMID: 25994221 PMCID: PMC4765995 DOI: 10.1136/gutjnl-2014-308075] [Citation(s) in RCA: 84] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2015] [Accepted: 04/17/2015] [Indexed: 12/12/2022]
Abstract
Colorectal cancer (CRC), although a significant cause of morbidity and mortality worldwide, has seen a declining incidence and mortality in countries with programmatic screening. Faecal occult blood testing and endoscopic approaches are the predominant screening methods currently. The discovery of the adenoma-carcinoma sequence and a greater understanding of the genetic and epigenetic changes that drive the formation of CRC have contributed to innovative research to identify molecular markers for highly accurate, non-invasive screening tests for CRC. DNA, proteins, messenger RNA and micro-RNA have all been evaluated. The observation of tumour cell exfoliation into the mucocellular layer of the colonic epithelium and proven stability of DNA in a harsh stool environment make stool DNA a particularly promising marker. The development of a clinically useful stool DNA test has required numerous technical advances, including optimisation in DNA stabilisation, the development of assays with high analytical sensitivity, and the identification of specific and broadly informative molecular markers. A multitarget stool DNA test, which combines mutant and methylated DNA markers and a faecal immunochemical test, recently performed favourably in a large cross-sectional validation study and has been approved by the US Food and Drug Administration for the screening of asymptomatic, average-risk individuals. The ultimate way in which molecular marker screening assays will be used in clinical practice will require additional studies to determine optimal screening intervals, factors affecting compliance, management of false-positive results, and the use of these assays in high-risk populations, as well as other considerations.
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Affiliation(s)
- Brandon T. Dickinson
- Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA
| | | | | | - William M. Grady
- Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA,Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA
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TCF4 Is a Molecular Target of Resveratrol in the Prevention of Colorectal Cancer. Int J Mol Sci 2015; 16:10411-25. [PMID: 25961950 PMCID: PMC4463653 DOI: 10.3390/ijms160510411] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2014] [Revised: 04/30/2015] [Accepted: 05/04/2015] [Indexed: 12/22/2022] Open
Abstract
The Wnt/β-catenin pathway plays an essential role in the tumorigenesis of colorectal cancer. T-cell factor-4 (TCF4) is a member of the TCF/LEF (lymphoid enhancer factor) family of transcription factors, and dysregulation of β-catenin is decisive for the initiation and progression of colorectal cancer. However, the role of TCF4 in the transcriptional regulation of its target gene remained poorly understood. Resveratrol is a dietary phytoalexin and present in many plants, including grape skin, nuts and fruits. Although resveratrol has been widely implicated in anti-tumorigenic and pro-apoptotic properties in several cancer models, the underlying cellular mechanisms are only partially understood. The current study was performed to elucidate the molecular mechanism of the anti-cancer activity of resveratrol in human colorectal cancer cells. The treatment of resveratrol and other phytochemicals decreased the expression of TCF4. Resveratrol decreases cellular accumulation of exogenously-introduced TCF4 protein, but did not change the TCF4 transcription. The inhibition of proteasomal degradation using MG132 (carbobenzoxy-Leu-Leu-leucinal) and lactacystin ameliorates resveratrol-stimulated down-regulation of TCF4. The half-life of TCF4 was decreased in the cells exposed to resveratrol. Resveratrol increased phosphorylation of TCF4 at serine/threonine residues through ERK (extracellular signal-regulated kinases) and p38-dependent pathways. The TCF4 knockdown decreased TCF/β-catenin-mediated transcriptional activity and sensitized resveratrol-induced apoptosis. The current study provides a new mechanistic link between resveratrol and TCF4 down-regulation and significant benefits for further preclinical and clinical practice.
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38
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Eo HJ, Park GH, Song HM, Lee JW, Kim MK, Lee MH, Lee JR, Koo JS, Jeong JB. Silymarin induces cyclin D1 proteasomal degradation via its phosphorylation of threonine-286 in human colorectal cancer cells. Int Immunopharmacol 2015; 24:1-6. [PMID: 25479723 DOI: 10.1016/j.intimp.2014.11.009] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2014] [Revised: 10/25/2014] [Accepted: 11/10/2014] [Indexed: 10/24/2022]
Abstract
Silymarin from milk thistle (Silybum marianum) plant has been reported to show anti-cancer, anti-inflammatory, antioxidant and hepatoprotective effects. For anti-cancer activity, silymarin is known to regulate cell cycle progression through cyclin D1 downregulation. However, the mechanism of silymarin-mediated cyclin D1 downregulation still remains unanswered. The current study was performed to elucidate the molecular mechanism of cyclin D1 downregulation by silymarin in human colorectal cancer cells. The treatment of silymarin suppressed the cell proliferation in HCT116 and SW480 cells and decreased cellular accumulation of exogenously-induced cyclin D1 protein. However, silymarin did not change the level of cyclin D1 mRNA. Inhibition of proteasomal degradation by MG132 attenuated silymarin-mediated cyclin D1 downregulation and the half-life of cyclin D1 was decreased in the cells treated with silymarin. In addition, silymarin increased phosphorylation of cyclin D1 at threonine-286 and a point mutation of threonine-286 to alanine attenuated silymarin-mediated cyclin D1 downregulation. Inhibition of NF-κB by a selective inhibitor, BAY 11-7082 suppressed cyclin D1 phosphorylation and downregulation by silymarin. From these results, we suggest that silymarin-mediated cyclin D1 downregulation may result from proteasomal degradation through its threonine-286 phosphorylation via NF-κB activation. The current study provides new mechanistic link between silymarin, cyclin D1 downregulation and cell growth in human colorectal cancer cells.
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Affiliation(s)
- Hyun Ji Eo
- Department of Bioresource Sciences, Andong National University, Andong 760749, Republic of Korea
| | - Gwang Hun Park
- Department of Bioresource Sciences, Andong National University, Andong 760749, Republic of Korea
| | - Hun Min Song
- Department of Bioresource Sciences, Andong National University, Andong 760749, Republic of Korea
| | - Jin Wook Lee
- Department of Bioresource Sciences, Andong National University, Andong 760749, Republic of Korea
| | - Mi Kyoung Kim
- Department of Bioresource Sciences, Andong National University, Andong 760749, Republic of Korea
| | - Man Hyo Lee
- Gyeongbuk Institute for Bio-industry, Andong 760380, Republic of Korea
| | - Jeong Rak Lee
- Gyeongbuk Institute for Bio-industry, Andong 760380, Republic of Korea
| | - Jin Suk Koo
- Department of Bioresource Sciences, Andong National University, Andong 760749, Republic of Korea; Institute of Agricultural Science and Technology, Andong National University, Andong 760749, Republic of Korea
| | - Jin Boo Jeong
- Department of Bioresource Sciences, Andong National University, Andong 760749, Republic of Korea; Institute of Agricultural Science and Technology, Andong National University, Andong 760749, Republic of Korea.
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Abstract
As the emergence of cancer is most frequent in proliferating tissues, replication errors are considered to be at the base of this disease. This review concentrates mainly on two neural cancers, neuroblastoma and glioma, with completely different backgrounds that are well documented with respect to their ontogeny. Although clinical data on other cancers of the nervous system are available, usually little can be said about their origins. Neuroblastoma is initiated in the embryo at a moment when the nervous system (NS) is in full expansion and occasionally genomic damage can lead to neoplasia. Glioma, to the contrary, occurs in the adult brain supposed to be mostly in a postmitotic state. According to current consensus, neural stem cells located in the subventricular zone (SVZ) in the adult are thought to accumulate enough genomic mutations to diverge on a carcinogenic course leading to diverse forms of glioma. After weighing the pros and cons of this current hypothesis in this review, it will be argued that this may be improbable, yielding to the original old concept of glial origin of glioma.
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40
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Lee SY, Haq F, Kim D, Jun C, Jo HJ, Ahn SM, Lee WS. Comparative genomic analysis of primary and synchronous metastatic colorectal cancers. PLoS One 2014; 9:e90459. [PMID: 24599305 PMCID: PMC3944022 DOI: 10.1371/journal.pone.0090459] [Citation(s) in RCA: 87] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2013] [Accepted: 01/30/2014] [Indexed: 12/30/2022] Open
Abstract
Approximately 50% of patients with primary colorectal carcinoma develop liver metastases. Understanding the genetic differences between primary colon cancer and their metastases to the liver is essential for devising a better therapeutic approach for this disease. We performed whole exome sequencing and copy number analysis for 15 triplets, each comprising normal colorectal tissue, primary colorectal carcinoma, and its synchronous matched liver metastasis. We analyzed the similarities and differences between primary colorectal carcinoma and matched liver metastases in regards to somatic mutations and somatic copy number alterationss. The genomic profiling demonstrated mutations in APC(73%), KRAS (33%), ARID1A and PIK3CA (6.7%) genes between primary colorectal and metastatic liver tumors. TP53 mutation was observed in 47% of the primary samples and 67% in liver metastatic samples. The grouped pairs, in hierarchical clustering showed similar somatic copy number alteration patterns, in contrast to the ungrouped pairs. Many mutations (including those of known key cancer driver genes) were shared in the grouped pairs. The ungrouped pairs exhibited distinct mutation patterns with no shared mutations in key driver genes. Four ungrouped liver metastasis samples had mutations in DNA mismatch repair genes along with hypermutations and a substantial number of copy number alterations. Our results suggest that about half of the metastatic colorectal carcinoma had the same clonal origin with their primary colorectal carcinomas, whereas remaining cases were genetically distinct from their primary carcinomas. These findings underscore the need to evaluate metastatic lesions separately for optimized therapy, rather than to extrapolate from primary tumor data.
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Affiliation(s)
- Sun Young Lee
- Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, Korea
| | - Farhan Haq
- Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, Korea
| | - Deokhoon Kim
- Center for Cancer Genome Discovery, Asan Institute for Life Science, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea
| | - Cui Jun
- Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, Korea
| | - Hui-Jong Jo
- Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, Korea
| | - Sung-Min Ahn
- Center for Cancer Genome Discovery, Asan Institute for Life Science, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea
- Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
- Department of Biomedical Informatics, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea
- * E-mail: (SMA); (WSL)
| | - Won-Suk Lee
- Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, Korea
- Department of Surgery, Gil Medical Center, Gachon University, Incheon, Korea
- * E-mail: (SMA); (WSL)
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41
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Ong BA, Vega KJ, Houchen CW. Intestinal stem cells and the colorectal cancer microenvironment. World J Gastroenterol 2014; 20:1898-1909. [PMID: 24587669 PMCID: PMC3934460 DOI: 10.3748/wjg.v20.i8.1898] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2013] [Revised: 12/03/2013] [Accepted: 01/05/2014] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) remains a highly fatal condition in part due to its resilience to treatment and its propensity to spread beyond the site of primary occurrence. One possible avenue for cancer to escape eradication is via stem-like cancer cells that, through phenotypic heterogeneity, are more resilient than other tumor constituents and are key contributors to cancer growth and metastasis. These proliferative tumor cells are theorized to possess many properties akin to normal intestinal stem cells. Not only do these CRC “stem” cells demonstrate similar restorative ability, they also share many cell pathways and surface markers in common, as well as respond to the same key niche stimuli. With the improvement of techniques for epithelial stem cell identification, our understanding of CRC behavior is also evolving. Emerging evidence about cellular plasticity and epithelial mesenchymal transition are shedding light onto metastatic CRC processes and are also challenging fundamental concepts about unidirectional epithelial proliferation. This review aims to reappraise evidence supporting the existence and behavior of CRC stem cells, their relationship to normal stem cells, and their possible dependence on the stem cell niche.
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42
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Sun Y, Myers CJ, Dicker AP, Lu B. A novel radiation-induced p53 mutation is not implicated in radiation resistance via a dominant-negative effect. PLoS One 2014; 9:e87492. [PMID: 24558369 PMCID: PMC3928108 DOI: 10.1371/journal.pone.0087492] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2013] [Accepted: 12/27/2013] [Indexed: 11/19/2022] Open
Abstract
Understanding the mutations that confer radiation resistance is crucial to developing mechanisms to subvert this resistance. Here we describe the creation of a radiation resistant cell line and characterization of a novel p53 mutation. Treatment with 20 Gy radiation was used to induce mutations in the H460 lung cancer cell line; radiation resistance was confirmed by clonogenic assay. Limited sequencing was performed on the resistant cells created and compared to the parent cell line, leading to the identification of a novel mutation (del) at the end of the DNA binding domain of p53. Levels of p53, phospho-p53, p21, total caspase 3 and cleaved caspase 3 in radiation resistant cells and the radiation susceptible (parent) line were compared, all of which were found to be similar. These patterns held true after analysis of p53 overexpression in H460 cells; however, H1299 cells transfected with mutant p53 did not express p21, whereas those given WT p53 produced a significant amount, as expected. A luciferase assay demonstrated the inability of mutant p53 to bind its consensus elements. An MTS assay using H460 and H1299 cells transfected with WT or mutant p53 showed that the novel mutation did not improve cell survival. In summary, functional characterization of a radiation-induced p53 mutation in the H460 lung cancer cell line does not implicate it in the development of radiation resistance.
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Affiliation(s)
- Yunguang Sun
- Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America
| | - Carey Jeanne Myers
- Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America
| | - Adam Paul Dicker
- Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America
| | - Bo Lu
- Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America
- * E-mail:
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Beggs AD, Domingo E, Abulafi M, Hodgson SV, Tomlinson IPM. A study of genomic instability in early preneoplastic colonic lesions. Oncogene 2013; 32:5333-7. [PMID: 23246972 PMCID: PMC3898108 DOI: 10.1038/onc.2012.584] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2012] [Revised: 10/15/2012] [Accepted: 10/28/2012] [Indexed: 12/16/2022]
Abstract
It is difficult to explain the differential rates of progression of premalignant colonic lesions and differences in behaviour of morphologically similar lesions. Heterogeneity for microsatellite instability (MSI) and promoter methylation in driving these phenomena forward may explain this; however, no previous analysis has examined this in detail at the gland level, the smallest unit of colorectal premalignant lesions. We aimed to carry out an analysis of gland level genomic instability for MSI and promoter methylation. MSI occurred significantly more frequently (20%) in colonic glands than has previously been observed in whole colorectal polyps. Significant promoter methylation was seen in MLH1, PMS2, MLH3 and MSH3 as well as significant heterogeneity for both MSI and promoter methylation. Methylation and MSI may have a significant role in driving forward colorectal carcinogenesis, although in the case of MSI, this association is less clear as it occurs significantly more frequently than previously thought, and may simply be a passenger in the adenoma-carcinoma sequence. Promoter methylation in MLH1, MLH3, MSH3 and PMS2 was also found to be significantly associated with MSI and should be investigated further. A total of 273 colorectal glands (126 hyperplastic, 147 adenomatous) were isolated via laser capture microdissection (targeted at regions of MLH1 loss) from 93 colonic polyps and tested for MSI, and promoter methylation of the DNA mismatch repair genes MLH1, MSH2, MLH3, MSH6, PMS2, MGMT and MLH3 via methylation specific multiplex ligation-dependent probe amplification. Logistic regression modelling was then used to identify significant associations between promoter methylation and gland histological type and MSI status.
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Affiliation(s)
- A D Beggs
- Molecular and Population Genetics Laboratory and NIHR Comprehensive Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
- Department of Surgery, Croydon University Hospital, Croydon, UK
| | - E Domingo
- Molecular and Population Genetics Laboratory and NIHR Comprehensive Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
| | - M Abulafi
- Department of Surgery, Croydon University Hospital, Croydon, UK
| | - S V Hodgson
- Department of Medical Genetics, St George's University of London, Cranmer Terrace, Tooting, London, UK
| | - I P M Tomlinson
- Molecular and Population Genetics Laboratory and NIHR Comprehensive Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
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Kisiel JB, Ahlquist DA. Stool DNA testing for cancer surveillance in inflammatory bowel disease: an early view. Therap Adv Gastroenterol 2013; 6:371-80. [PMID: 24003338 PMCID: PMC3756632 DOI: 10.1177/1756283x13487941] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
Patients with inflammatory bowel disease (IBD) are at increased risk for colorectal cancer (CRC). Despite weak supporting evidence, important logistic barriers and high cost, colonoscopy is currently the only recommended approach to CRC surveillance in patients with IBD. As such, there is imperative to explore alternative or complementary strategies with potential to improve the efficiency and effectiveness of surveillance in IBD. Given our increasing understanding of tumorigenesis in IBD and the accompanying cascade of molecular alterations, there is a strong rationale to pursue biomarker assays for this application. Stool-based DNA testing with advanced technology has been shown to be highly discriminatory for detection of sporadic colorectal cancer and advanced precancers. In early observations, stool DNA testing also shows promise for the accurate detection of IBD-associated colorectal neoplasms. These findings raise important clinical and translational questions about how to best evaluate and develop this technology, and devise clinical algorithms that will complement colonoscopy to improve patient outcomes.
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Affiliation(s)
- John B Kisiel
- Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First Street Southwest, Rochester, MN 55905, USA
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45
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Fischer JM, Schepers AG, Clevers H, Shibata D, Liskay RM. Occult progression by Apc-deficient intestinal crypts as a target for chemoprevention. Carcinogenesis 2013; 35:237-46. [PMID: 23996931 DOI: 10.1093/carcin/bgt296] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Although Apc mutation is widely considered an initiating event in colorectal cancer, little is known about the earliest stages of tumorigenesis following sporadic Apc loss. Therefore, we have utilized a novel mouse model that facilitates the sporadic inactivation of Apc via frameshift reversion of Cre in single, isolated cells and subsequently tracks the fates of Apc-deficient intestinal cells. Our results suggest that consistent with Apc being a 'gatekeeper', loss of Apc early in life during intestinal growth leads to adenomas or increased crypt fission, manifested by fields of mutant but otherwise normal-appearing crypts. In contrast, Apc loss occurring later in life has minimal consequences, with mutant crypts being less prone to either increased crypt fission or adenoma formation. Using the stem cell-specific Lgr5-CreER mouse, we generated different sized fields of Apc-deficient crypts via independent recombination events and found that field size correlates with progression to adenoma. To evaluate this early stage prior to adenoma formation as a therapeutic target, we examined the chemopreventive effects of sulindac on Apc-deficient occult crypt fission. We found that sulindac treatment started early in life inhibits the morphologically occult spread of Apc-deficient crypts and thus reduces adenoma numbers. Taken together these results suggest that: (i) earlier Apc loss promotes increased crypt fission, (ii) a field of Apc-deficient crypts, which can form via occult crypt fission or independent neighboring events, is an important intermediate between loss of Apc and adenoma formation and (iii) normal-appearing Apc-deficient crypts are potential unappreciated targets for cancer screening and chemoprevention.
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Affiliation(s)
- Jared M Fischer
- Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR 97239, USA
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Soto-Ortiz L, Brody JP. Similarities in the Age-Specific Incidence of Colon and Testicular Cancers. PLoS One 2013; 8:e66694. [PMID: 23840520 PMCID: PMC3694153 DOI: 10.1371/journal.pone.0066694] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2013] [Accepted: 05/09/2013] [Indexed: 12/20/2022] Open
Abstract
Colon cancers are thought to be an inevitable result of aging, while testicular cancers are thought to develop in only a small fraction of men, beginning in utero. These models of carcinogenesis are, in part, based upon age-specific incidence data. The specific incidence for colon cancer appears to monotonically increase with age, while that of testicular cancer increases to a maximum value at about 35 years of age, then declines to nearly zero by the age of 80. We hypothesized that the age-specific incidence for these two cancers is similar; the apparent difference is caused by a longer development time for colon cancer and the lack of age-specific incidence data for people over 84 years of age. Here we show that a single distribution can describe the age-specific incidence of both colon carcinoma and testicular cancer. Furthermore, this distribution predicts that the specific incidence of colon cancer should reach a maximum at about age 90 and then decrease. Data on the incidence of colon carcinoma for women aged 85–99, acquired from SEER and the US Census, is consistent with this prediction. We conclude that the age specific data for testicular cancers and colon cancers is similar, suggesting that the underlying process leading to the development of these two forms of cancer may be similar.
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Affiliation(s)
- Luis Soto-Ortiz
- Department of Biomedical Engineering, University of California Irvine, Irvine, California, United States of America
| | - James P. Brody
- Department of Biomedical Engineering, University of California Irvine, Irvine, California, United States of America
- * E-mail:
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Cancer systems biology in the genome sequencing era: part 1, dissecting and modeling of tumor clones and their networks. Semin Cancer Biol 2013; 23:279-85. [PMID: 23791722 DOI: 10.1016/j.semcancer.2013.06.002] [Citation(s) in RCA: 62] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2013] [Revised: 06/04/2013] [Accepted: 06/09/2013] [Indexed: 02/05/2023]
Abstract
Recent tumor genome sequencing confirmed that one tumor often consists of multiple cell subpopulations (clones) which bear different, but related, genetic profiles such as mutation and copy number variation profiles. Thus far, one tumor has been viewed as a whole entity in cancer functional studies. With the advances of genome sequencing and computational analysis, we are able to quantify and computationally dissect clones from tumors, and then conduct clone-based analysis. Emerging technologies such as single-cell genome sequencing and RNA-Seq could profile tumor clones. Thus, we should reconsider how to conduct cancer systems biology studies in the genome sequencing era. We will outline new directions for conducting cancer systems biology by considering that genome sequencing technology can be used for dissecting, quantifying and genetically characterizing clones from tumors. Topics discussed in Part 1 of this review include computationally quantifying of tumor subpopulations; clone-based network modeling, cancer hallmark-based networks and their high-order rewiring principles and the principles of cell survival networks of fast-growing clones.
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Lee KB, Park DJ, Choe G, Kim HH, Kim WH, Lee HS. Protein expression status in mucosal and submucosal portions of early gastric cancers and their predictive value for lymph node metastasis. APMIS 2013; 121:926-37. [PMID: 23758612 DOI: 10.1111/apm.12119] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2012] [Accepted: 04/02/2013] [Indexed: 01/28/2023]
Abstract
We aimed to find out predictive markers for lymph node (LN) metastasis of early gastric carcinoma (EGC) by separating evaluation of protein expression in mucosa and submucosa considering tumor heterogeneity. We selected 37 pN1-3 EGCs and depth- and size-matched 31 pN0 EGCs as training set and 72 EGCs including 14 pN1-3 EGCs as test set. Protein expression for β-catenin, E-cadherin, N-cadherin, galectin-3, c-MET, TrkB, and Ki-67 was assessed by immunohistochemistry in mucosal (-m) and submucosal (-sm) portions of tumor. In the training set, Ki67-m was higher than in Ki67-sm (mean ± SD: 82.67 ± 11.99% vs 61.79 ± 22.53%, p < 0.001). Altered E-cadherin-sm, high Ki67-m, and high Ki67-sm were correlated with LN metastasis (p < 0.05) and Ki67-sm was independent with lymphatic invasion and desmoplasia (p = 0.015 by multivariate logistic analysis). The test set confirmed Ki67-sm and E-cadherin-sm as predictors of LN metastasis (p < 0.05). Submucosal EGCs with ≥2 predictive factors out of high Ki67-sm, altered E-cadherin-sm, large tumor size (≥3 cm), diffuse type histology, and present lymphatic invasion yielded 100% sensitivity and 90.9% specificity for prediction of LN metastasis in 21 submucosal EGCs of test set. The proliferative activity of tumor in submucosa is suggested to be an independent predictor for LN metastasis in EGC.
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Affiliation(s)
- Kyoung Bun Lee
- Department of Pathology, Seoul National University College of Medicine, Seoul, Korea
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Abstract
The generation of chimeras, which is now a standard technology for producing gene modified mutant mice, was originally developed as a tool for developmental biology. However, the application of conventional single marker chimeric mice for developmental study was initially limited. This situation has been dramatically changed by development of multicolor chimeric mice using various kinds of fluorescent proteins. Now using our technology, up to ten different clones could be distinguished by their colors, which enable us to perform more accurate statistical analyses and lineage tracing experiments than by conventional methods. This method could be applied to visualize not only cell turnover of normal stem cells but also cancer development of live tissues in vivo. In the present review, we will discuss how these methods have been developed and what questions they are now answering by mainly focusing on intestinal stem cells and intestinal tumors.
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Redirection of Human Cancer Cells upon the Interaction with the Regenerating Mouse Mammary Gland Microenvironment. Cells 2013; 2:43-56. [PMID: 24709643 PMCID: PMC3972660 DOI: 10.3390/cells2010043] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2012] [Revised: 12/24/2012] [Accepted: 01/08/2013] [Indexed: 11/29/2022] Open
Abstract
Tumorigenesis is often described as a result of accumulated mutations that lead to growth advantage and clonal expansion of mutated cells. There is evidence in the literature that cancer cells are influenced by the microenvironment. Our previous studies demonstrated that the mouse mammary gland is capable of redirecting mouse cells of non-mammary origins as well as Mouse Mammary Tumor Virus (MMTV)-neu transformed cells toward normal mammary epithelial cell fate during gland regeneration. Interestingly, the malignant phenotype of MMTV-neu transformed cells was suppressed during serial transplantation experiments. Here, we discuss our studies that demonstrated the potential of the regenerating mouse mammary gland to redirect cancer cells of different species into a functional tumor-free mammary epithelial cell progeny. Immunochemistry for human specific CD133, mitochondria, cytokeratins as well as milk proteins and FISH for human specific probe identified human epithelial cell progeny in ducts, lobules, and secretory acini. Fluorescent In Situ Hybridization (FISH) for human centromeric DNA and FACS analysis of propidium iodine staining excluded the possibility of mouse-human cell fusion. To our knowledge this is the first evidence that human cancer cells of embryonic or somatic origins respond to developmental signals generated by the mouse mammary gland microenvironment during gland regeneration in vivo.
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