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Mehra L, Bhowmik S, Makharia GK, Das P. Intestinal stem cell niche: An upcoming area of immense importance in gastrointestinal disorders. Indian J Gastroenterol 2025; 44:8-23. [PMID: 39514159 DOI: 10.1007/s12664-024-01699-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Accepted: 09/29/2024] [Indexed: 11/16/2024]
Abstract
The intestinal stem cell (ISC) niche is vital for maintaining the integrity and function of the intestinal epithelium. ISC populations, characterized by their high proliferation and multipotency, reside within a specialized microenvironment at the base of crypts. Crypt base columnar (CBC) cells at the deepest part of crypts serve as replicating ISCs, while position 4 label-retaining cells (LRCs) located higher up in the crypts are also important for ISC maintenance during experiments. The interplay between CBCs, position 4 LRCs, transient amplifying (TA) cells and other niche components, including the pericrypt stromal cells, ensures a continuous supply of differentiated epithelial cells. Recent advancements in ISC biomarker studies have provided valuable insights into their molecular signatures, regulatory pathways and roles in the pathogenesis of intestinal disorders. Understanding the ISC niche has significant therapeutic implications, as manipulating ISC behaviors and regenerating damaged or diseased intestinal tissue show promise for novel therapeutic approaches. ISC organoids have also provided a platform for studying intestinal diseases and testing personalized therapies. This comprehensive review covers the anatomical composition, physiological regulation, ISC biomarker studies, contribution to intestinal disorder pathogenesis and potential therapeutic implications of the ISC niche.
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Affiliation(s)
- Lalita Mehra
- Department of Pathology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110 029, India
| | - Subham Bhowmik
- Department of Pathology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110 029, India
| | - Govind K Makharia
- Department of Gastroenterology and Human Nutritions, All India Institute of Medical Sciences, New Delhi, 110 029, India
| | - Prasenjit Das
- Department of Pathology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110 029, India.
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Kumari B, Tiwari A, Meena S, Ahirwar DK. Inflammation-Associated Stem Cells in Gastrointestinal Cancers: Their Utility as Prognostic Biomarkers and Therapeutic Targets. Cancers (Basel) 2024; 16:3134. [PMID: 39335106 PMCID: PMC11429849 DOI: 10.3390/cancers16183134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2024] [Revised: 08/30/2024] [Accepted: 09/10/2024] [Indexed: 09/30/2024] Open
Abstract
Stem cells are critical for the development and homeostasis of the gastrointestinal (GI) tract. Inflammatory molecules are known to regulate the activity of stem cells. A comprehensive review specifically describing the role of inflammatory molecules in the regulation of stem cells within the GI tract and in GI cancers (GICs) is not available. This review focuses on understanding the role of inflammatory molecules and stem cells in maintaining homeostasis of the GI tract. We further discuss how inflammatory conditions contribute to the transformation of stem cells into tumor-initiating cells. We also describe the molecular mechanisms of inflammation and stem cell-driven progression and metastasis of GICs. Furthermore, we report on studies describing the prognostic value of cancer stem cells and the clinical trials evaluating their therapeutic utility. This review provides a detailed overview on the role of inflammatory molecules and stem cells in maintaining GI tract homeostasis and their implications for GI-related malignancies.
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Affiliation(s)
- Beauty Kumari
- Department of Bioscience & Bioengineering, Indian Institute of Technology Jodhpur, Jodhpur 342030, Rajasthan, India; (B.K.); (A.T.)
| | - Aniket Tiwari
- Department of Bioscience & Bioengineering, Indian Institute of Technology Jodhpur, Jodhpur 342030, Rajasthan, India; (B.K.); (A.T.)
| | - Sakshi Meena
- School of Life Sciences, Devi Ahilya Vishwavidyalaya Indore, Indore 452001, Madhya Pradesh, India;
| | - Dinesh Kumar Ahirwar
- Department of Bioscience & Bioengineering, Indian Institute of Technology Jodhpur, Jodhpur 342030, Rajasthan, India; (B.K.); (A.T.)
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3
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Dezfuli AAZ, Abu-Elghait M, Salem SS. Recent Insights into Nanotechnology in Colorectal Cancer. Appl Biochem Biotechnol 2024; 196:4457-4471. [PMID: 37751009 DOI: 10.1007/s12010-023-04696-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/16/2023] [Indexed: 09/27/2023]
Abstract
Colorectal cancer (CRC) is the third cancer among the known causes of cancer that impact people. Although CRC drug options are imperfect, primary detection of CRC can play a key role in treating the disease and reducing mortality. Cancer tissues show many molecular markers that can be used as a new way to advance therapeutic methods. Nanotechnology includes a wide range of nanomaterials with high diagnostic and therapeutic power. Several nanomaterials and nanoformulations can be used to treat cancer, especially CRC. In this review, we discuss recent insights into nanotechnology in colorectal cancer.
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Affiliation(s)
- Aram Asareh Zadegan Dezfuli
- Department of Microbiology, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
| | - Mohammed Abu-Elghait
- Department of Botany and Microbiology, Faculty of Science, Al-Azhar University, Cairo, Egypt
| | - Salem S Salem
- Department of Botany and Microbiology, Faculty of Science, Al-Azhar University, Cairo, Egypt.
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Xiang T, Wang J, Li H. Current applications of intestinal organoids: a review. Stem Cell Res Ther 2024; 15:155. [PMID: 38816841 PMCID: PMC11140936 DOI: 10.1186/s13287-024-03768-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2024] [Accepted: 05/21/2024] [Indexed: 06/01/2024] Open
Abstract
In the past decade, intestinal organoid technology has paved the way for reproducing tissue or organ morphogenesis during intestinal physiological processes in vitro and studying the pathogenesis of various intestinal diseases. Intestinal organoids are favored in drug screening due to their ability for high-throughput in vitro cultivation and their closer resemblance to patient genetic characteristics. Furthermore, as disease models, intestinal organoids find wide applications in screening diagnostic markers, identifying therapeutic targets, and exploring epigenetic mechanisms of diseases. Additionally, as a transplantable cellular system, organoids have played a significant role in the reconstruction of damaged epithelium in conditions such as ulcerative colitis and short bowel syndrome, as well as in intestinal material exchange and metabolic function restoration. The rise of interdisciplinary approaches, including organoid-on-chip technology, genome editing techniques, and microfluidics, has greatly accelerated the development of organoids. In this review, VOSviewer software is used to visualize hot co-cited journal and keywords trends of intestinal organoid firstly. Subsequently, we have summarized the current applications of intestinal organoid technology in disease modeling, drug screening, and regenerative medicine. This will deepen our understanding of intestinal organoids and further explore the physiological mechanisms of the intestine and drug development for intestinal diseases.
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Affiliation(s)
- Tao Xiang
- Department of Colorectal Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Jie Wang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Hangzhou, Zhejiang, China
| | - Hui Li
- Surgical Intensive Care Unit, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
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5
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Hu X, Yuan X, Zhang G, Song H, Ji P, Guo Y, Liu Z, Tian Y, Shen R, Wang D. The intestinal epithelial-macrophage-crypt stem cell axis plays a crucial role in regulating and maintaining intestinal homeostasis. Life Sci 2024; 344:122452. [PMID: 38462226 DOI: 10.1016/j.lfs.2024.122452] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2023] [Revised: 01/18/2024] [Accepted: 01/18/2024] [Indexed: 03/12/2024]
Abstract
The intestinal tract plays a vital role in both digestion and immunity, making its equilibrium crucial for overall health. This equilibrium relies on the dynamic interplay among intestinal epithelial cells, macrophages, and crypt stem cells. Intestinal epithelial cells play a pivotal role in protecting and regulating the gut. They form vital barriers, modulate immune responses, and engage in pathogen defense and cytokine secretion. Moreover, they supervise the regulation of intestinal stem cells. Macrophages, serving as immune cells, actively influence the immune response through the phagocytosis of pathogens and the release of cytokines. They also contribute to regulating intestinal stem cells. Stem cells, known for their self-renewal and differentiation abilities, play a vital role in repairing damaged intestinal epithelium and maintaining homeostasis. Although research has primarily concentrated on the connections between epithelial and stem cells, interactions with macrophages have been less explored. This review aims to fill this gap by exploring the roles of the intestinal epithelial-macrophage-crypt stem cell axis in maintaining intestinal balance. It seeks to unravel the intricate dynamics and regulatory mechanisms among these essential players. A comprehensive understanding of these cell types' functions and interactions promises insights into intestinal homeostasis regulation. Moreover, it holds potential for innovative approaches to manage conditions like radiation-induced intestinal injury, inflammatory bowel disease, and related diseases.
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Affiliation(s)
- Xiaohui Hu
- School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu Province 73000, China.
| | - Xinyi Yuan
- School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu Province 73000, China.
| | - Guokun Zhang
- School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu Province 73000, China.
| | - Haoyun Song
- School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu Province 73000, China.
| | - Pengfei Ji
- School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu Province 73000, China.
| | - Yanan Guo
- School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu Province 73000, China.
| | - Zihua Liu
- Lanzhou University Second Hospital, Lanzhou University, Lanzhou, Gansu Province 73000, China
| | - Yixiao Tian
- School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu Province 73000, China.
| | - Rong Shen
- School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu Province 73000, China.
| | - Degui Wang
- School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu Province 73000, China; NHC Key Laboratory of Diagnosis and Therapy of Gastrointestinal Tumor, Lanzhou, Gansu Province 730000, China.
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Wang H, Zheng H, Cao X, Meng P, Liu J, Zuo H, Zhang T, Wang Z. Association between serum γ-glutamyl transferase and advanced colorectal adenoma among inpatients: a case-control study. Front Oncol 2024; 13:1188017. [PMID: 38282678 PMCID: PMC10816217 DOI: 10.3389/fonc.2023.1188017] [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: 03/22/2023] [Accepted: 12/20/2023] [Indexed: 01/30/2024] Open
Abstract
Emerging evidence suggests a link between γ-glutamyl transferase (GGT) and various malignancies. However, the relationship between GGT and advanced colorectal adenoma, a critical precursor to colorectal cancer, remains unclear. This study aimed to elucidate this relationship. We conducted a single-center retrospective study from April 2015 to June 2022, enrolling 3534 inpatients including 525 cases and 3009 controls. Data were extracted from the electronic medical records, encompassing clinicodemographic characteristics, co-morbidities, and several blood biochemical indicators. Utilizing logistic regression and curve fitting, we explored the relationship between GGT and advanced colorectal adenoma. After adjustment for confounding factors, we found that for each 20-unit increase in GGT, the risk of advanced colorectal adenoma increased by 6% (OR= 1.06 [1.01-1.12]). Moreover, individuals with high GGT levels (≥50 U/L) had a 61% higher risk of advanced colorectal adenoma compared to those with low GGT levels (<50 U/L) (OR=1.61 [1.13-2.31]). Subgroup analysis demonstrated the robustness of these findings across subjects with different characteristics. High GGT levels were associated with higher odds of advanced colorectal adenoma. Our findings suggest that elevated GGT levels may serve as a potential diagnostic marker for advanced colorectal adenoma, providing new insights into its screening strategies.
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Affiliation(s)
- Huijie Wang
- Department of Endoscopy, Shijiazhuang Traditional Chinese Medicine Hospital, Shijiazhuang, China
| | - Huanwei Zheng
- Department of Gastroenterology, Shijiazhuang Traditional Chinese Medicine Hospital, Shijiazhuang, China
| | - Xu Cao
- Department of Endoscopy, Shijiazhuang Traditional Chinese Medicine Hospital, Shijiazhuang, China
| | - Ping Meng
- Department of Gastroenterology, Shijiazhuang Traditional Chinese Medicine Hospital, Shijiazhuang, China
| | - Jinli Liu
- Department of Endoscopy, Shijiazhuang Traditional Chinese Medicine Hospital, Shijiazhuang, China
| | - Haiying Zuo
- Graduate School, Hebei North University, Zhangjiakou, China
| | - Teng Zhang
- Institute of Traditional Chinese Medicine, North China University of Science and Technology, Tangshan, China
| | - Zhichao Wang
- Graduate School, Hebei North University, Zhangjiakou, China
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Soleimani A, Saeedi N, Al-Asady AM, Nazari E, Hanaie R, Khazaei M, Ghorbani E, Akbarzade H, Ryzhikov M, Avan A, Mehr SMH. Colorectal Cancer Stem Cell Biomarkers: Biological Traits and Prognostic Insights. Curr Pharm Des 2024; 30:1386-1397. [PMID: 38623972 DOI: 10.2174/0113816128291321240329050945] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2023] [Revised: 03/08/2024] [Accepted: 03/13/2024] [Indexed: 04/17/2024]
Abstract
Due to self-renewal, differentiation, and limitless proliferation properties, Cancer Stem Cells (CSCs) increase the probability of tumor development. These cells are identified by using CSC markers, which are highly expressed proteins on the cell surface of CSCs. Recently, the therapeutic application of CSCs as novel biomarkers improved both the prognosis and diagnosis outcome of colorectal Cancer. In the present review, we focused on a specific panel of colorectal CSC markers, including LGR5, ALDH, CD166, CD133, and CD44, which offers a targeted and comprehensive analysis of their functions. The selection criteria for these markers cancer were based on their established significance in Colorectal Cancer (CRC) pathogenesis and clinical outcomes, providing novel insights into the CSC biology of CRC. Through this approach, we aim to elevate understanding and stimulate further research for developing effective diagnostic and therapeutic strategies in CRC.
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Affiliation(s)
- Atena Soleimani
- Department of Biochemistry, Mashhad University of Medical Sciences, Razavi Khorasan, Mashhad, Iran
| | - Nikoo Saeedi
- Medical School, Islamic Azad University, Mashhad, Iran
| | | | - Elnaz Nazari
- Department of Physiology, Mashhad University of Medical Sciences, Razavi Khorasan, Mashhad, Iran
| | - Reyhane Hanaie
- Department of Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Razavi Khorasan, Mashhad, Iran
| | - Majid Khazaei
- Department of Physiology, Mashhad University of Medical Sciences, Razavi Khorasan, Mashhad, Iran
| | - Elnaz Ghorbani
- Department of Microbiology, Mashhad University of Medical Sciences, Razavi Khorasan, Mashhad, Iran
| | - Hamed Akbarzade
- Department of Biochemistry, Mashhad University of Medical Sciences, Razavi Khorasan, Mashhad, Iran
| | - Mikhail Ryzhikov
- Department of Biochemistry, Saint Louis University, St. Louis, MO 63103, USA
| | - Amir Avan
- Department of Genetics, Mashhad University of Medical Sciences, Razavi Khorasan, Mashhad, Iran
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Fang KT, Hung H, Lau NYS, Chi JH, Wu DC, Cheng KH. Development of a Genetically Engineered Mouse Model Recapitulating LKB1 and PTEN Deficiency in Gastric Cancer Pathogenesis. Cancers (Basel) 2023; 15:5893. [PMID: 38136437 PMCID: PMC10741874 DOI: 10.3390/cancers15245893] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Revised: 12/12/2023] [Accepted: 12/15/2023] [Indexed: 12/24/2023] Open
Abstract
The LKB1 and PTEN genes are critical in gastric cancer (G.C.) development. LKB1, a robust tumor suppressor gene, encodes a serine/threonine kinase that directly triggers the activation of AMPK-an integral cellular metabolic kinase. The role of the LKB1 pathway extends to maintaining the stability of epithelial junctions by regulating E-cadherin expression. Conversely, PTEN, a frequently mutated tumor suppressor gene in various human cancers, emerges as a pivotal negative regulator of the phosphoinositide 3-kinase (PI3K) signaling pathway. This study is set to leverage the H+/K+ ATPase Cre transgene strain to precisely target Cre recombinase expression at parietal cells within the stomach. This strategic maneuver seeks to selectively nullify the functions of both LKB1 and PTEN in a manner specific to the stomach, thereby instigating the development of G.C. in a fashion akin to human gastric adenocarcinoma. Moreover, this study endeavors to dissect the intricate ways in which these alterations contribute to the histopathologic advancement of gastric tumors, their potential for invasiveness and metastasis, their angiogenesis, and the evolving tumor stromal microenvironment. Our results show that conditional deletion of PTEN and LKB1 provides an ideal cancer microenvironment for G.C. tumorigenesis by promoting cancer cell proliferation, angiogenesis, and metastasis.
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Affiliation(s)
- Kuan-Te Fang
- Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 80424, Taiwan; (K.-T.F.); (H.H.); (N.Y.S.L.); (J.-H.C.)
| | - Hsin Hung
- Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 80424, Taiwan; (K.-T.F.); (H.H.); (N.Y.S.L.); (J.-H.C.)
| | - Nga Yin Sadonna Lau
- Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 80424, Taiwan; (K.-T.F.); (H.H.); (N.Y.S.L.); (J.-H.C.)
- Center of Excellence for Metabolic Associated Fatty Liver Disease, National Sun Yat-Sen University, Kaohsiung 80424, Taiwan
| | - Jou-Hsi Chi
- Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 80424, Taiwan; (K.-T.F.); (H.H.); (N.Y.S.L.); (J.-H.C.)
- Center of Excellence for Metabolic Associated Fatty Liver Disease, National Sun Yat-Sen University, Kaohsiung 80424, Taiwan
| | - Deng-Chyang Wu
- Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan;
| | - Kuang-Hung Cheng
- Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 80424, Taiwan; (K.-T.F.); (H.H.); (N.Y.S.L.); (J.-H.C.)
- Center of Excellence for Metabolic Associated Fatty Liver Disease, National Sun Yat-Sen University, Kaohsiung 80424, Taiwan
- Department of Medical Laboratory Science and Biotechnology, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- National Institute of Cancer Research, National Health Research Institutes, Tainan 70456, Taiwan
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Ahmad Sophien AN, Jusop AS, Tye GJ, Tan YF, Wan Kamarul Zaman WS, Nordin F. Intestinal stem cells and gut microbiota therapeutics: hype or hope? Front Med (Lausanne) 2023; 10:1195374. [PMID: 37547615 PMCID: PMC10400779 DOI: 10.3389/fmed.2023.1195374] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Accepted: 07/10/2023] [Indexed: 08/08/2023] Open
Abstract
The vital role of the intestines as the main site for the digestion and absorption of nutrients for the body continues subconsciously throughout one's lifetime, but underneath all the complex processes lie the intestinal stem cells and the gut microbiota that work together to maintain the intestinal epithelium. Intestinal stem cells (ISC) are multipotent stem cells from which all intestinal epithelial cells originate, and the gut microbiota refers to the abundant collection of various microorganisms that reside in the gastrointestinal tract. Both reside in the intestines and have many mechanisms and pathways in place with the ultimate goal of co-managing human gastrointestinal tract homeostasis. Based on the abundance of research that is focused on either of these two topics, this suggests that there are many methods by which both players affect one another. Therefore, this review aims to address the relationship between ISC and the gut microbiota in the context of regenerative medicine. Understanding the principles behind both aspects is therefore essential in further studies in the field of regenerative medicine by making use of the underlying designed mechanisms.
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Affiliation(s)
- Ahmad Naqiuddin Ahmad Sophien
- Centre for Tissue Engineering and Regenerative Medicine (CTERM), Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Amirah Syamimi Jusop
- Centre for Tissue Engineering and Regenerative Medicine (CTERM), Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Gee Jun Tye
- Institute for Research in Molecular Medicine (INFORMM), Universiti Sains Malaysia, Gelugor, Malaysia
| | - Yuen-Fen Tan
- PPUKM-MAKNA Cancer Center, Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur, Malaysia
- M. Kandiah Faculty of Medicine and Health Sciences (MK FMHS), Universiti Tunku Abdul Rahman, Kajang, Malaysia
| | - Wan Safwani Wan Kamarul Zaman
- Department of Biomedical Engineering, Faculty of Engineering, Universiti Malaya, Kuala Lumpur, Malaysia
- Centre for Innovation in Medical Engineering (CIME), Department of Biomedical Engineering, Faculty of Engineering, Universiti Malaya, Kuala Lumpur, Malaysia
| | - Fazlina Nordin
- Centre for Tissue Engineering and Regenerative Medicine (CTERM), Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
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Ma N, Chen X, Johnston LJ, Ma X. Gut microbiota-stem cell niche crosstalk: A new territory for maintaining intestinal homeostasis. IMETA 2022; 1:e54. [PMID: 38867904 PMCID: PMC10989768 DOI: 10.1002/imt2.54] [Citation(s) in RCA: 70] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/18/2022] [Revised: 08/04/2022] [Accepted: 08/14/2022] [Indexed: 06/14/2024]
Abstract
Intestinal epithelium undergoes rapid cellular turnover, relying on the local niche, to support intestinal stem cells (ISCs) function and self-renewal. Research into the association between ISCs and disease continues to expand at a rapid rate. However, the detailed interaction of ISCs and gut microbes remains to be elucidated. Thus, this review witnessed major advances in the crosstalk between ISCs and gut microbes, delivering key insights into (1) construction of ISC niche and molecular mechanism of how to jointly govern epithelial homeostasis and protect against intestinal diseases with the participation of Wnt, bone morphogenetic protein, and Notch; (2) differentiation fate of ISCs affect the gut microbiota. Meanwhile, the presence of intestinal microbes also regulates ISC function; (3) microbiota regulation on ISCs by Wnt and Notch signals through pattern recognition receptors; (4) how do specific microbiota-related postbiotics influence ISCs to maintain intestinal epithelial regeneration and homeostasis that provide insights into a promising alternative therapeutic method for intestinal diseases. Considering the detailed interaction is still unclear, it is necessary to further explore the regulatory role of gut microbiota on ISCs to utilize microbes to alleviate gut disorders. Furthermore, these major advances collectively drive us ever closer to breakthroughs in regenerative medicine and cancer treatment by microbial transplantation in the clinic.
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Affiliation(s)
- Ning Ma
- State Key Laboratory of Animal Nutrition, College of Animal Science and TechnologyChina Agricultural UniversityBeijingChina
| | - Xiyue Chen
- State Key Laboratory of Animal Nutrition, College of Animal Science and TechnologyChina Agricultural UniversityBeijingChina
| | - Lee J. Johnston
- West Central Research & Outreach CenterUniversity of MinnesotaMorrisMinnesotaUSA
| | - Xi Ma
- State Key Laboratory of Animal Nutrition, College of Animal Science and TechnologyChina Agricultural UniversityBeijingChina
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11
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Pashirzad M, Sathyapalan T, Sheikh A, Kesharwani P, Sahebkar A. Cancer stem cells: An overview of the pathophysiological and prognostic roles in colorectal cancer. Process Biochem 2022. [DOI: 10.1016/j.procbio.2022.02.006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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12
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Boby N, Cao X, Ransom A, Pace BT, Mabee C, Shroyer MN, Das A, Didier PJ, Srivastav SK, Porter E, Sha Q, Pahar B. Identification, Characterization, and Transcriptional Reprogramming of Epithelial Stem Cells and Intestinal Enteroids in Simian Immunodeficiency Virus Infected Rhesus Macaques. Front Immunol 2021; 12:769990. [PMID: 34887863 PMCID: PMC8650114 DOI: 10.3389/fimmu.2021.769990] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Accepted: 11/02/2021] [Indexed: 12/18/2022] Open
Abstract
Epithelial cell injury and impaired epithelial regeneration are considered key features in HIV pathogenesis and contribute to HIV-induced generalized immune activation. Understanding the molecular mechanisms underlying the disrupted epithelial regeneration might provide an alternative approach for the treatment of HIV-mediated enteropathy and immune activation. We have observed a significant increased presence of α defensin5+ (HD5) Paneth cells and proliferating Ki67+ epithelial cells as well as decreased expression of E-cadherin expression in epithelial cells during SIV infection. SIV infection did not significantly influence the frequency of LGR5+ stem cells, but the frequency of HD5+ cells was significantly higher compared to uninfected controls in jejunum. Our global transcriptomics analysis of enteroids provided novel information about highly significant changes in several important pathways like metabolic, TCA cycle, and oxidative phosphorylation, where the majority of the differentially expressed genes were downregulated in enteroids grown from chronically SIV-infected macaques compared to the SIV-uninfected controls. Despite the lack of significant reduction in LGR5+ stem cell population, the dysregulation of several intestinal stem cell niche factors including Notch, mTOR, AMPK and Wnt pathways as well as persistence of inflammatory cytokines and chemokines and loss of epithelial barrier function in enteroids further supports that SIV infection impacts on epithelial cell proliferation and intestinal homeostasis.
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Affiliation(s)
- Nongthombam Boby
- Division of Comparative Pathology, Tulane National Primate Research Center, Covington, LA, United States
| | - Xuewei Cao
- Department of Mathematical Sciences, Michigan Technological University, Houghton, MI, United States
| | - Alyssa Ransom
- Division of Comparative Pathology, Tulane National Primate Research Center, Covington, LA, United States
| | - Barcley T Pace
- Division of Comparative Pathology, Tulane National Primate Research Center, Covington, LA, United States
| | - Christopher Mabee
- Division of Comparative Pathology, Tulane National Primate Research Center, Covington, LA, United States
| | - Monica N Shroyer
- Division of Veterinary Medicine, Tulane National Primate Research Center, Covington, LA, United States
| | - Arpita Das
- Division of Microbiology, Tulane National Primate Research Center, Covington, LA, United States
| | - Peter J Didier
- Division of Comparative Pathology, Tulane National Primate Research Center, Covington, LA, United States
| | - Sudesh K Srivastav
- Department of Biostatistics, Tulane University, New Orleans, LA, United States
| | - Edith Porter
- Department of Biological Sciences, California State University, Los Angeles, Los Angeles, CA, United States
| | - Qiuying Sha
- Department of Mathematical Sciences, Michigan Technological University, Houghton, MI, United States
| | - Bapi Pahar
- Division of Comparative Pathology, Tulane National Primate Research Center, Covington, LA, United States.,Department of Microbiology and Immunology, Tulane University School of Medicine, New Orleans, LA, United States.,Department of Tropical Medicine, Tulane School of Public Health and Tropical Medicine, New Orleans, LA, United States
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13
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Deng S, Li L, Xu S, Wang X, Han T. Promotion of gastric tumor initiating cells in a 3D collagen gel culture model via YBX1/SPP1/NF-κB signaling. Cancer Cell Int 2021; 21:599. [PMID: 34758833 PMCID: PMC8579534 DOI: 10.1186/s12935-021-02307-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Accepted: 10/29/2021] [Indexed: 01/07/2023] Open
Abstract
Background The high potential for tumor recurrence and chemoresistance is a major challenge of clinical gastric cancer treatment. Increasing evidence suggests that the presence of tumor initiating cells (TICs) is the principal cause of tumor recurrence and chemoresistance. However, the underlying mechanism of TIC development remains controversial. Methods To identify novel molecular pathways in gastric cancer, we screened the genomic expression profile of 155 gastric cancer patients from the TCGA database. We then described an improved 3D collagen I gels and tested the effects of collagen on the TIC phenotype of gastric cells using colony formation assay, transwell assay, and nude mouse models. Additionally, cell apoptosis assay was performed to examine the cytotoxicity of 5-fluorine and paclitaxel on gastric cancer cells cultured in 3D collagen I gels. Results Elevated expression of type I collagen was observed in tumor tissues from high stage patients (stage T3–T4) when compared to the low stage group (n=10, stage T1–T2). Furthermore, tumor cells seeded in a low concentration of collagen gels acquired TIC-like phenotypes and revealed enhanced resistance to chemotherapeutic agents, which was dependent on an integrin β1 (ITGB1)/Y-box Binding Protein 1 (YBX1)/Secreted Phosphoprotein 1 (SPP1)/NF-κB signaling pathway. Importantly, inhibition of ITGB1/NF-κB signaling efficiently reversed the chemoresistance induced by collagen and promoted anticancer effects in vivo. Conclusions Our findings demonstrated that type I collagen promoted TIC-like phenotypes and chemoresistance through ITGB1/YBX1/SPP1/NF-κB pathway, which may provide novel insights into gastric cancer therapy. Supplementary Information The online version contains supplementary material available at 10.1186/s12935-021-02307-x.
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Affiliation(s)
- Shuangya Deng
- Department of General Surgery, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Lun Li
- Department of General Surgery, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Shu Xu
- Department of General Surgery, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Xiaobo Wang
- Department of General Surgery, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Tong Han
- Department of General Surgery, The Second Xiangya Hospital of Central South University, Changsha, China.
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14
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Moving Up a NOTCH: Defining the Stem Cell Niche in the Gastric Antrum. Cell Mol Gastroenterol Hepatol 2021; 13:339-340. [PMID: 34728187 PMCID: PMC8703116 DOI: 10.1016/j.jcmgh.2021.10.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 10/05/2021] [Accepted: 10/08/2021] [Indexed: 12/10/2022]
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15
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Paul B, Kysenius K, Hilton JB, Jones MWM, Hutchinson RW, Buchanan DD, Rosty C, Fryer F, Bush AI, Hergt JM, Woodhead JD, Bishop DP, Doble PA, Hill MM, Crouch PJ, Hare DJ. An integrated mass spectrometry imaging and digital pathology workflow for objective detection of colorectal tumours by unique atomic signatures. Chem Sci 2021; 12:10321-10333. [PMID: 34476052 PMCID: PMC8386113 DOI: 10.1039/d1sc02237g] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Accepted: 06/29/2021] [Indexed: 12/21/2022] Open
Abstract
Tumours are abnormal growths of cells that reproduce by redirecting essential nutrients and resources from surrounding tissue. Changes to cell metabolism that trigger the growth of tumours are reflected in subtle differences between the chemical composition of healthy and malignant cells. We used LA-ICP-MS imaging to investigate whether these chemical differences can be used to spatially identify tumours and support detection of primary colorectal tumours in anatomical pathology. First, we generated quantitative LA-ICP-MS images of three colorectal surgical resections with case-matched normal intestinal wall tissue and used this data in a Monte Carlo optimisation experiment to develop an algorithm that can classify pixels as tumour positive or negative. Blinded testing and interrogation of LA-ICP-MS images with micrographs of haematoxylin and eosin stained and Ki67 immunolabelled sections revealed Monte Carlo optimisation accurately identified primary tumour cells, as well as returning false positive pixels in areas of high cell proliferation. We analysed an additional 11 surgical resections of primary colorectal tumours and re-developed our image processing method to include a random forest regression machine learning model to correctly identify heterogenous tumours and exclude false positive pixels in images of non-malignant tissue. Our final model used over 1.6 billion calculations to correctly discern healthy cells from various types and stages of invasive colorectal tumours. The imaging mass spectrometry and data analysis methods described, developed in partnership with clinical cancer researchers, have the potential to further support cancer detection as part of a comprehensive digital pathology approach to cancer care through validation of a new chemical biomarker of tumour cells.
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Affiliation(s)
- Bence Paul
- School of Geography, Earth and Atmospheric Sciences, The University of Melbourne Parkville Victoria 3010 Australia
| | - Kai Kysenius
- Department of Biochemistry and Pharmacology, School of Biomedical Sciences, The University of Melbourne Parkville Victoria 3010 Australia
| | - James B Hilton
- Department of Biochemistry and Pharmacology, School of Biomedical Sciences, The University of Melbourne Parkville Victoria 3010 Australia
| | - Michael W M Jones
- Central Analytical Research Facility, Queensland University of Technology Brisbane Queensland 4000 Australia
| | | | - Daniel D Buchanan
- Department of Clinical Pathology, Melbourne Medical School, The University of Melbourne Parkville Victoria 3010 Australia
- University of Melbourne Centre for Cancer Research, The University of Melbourne Parkville Victoria 3010 Australia
- Genomic Medicine and Family Cancer Clinic, Royal Melbourne Hospital Melbourne Victoria 3000 Australia
| | - Christophe Rosty
- Envoi Pathology Brisbane Queensland 4000 Australia
- Faculty of Medicine, The University of Queensland Brisbane Queensland 4000 Australia
- Department of Clinical Pathology, The University of Melbourne Parkville Victoria 3010 Australia
| | - Fred Fryer
- Agilent Technologies Australia Mulgrave Victoria 3170 Australia
| | - Ashley I Bush
- Melbourne Dementia Research Centre at the Florey Institute of Neuroscience and Mental Health, The University of Melbourne Parkville Victoria 3010 Australia
| | - Janet M Hergt
- School of Geography, Earth and Atmospheric Sciences, The University of Melbourne Parkville Victoria 3010 Australia
| | - Jon D Woodhead
- School of Geography, Earth and Atmospheric Sciences, The University of Melbourne Parkville Victoria 3010 Australia
| | - David P Bishop
- Atomic Medicine Initiative, University of Technology Sydney Broadway NSW 2007 Australia
| | - Philip A Doble
- Atomic Medicine Initiative, University of Technology Sydney Broadway NSW 2007 Australia
| | - Michelle M Hill
- Centre for Clinical Research, Faculty of Medicine, The University of Queensland Herston Qld 4006 Australia
- QIMR Berghofer Medical Research Institute Herston Queensland 4006 Australia
| | - Peter J Crouch
- Department of Biochemistry and Pharmacology, School of Biomedical Sciences, The University of Melbourne Parkville Victoria 3010 Australia
| | - Dominic J Hare
- Melbourne Dementia Research Centre at the Florey Institute of Neuroscience and Mental Health, The University of Melbourne Parkville Victoria 3010 Australia
- Atomic Medicine Initiative, University of Technology Sydney Broadway NSW 2007 Australia
- School of BioSciences, The University of Melbourne Parkville Victoria 3010 Australia
- Monash eResearch Centre, Monash University Clayton Victoria 3800 Australia
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16
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Alharbi SA, Ovchinnikov DA, Wolvetang E. Leucine-rich repeat-containing G protein-coupled receptor 5 marks different cancer stem cell compartments in human Caco-2 and LoVo colon cancer lines. World J Gastroenterol 2021; 27:1578-1594. [PMID: 33958845 PMCID: PMC8058648 DOI: 10.3748/wjg.v27.i15.1578] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Revised: 01/22/2021] [Accepted: 02/25/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Colon cancer cell lines are widely used for research and for the screening of drugs that specifically target the stem cell compartment of colon cancers. It was reported that colon cancer carcinoma specimens contain a subset of leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5)-expressing stem cells, these so-called “tumour-initiating” cells, reminiscent in their properties of the normal intestinal stem cells (ISCs), may explain the apparent heterogeneity of colon cancer cell lines. Also, colon cancer is initiated by aberrant Wnt signaling in ISCs known to express high levels of LGR5. Furthermore, in vivo reports demonstrate the clonal expansion of intestinal adenomas from a single LGR5-expressing cell.
AIM To investigate whether colon cancer cell lines contain cancer stem cells and to characterize these putative cancer stem cells.
METHODS A portable fluorescent reporter construct based on a conserved fragment of the LGR5 promoter was used to isolate the cell compartments expressing different levels of LGR5 in two widely used colon cancer cell lines (Caco-2 and LoVo). These cells were then characterized according to their proliferation capacity, gene expression signatures of ISC markers, and their tumorigenic properties in vivo and in vitro.
RESULTS The data revealed that the LGR5 reporter can be used to identify and isolate a classical intestinal crypt stem cell-like population from the Caco-2, but not from the LoVo, cell lines, in which the cancer stem cell population is more akin to B lymphoma Moloney murine leukemia virus insertion region 1 homolog (+4 crypt) stem cells. This sub-population within Caco-2 cells exhibits an intestinal cancer stem cell gene expression signature and can both self-renew and generate differentiated LGR5 negative progeny. Our data also show that cells expressing high levels of LGR5/enhanced yellow fluorescent protein (EYFP) from this cell line exhibit tumorigenic-like properties in vivo and in vitro. In contrast, cell compartments of LoVo that are expressing high levels of LGR5/EYFP did not show these stem cell-like properties. Thus, cells that exhibit high levels of LGR5/EYFP expression represent the cancer stem cell compartment of Caco-2 colon cancer cells, but not LoVo cells.
CONCLUSION Our findings highlight the presence of a spectrum of different ISC-like compartments in different colon cancer cell lines. Their existence is an important consideration for their screening applications and should be taken into account when interpreting drug screening data. We have generated a portable LGR5-reporter that serves as a valuable tool for the identification and isolation of different colon cancer stem cell populations in colon cancer lines.
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Affiliation(s)
- Samah Abdulaali Alharbi
- Physiology Department, College of Medicine, Umm Al-Qura University, Makkah 24231, Saudi Arabia
- Department of Stem Cell Engineering Group, Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane 4072, QLD, Australia
| | - Dmitry A Ovchinnikov
- Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane 4072, QLD, Australia
| | - Ernst Wolvetang
- Department of Stem Cell Engineering Group, Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane 4072, QLD, Australia
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17
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Wang C, Ding S, Wang S, Shi Z, Pandey NK, Chudal L, Wang L, Zhang Z, Wen Y, Yao H, Lin L, Chen W, Xiong L. Endogenous tumor microenvironment-responsive multifunctional nanoplatforms for precision cancer theranostics. Coord Chem Rev 2021; 426:213529. [DOI: 10.1016/j.ccr.2020.213529] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
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18
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Aslam N, Abusharieh E, Abuarqoub D, Ali D, Al-Hattab D, Wehaibi S, Al-Kurdi B, Jamali F, Alshaer W, Jafar H, Awidi AS. Anti-oncogenic activities exhibited by paracrine factors of MSCs can be mediated by modulation of KITLG and DKK1 genes in glioma SCs in vitro. MOLECULAR THERAPY-ONCOLYTICS 2020; 20:147-165. [PMID: 33575478 PMCID: PMC7851499 DOI: 10.1016/j.omto.2020.11.005] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Accepted: 11/19/2020] [Indexed: 12/12/2022]
Abstract
Cancer stem cells (CSCs) use their stemness properties to perpetuate their lineage and survive chemotherapy. Currently cell-based and cell-free therapies are under investigation to develop novel anti-cancer treatment modalities. We designed this study to investigate how cell extracts of mesenchymal stem cells affect the growth of glioma stem cells in vitro. Gliospheres were generated from the U87MG cell line and treated with conditioned media of Wharton’s jelly and bone marrow mesenchymal stem cells. The effects were investigated at the functional and molecular levels. Our results showed that conditioned media from both types of mesenchymal stem cells changed the morphology of spheres and inhibited the proliferation, invasion, and self-renewal ability of glioma stem cells. At the molecular level, metabolism interruption at oxidative phosphorylation, cell cycle arrest, cell differentiation, and upregulation of the immune response were observed. Furthermore, this effect was mediated by the upregulation of the DKK1 gene inhibiting the Wnt pathway mediated by growth factor activity and downregulation of the KITLG gene activated by growth factor and cytokine activity, inhibiting multiple pathways. We conclude that different types of mesenchymal stem cells possess antitumor properties and their paracrine factors, in combination with anti-immune modalities, can provide practical therapeutic targets for glioblastoma treatment.
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Affiliation(s)
- Nazneen Aslam
- Cell Therapy Center, The University of Jordan, Amman 11942, Jordan
| | - Elham Abusharieh
- Cell Therapy Center, The University of Jordan, Amman 11942, Jordan.,Faculty of Pharmacy, The University of Jordan, Amman 11942, Jordan
| | - Duaa Abuarqoub
- Cell Therapy Center, The University of Jordan, Amman 11942, Jordan.,Department of Pharmacology and Biomedical Sciences, Faculty of Pharmacy and Medical Sciences, University of Petra, Amman 11196, Jordan
| | - Dema Ali
- Cell Therapy Center, The University of Jordan, Amman 11942, Jordan
| | - Dana Al-Hattab
- Cell Therapy Center, The University of Jordan, Amman 11942, Jordan.,Laboratory for Nanomedicine, Division of Biological & Environmental Science & Engineering (BESE), King Abdullah University of Science and Technology (KAUST), Thuwal 23955-6900, Saudi Arabia
| | - Suha Wehaibi
- Cell Therapy Center, The University of Jordan, Amman 11942, Jordan
| | - Ban Al-Kurdi
- Cell Therapy Center, The University of Jordan, Amman 11942, Jordan
| | - Fatima Jamali
- Cell Therapy Center, The University of Jordan, Amman 11942, Jordan
| | - Walhan Alshaer
- Cell Therapy Center, The University of Jordan, Amman 11942, Jordan
| | - Hanan Jafar
- Cell Therapy Center, The University of Jordan, Amman 11942, Jordan.,Department of Anatomy and Histology, School of Medicine, The University of Jordan, Amman 11942, Jordan
| | - Abdalla S Awidi
- Cell Therapy Center, The University of Jordan, Amman 11942, Jordan.,Department of Medicine, School of Medicine, The University of Jordan, Amman 11942, Jordan.,Department of Hematology and Oncology, Jordan University Hospital, The University of Jordan, Amman 11942, Jordan
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19
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Maric S, Flüchter P, Guglielmetti LC, Staerkle RF, Sasse T, Restin T, Schneider C, Holland-Cunz SG, Crenn P, Vuille-Dit-Bille RN. Plasma citrulline correlates with basolateral amino acid transporter LAT4 expression in human small intestine. Clin Nutr 2020; 40:2244-2251. [PMID: 33077272 PMCID: PMC7546687 DOI: 10.1016/j.clnu.2020.10.003] [Citation(s) in RCA: 5] [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: 05/16/2020] [Revised: 09/29/2020] [Accepted: 10/01/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND & AIMS Plasma citrulline, a non-protein amino acid, is a biochemical marker of small intestine enterocyte mass in humans. Indeed, citrulline is highly correlated with residual bowel length in patients with short bowel syndrome. It is known to be synthesised in epithelial cells of the small intestine from other amino acids (precursors). Citrulline is then released into systemic circulation and interconverted into arginine in kidneys. If plasma citrulline concentration depends on abundance of intestinal amino acid transporters is not known. The aim of the present study was to explore whether plasma citrulline concentration correlates with the expression of intestinal amino acid transporters. Furthermore, we assessed if arginine in urine correlates with plasma citrulline. METHODS Duodenal samples, blood plasma and urine were collected from 43 subjects undergoing routine gastroduodenoscopy. mRNA expression of seven basolateral membrane amino acid transporters/transporter subunits were assessed by real-time PCR. Plasma and urine amino acid concentrations of citrulline, its precursors and other amino acids were analysed using High Performance Liquid Chromatography measurements. Amino acid transporter mRNA expression was correlated with blood plasma and urine levels of citrulline and its precursors using Spearman's rank correlation. Likewise, urine arginine was correlated with plasma citrulline. RESULTS Plasma citrulline correlated with the mRNA expression of basolateral amino acid transporter LAT4 (Spearman's r = 0.467, p = 0.028) in small intestine. None of the other basolateral membrane transporters/transporter subunits assessed correlated with plasma citrulline. Plasma citrulline correlated with urinary arginine, (Spearman's r = 0.419, p = 0.017), but not with urinary citrulline or other proteinogenic amino acids in the urine. CONCLUSIONS In this study, we showed for the first time that small intestinal basolateral LAT4 expression correlates with plasma citrulline concentration. This finding indicates that LAT4 has an important function in mediating citrulline efflux from enterocytes. Furthermore, urine arginine correlated with plasma citrulline, indicating arginine in the urine as possible additional marker for small intestine enterocyte mass. Finally, basolateral LAT4 expression along the human small intestine was shown for the first time.
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Affiliation(s)
- Stefano Maric
- University of Basel, School of Medicine, Basel, Switzerland
| | | | | | - Ralph Fabian Staerkle
- Clarunis, University Center for Gastrointestinal and Liver Diseases, Basel, Switzerland
| | - Tom Sasse
- Department of Cardiology, University Hospital of Zurich, Switzerland
| | - Tanja Restin
- Institute of Physiology, University of Zurich, Switzerland; Newborn Research Zurich, Department of Neonatology, University Hospital Zurich and University of Zurich, Zurich, Switzerland
| | | | | | - Pascal Crenn
- Hepato-gastroenterology and Nutrition, Hôpital Ambroise Paré, APHP-Université Paris Saclay, Boulogne Billancourt, France
| | - Raphael Nicolas Vuille-Dit-Bille
- Institute of Physiology, University of Zurich, Switzerland; Department of Pediatric Surgery, University Children's Hospital of Basel, Switzerland.
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20
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Nanostructured metal oxides and its hybrids for photocatalytic and biomedical applications. Adv Colloid Interface Sci 2020; 281:102178. [PMID: 32470668 DOI: 10.1016/j.cis.2020.102178] [Citation(s) in RCA: 116] [Impact Index Per Article: 23.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2020] [Revised: 05/06/2020] [Accepted: 05/14/2020] [Indexed: 01/31/2023]
Abstract
Metal oxide nanoparticles and its hybrids are deemed to be one of the most attractive materials in an extensive range of applications due to their impressive optical, electronic, photocatalytic, and biological properties. Metal oxide based nanomaterials with extraordinary characteristics have been proposed, prepared, and used as main materials in the recent area of photocatalysis and biomedicine, due to their non-toxic nature, large specific surface area, useful optical bandgap, and high biological activity. Herein, this review reveals the recent advance development in the area like photocatalytic, anticancer and antibacterial performance of metal oxide nanomaterials for multidimensional applications. Consequently, we also focused on the encountered difficulties and prospects for the future application of metal oxide-based composites as promising candidates for the development of highly efficient photocatalytic and biomedical systems. This review article also delivers advanced knowledge to the scientific community who intends to design efficient photocatalytic and biomedical systems.
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21
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Personalizing Gastric Cancer Screening With Predictive Modeling of Disease Progression Biomarkers. Appl Immunohistochem Mol Morphol 2020; 27:270-277. [PMID: 29084052 DOI: 10.1097/pai.0000000000000598] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Gastric cancer (GC) remains the third most common cause of cancer-related death worldwide. Infection with Helicobacter pylori is responsible for over 70% of GC incidence; colonization induces chronic inflammation, which can facilitate progression to intestinal metaplasia, dysplasia, and GC (Correa pathway). Although H. pylori eradication is a necessary first step in GC prevention, some patients continue to progress to advanced stage disease if substantial tissue damage has occurred or inflammation persists. This progression is often asymptomatic until cancer reaches stage IV, yet efficient, cost-effective screening protocols for patients who present with early stages of the Correa pathway do not exist. Given the high interpatient heterogeneity in progression time through this pathway, such screening protocols must necessarily be personalized. This requires the identification of reliable and longitudinally assessable biomarkers of patient-specific progression. Several gastric stem cell (GSC) markers including CD44, CD133, and Lgr5 are upregulated in GC. Here we show a significant stepwise increase in immunohistochemical staining for these markers in biopsies at different stages of the Correa pathway, suggesting GSC fraction to be a promising candidate biomarker for early detection of malignant transformation. We present a mathematical model capable of both simulating clinically observed increases in GSC fraction in longitudinal biopsy samples of individual patients, and forecasting patient-specific disease progression trajectories based only on characteristics identified from immunohistochemistry at initial presentation. From these forecasts, personalized screening schedules may be identified that would allow early stratification of high-risk patients, and potentially earlier detection of dysplasia or early-stage GC.
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22
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Balic JJ, Saad MI, Dawson R, West AJ, McLeod L, West AC, D'Costa K, Deswaerte V, Dev A, Sievert W, Gough DJ, Bhathal PS, Ferrero RL, Jenkins BJ. Constitutive STAT3 Serine Phosphorylation Promotes Helicobacter-Mediated Gastric Disease. THE AMERICAN JOURNAL OF PATHOLOGY 2020; 190:1256-1270. [PMID: 32201262 DOI: 10.1016/j.ajpath.2020.01.021] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/15/2019] [Revised: 12/17/2019] [Accepted: 01/27/2020] [Indexed: 12/16/2022]
Abstract
Gastric cancer is associated with chronic inflammation (gastritis) triggered by persistent Helicobacter pylori (H. pylori) infection. Elevated tyrosine phosphorylation of the latent transcription factor STAT3 is a feature of gastric cancer, including H. pylori-infected tissues, and aligns with nuclear transcriptional activity. However, the transcriptional role of STAT3 serine phosphorylation, which promotes STAT3-driven mitochondrial activities, is unclear. Here, by coupling serine-phosphorylated (pS)-STAT3-deficient Stat3SA/SA mice with chronic H. felis infection, which mimics human H. pylori infection in mice, we reveal a key role for pS-STAT3 in promoting Helicobacter-induced gastric pathology. Immunohistochemical staining for infiltrating immune cells and expression analyses of inflammatory genes revealed that gastritis was markedly suppressed in infected Stat3SA/SA mice compared with wild-type mice. Stomach weight and gastric mucosal thickness were also reduced in infected Stat3SA/SA mice, which was associated with reduced proliferative potential of infected Stat3SA/SA gastric mucosa. The suppressed H. felis-induced gastric phenotype of Stat3SA/SA mice was phenocopied upon genetic ablation of signaling by the cytokine IL-11, which promotes gastric tumorigenesis via STAT3. pS-STAT3 dependency by Helicobacter coincided with transcriptional activity on STAT3-regulated genes, rather than mitochondrial and metabolic genes. In the gastric mucosa of mice and patients with gastritis, pS-STAT3 was constitutively expressed irrespective of Helicobacter infection. Collectively, these findings suggest an obligate requirement for IL-11 signaling via constitutive pS-STAT3 in Helicobacter-induced gastric carcinogenesis.
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Affiliation(s)
- Jesse J Balic
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia; Department of Molecular Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia
| | - Mohamed I Saad
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia; Department of Molecular Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia
| | - Ruby Dawson
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia; Department of Molecular Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia
| | - Alice J West
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia; Department of Molecular Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia
| | - Louise McLeod
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia; Department of Molecular Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia
| | - Alison C West
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia; Department of Molecular Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia
| | - Kimberley D'Costa
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia; Department of Molecular Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia
| | - Virginie Deswaerte
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia; Department of Molecular Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia
| | - Anouk Dev
- Department of Gastroenterology and Hepatology, Monash Health, Melbourne, Victoria, Australia
| | - William Sievert
- Department of Gastroenterology and Hepatology, Monash Health, Melbourne, Victoria, Australia
| | - Daniel J Gough
- Department of Molecular Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia; Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, Victoria, Australia
| | - Prithi S Bhathal
- Department of Molecular Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia
| | - Richard L Ferrero
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia; Department of Molecular Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia; Department of Microbiology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia
| | - Brendan J Jenkins
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia; Department of Molecular Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia.
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23
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Aceto GM, Catalano T, Curia MC. Molecular Aspects of Colorectal Adenomas: The Interplay among Microenvironment, Oxidative Stress, and Predisposition. BIOMED RESEARCH INTERNATIONAL 2020; 2020:1726309. [PMID: 32258104 PMCID: PMC7102468 DOI: 10.1155/2020/1726309] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/26/2019] [Revised: 12/23/2019] [Accepted: 12/30/2019] [Indexed: 12/11/2022]
Abstract
The development of colorectal cancer (CRC) is a multistep process initiated by a benign polyp that has the potential to evolve into in situ carcinoma through the interactions between environmental and genetic factors. CRC incidence rates are constantly increased for young adult patients presenting an advanced tumor stage. The majority of CRCs arise from colonic adenomas originating from aberrant cell proliferation of colon epithelium. Endoscopic polypectomy represents a tool for early detection and removal of polyps, although the occurrence of cancers after negative colonoscopy shows a significant incidence. It has long been recognized that the aberrant regulation of Wingless/It (Wnt)/β-Catenin signaling in the pathogenesis of colorectal cancer is supported by its critical role in the differentiation of stem cells in intestinal crypts and in the maintenance of intestinal homeostasis. For this review, we will focus on the development of adenomatous polyps through the interplay between renewal signaling in the colon epithelium and reactive oxygen species (ROS) production. The current knowledge of molecular pathology allows us to deepen the relationships between oxidative stress and other risk factors as lifestyle, microbiota, and predisposition. We underline that the chronic inflammation and ROS production in the colon epithelium can impair the Wnt/β-catenin and/or base excision repair (BER) pathways and predispose to polyp development. In fact, the coexistence of oxidative DNA damage and errors in DNA polymerase can foster C>T transitions in various types of cancer and adenomas, leading to a hypermutated phenotype of tumor cells. Moreover, the function of Adenomatous Polyposis Coli (APC) protein in regulating DNA repair is very important as therapeutic implication making DNA damaging chemotherapeutic agents more effective in CRC cells that tend to accumulate mutations. Additional studies will determine whether approaches based on Wnt inhibition would provide long-term therapeutic value in CRC, but it is clear that APC disruption plays a central role in driving and maintaining tumorigenesis.
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Affiliation(s)
- Gitana Maria Aceto
- Department of Medical, Oral and Biotechnological Sciences, G. d'Annunzio University of Chieti-Pescara, 66100 Chieti, Italy
| | - Teresa Catalano
- Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy
| | - Maria Cristina Curia
- Department of Medical, Oral and Biotechnological Sciences, G. d'Annunzio University of Chieti-Pescara, 66100 Chieti, Italy
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Poirier MC, Beland FA, Divi KV, Damon AL, Ali M, Vanlandingham MM, Churchwell MI, Von Tungeln LS, Dwyer JE, Divi RL, Beauchamp G, Martineau D. In vivo localization and postmortem stability of benzo[a]pyrene-DNA adducts. ENVIRONMENTAL AND MOLECULAR MUTAGENESIS 2020; 61:216-223. [PMID: 31569280 DOI: 10.1002/em.22337] [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: 08/11/2019] [Revised: 09/11/2019] [Accepted: 09/15/2019] [Indexed: 06/10/2023]
Abstract
DNA adducts of carcinogenic polycyclic aromatic hydrocarbons (PAHs) play a critical role in the etiology of gastrointestinal tract cancers in humans and other species orally exposed to PAHs. Yet, the precise localization of PAH-DNA adducts in the gastrointestinal tract, and the long-term postmortem PAH-DNA adduct stability are unknown. To address these issues, the following experiment was performed. Mice were injected intraperitoneally with the PAH carcinogen benzo[a]pyrene (BP) and euthanized at 24 h. Tissues were harvested either at euthanasia (0 time), or after 4, 8, 12, 24, 48, and 168 hr (7 days) of storage at 4°C. Portions of mouse tissues were formalin-fixed, paraffin-embedded, and immunohistochemically (IHC) evaluated by incubation with r7,t8-dihydroxy-t-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BPDE)-DNA antiserum and H-scoring. The remaining tissues were frozen, and DNA was extracted and assayed for the r7,t8,t9-trihydroxy-c-10-(N 2 -deoxyguanosyl)-7,8,9,10-tetrahydrobenzo[a]pyrene (BPdG) adduct using two quantitative assays, the BPDE-DNA chemiluminescence immunoassay (CIA), and high-performance liquid chromatography electrospray ionization tandem mass spectrometry (HPLC-ES-MS/MS). By IHC, which required intact nuclei, BPdG adducts were visualized in forestomach basal cells, which included gastric stem cells, for up to 7 days. In proximal small intestine villus epithelium BPdG adducts were visualized for up to 12 hr. By BPDE-DNA CIA and HPLC-ES-MS/MS, both of which used DNA for analysis and correlated well (P= 0.0001), BPdG adducts were unchanged in small intestine, forestomach, and lung stored at 4°C for up to 7 days postmortem. In addition to localization of BPdG adducts, this study reveals the feasibility of examining PAH-DNA adduct formation in wildlife species living in colder climates. Environ. Mol. Mutagen. 61:216-223, 2020. © 2019 Wiley Periodicals, Inc.
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Affiliation(s)
- Miriam C Poirier
- Carcinogen-DNA Interactions Section, Laboratory of Cancer Biology and Genetics, CCR, National Cancer Institute, NIH, Bethesda, Maryland
| | - Frederick A Beland
- Division of Biochemical Toxicology, National Center for Toxicological Research, USFDA, Jefferson, Arkansas
| | - Kathyayini V Divi
- Carcinogen-DNA Interactions Section, Laboratory of Cancer Biology and Genetics, CCR, National Cancer Institute, NIH, Bethesda, Maryland
| | - Alyssa L Damon
- Carcinogen-DNA Interactions Section, Laboratory of Cancer Biology and Genetics, CCR, National Cancer Institute, NIH, Bethesda, Maryland
| | - Mehnaz Ali
- Carcinogen-DNA Interactions Section, Laboratory of Cancer Biology and Genetics, CCR, National Cancer Institute, NIH, Bethesda, Maryland
| | - Michelle M Vanlandingham
- Division of Biochemical Toxicology, National Center for Toxicological Research, USFDA, Jefferson, Arkansas
| | - Mona I Churchwell
- Division of Biochemical Toxicology, National Center for Toxicological Research, USFDA, Jefferson, Arkansas
| | - Linda S Von Tungeln
- Division of Biochemical Toxicology, National Center for Toxicological Research, USFDA, Jefferson, Arkansas
| | - Jennifer E Dwyer
- Carcinogen-DNA Interactions Section, Laboratory of Cancer Biology and Genetics, CCR, National Cancer Institute, NIH, Bethesda, Maryland
| | - Rao L Divi
- Methods and Technologies Branch, Epidemiology and Genomics Research Program, DCPC, National Cancer Institute, NIH, Bethesda, Maryland
| | - Guy Beauchamp
- Département de pathologie et microbiologie, Faculté de médecine vétérinaire, Université de Montréal, St. Hyacinthe, Quebec, Canada
| | - Daniel Martineau
- Département de pathologie et microbiologie, Faculté de médecine vétérinaire, Université de Montréal, St. Hyacinthe, Quebec, Canada
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Loss of TRIM29 suppresses cancer stem cell-like characteristics of PDACs via accelerating ISG15 degradation. Oncogene 2019; 39:546-559. [DOI: 10.1038/s41388-019-0992-2] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2018] [Revised: 06/13/2019] [Accepted: 06/15/2019] [Indexed: 12/30/2022]
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Visioli A, Giani F, Trivieri N, Pracella R, Miccinilli E, Cariglia MG, Palumbo O, Arleo A, Dezi F, Copetti M, Cajola L, Restelli S, Papa V, Sciuto A, Latiano TP, Carella M, Amadori D, Gallerani G, Ricci R, Alfieri S, Pesole G, Vescovi AL, Binda E. Stemness underpinning all steps of human colorectal cancer defines the core of effective therapeutic strategies. EBioMedicine 2019; 44:346-360. [PMID: 31056474 PMCID: PMC6603803 DOI: 10.1016/j.ebiom.2019.04.049] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2018] [Revised: 04/24/2019] [Accepted: 04/24/2019] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Despite their lethality and ensuing clinical and therapeutic relevance, circulating tumor cells (CTCs) from colorectal carcinoma (CRC) remain elusive, poorly characterized biological entities. METHODS AND FINDINGS We perfected a cell system of stable, primary lines from human CRC showing that they possess the full complement of ex- and in-vivo, in xenogeneic models, characteristics of CRC stem cells (CCSCs). Here we show how tumor-initiating, CCSCs cells can establish faithful orthotopic phenocopies of the original disease, which contain cells that spread into the circulatory system. While in the vascular bed, these cells retain stemness, thus qualifying as circulating CCSCs (cCCSCs). This is followed by the establishment of lesions in distant organs, which also contain resident metastatic CCSCs (mCCSCs). INTERPRETATION Our results support the concept that throughout all the stages of CRC, stemness is retained as a continuous property by some of their tumor cells. Importantly, we describe a useful standardized model that can enable isolation and stable perpetuation of human CRC's CCSCs, cCCSCs and mCCSCs, providing a useful platform for studies of CRC initiation and progression that is suitable for the discovery of reliable stage-specific biomarkers and the refinement of new patient-tailored therapies. FUND: This work was financially supported by grants from "Ministero della Salute Italiano"(GR-2011-02351534, RC1703IC36 and RC1803IC35) to Elena Binda and from "Associazione Italiana Cancro" (IG-14368) Angelo L. Vescovi. None of the above funders have any role in study design, data collection, data analysis, interpretation, writing the project.
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Affiliation(s)
| | | | - Nadia Trivieri
- Fondazione IRCCS Casa Sollievo della Sofferenza, Cancer Stem Cells Unit, ISBReMIT, Foggia, Italy
| | - Riccardo Pracella
- Fondazione IRCCS Casa Sollievo della Sofferenza, Cancer Stem Cells Unit, ISBReMIT, Foggia, Italy
| | - Elide Miccinilli
- Fondazione IRCCS Casa Sollievo della Sofferenza, Cancer Stem Cells Unit, ISBReMIT, Foggia, Italy
| | - Maria Grazia Cariglia
- Fondazione IRCCS Casa Sollievo della Sofferenza, Cancer Stem Cells Unit, ISBReMIT, Foggia, Italy
| | - Orazio Palumbo
- Fondazione IRCCS Casa Sollievo della Sofferenza, Medical Genetics Unit, Foggia, Italy
| | - Andrea Arleo
- Fondazione IRCCS Casa Sollievo della Sofferenza, Cancer Stem Cells Unit, ISBReMIT, Foggia, Italy
| | - Fabio Dezi
- Fondazione IRCCS Casa Sollievo della Sofferenza, Cancer Stem Cells Unit, ISBReMIT, Foggia, Italy
| | - Massimiliano Copetti
- Fondazione IRCCS Casa Sollievo della Sofferenza, Biostatistic Unit, Foggia, Italy
| | | | | | - Valerio Papa
- Digestive Surgery Unit, IRCCS "A. Gemelli", Catholic University of the Sacred Heart, Rome, Italy
| | - Antonio Sciuto
- IRCCS Casa Sollievo della Sofferenza, Abdominal Surgery Unit, Foggia, Italy
| | | | - Massimo Carella
- Fondazione IRCCS Casa Sollievo della Sofferenza, Medical Genetics Unit, Foggia, Italy
| | - Dino Amadori
- Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS Meldola, Italy
| | - Giulia Gallerani
- Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS Meldola, Biosciences Laboratory, Italy
| | - Riccardo Ricci
- Department of Pathology, IRCCS "A. Gemelli", Catholic University of the Sacred Heart, Rome, Italy
| | - Sergio Alfieri
- Department of Pathology, IRCCS "A. Gemelli", Catholic University of the Sacred Heart, Rome, Italy
| | - Graziano Pesole
- Istituto di Biomembrane, Bioenergetica e Biotecnologie Molecolari del Consiglio Nazionale delle Ricerche, Bari, Italy; Dipartimento di Bioscienze, Biotecnologie e Biofarmaceutica dell'Università di Bari "A. Moro". Bari, Italy
| | - Angelo L Vescovi
- Fondazione IRCCS Casa Sollievo della Sofferenza, Cancer Stem Cells Unit, ISBReMIT, Foggia, Italy; Hyperstem SA, Lugano, Switzerland.
| | - Elena Binda
- Fondazione IRCCS Casa Sollievo della Sofferenza, Cancer Stem Cells Unit, ISBReMIT, Foggia, Italy.
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Mahmoodi Chalbatani G, Dana H, Gharagouzloo E, Grijalvo S, Eritja R, Logsdon CD, Memari F, Miri SR, Rad MR, Marmari V. Small interfering RNAs (siRNAs) in cancer therapy: a nano-based approach. Int J Nanomedicine 2019; 14:3111-3128. [PMID: 31118626 PMCID: PMC6504672 DOI: 10.2147/ijn.s200253] [Citation(s) in RCA: 151] [Impact Index Per Article: 25.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2019] [Accepted: 03/23/2019] [Indexed: 12/31/2022] Open
Abstract
Cancer is one of the most complex diseases that has resulted in multiple genetic disorders and cellular abnormalities. Globally, cancer is the most common health concern disease that is affecting human beings. Great efforts have been made over the past decades in biology with the aim of searching novel and more efficient tools in therapy. Thus, small interfering RNAs (siRNAs) have been considered one of the most noteworthy developments which are able to regulate gene expression following a process known as RNA interference (RNAi). RNAi is a post-transcriptional mechanism that involves the inhibition of gene expression through promoting cleavage on a specific area of a target messenger RNA (mRNA). This technology has shown promising therapeutic results for a good number of diseases, especially in cancer. However, siRNA therapeutics have to face important drawbacks in therapy including stability and successful siRNA delivery in vivo. In this regard, the development of effective siRNA delivery systems has helped addressing these issues by opening novel therapeutic windows which have allowed to build up important advances in Nanomedicine. In this review, we discuss the progress of siRNA therapy as well as its medical application via nanoparticle-mediated delivery for cancer treatment.
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Affiliation(s)
| | - Hassan Dana
- Cancer Research Center, Cancer Institute of Iran, Tehran University of Medical Science, Tehran, Iran
- Department of Biology, Damghan Branch, Islamic Azad University, Damghan, Iran
| | - Elahe Gharagouzloo
- Cancer Research Center, Cancer Institute of Iran, Tehran University of Medical Science, Tehran, Iran
| | - Santiago Grijalvo
- Institute of Advanced Chemistry of Catalonia (IQAC-CSIC), Barcelona08034, Spain
- Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER BBN), Madrid, Spain
| | - Ramon Eritja
- Institute of Advanced Chemistry of Catalonia (IQAC-CSIC), Barcelona08034, Spain
- Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER BBN), Madrid, Spain
| | - Craig D Logsdon
- Department of Cancer Biology, University of Texas, M.D. Anderson Cancer Center, Houston, TX, USA
- Department of GI Medical Oncology, University of Texas, M.D. Anderson Cancer Center, Houston, TX, USA
| | - Fereidoon Memari
- Cancer Research Center, Cancer Institute of Iran, Tehran University of Medical Science, Tehran, Iran
| | - Seyed Rouhollah Miri
- Cancer Research Center, Cancer Institute of Iran, Tehran University of Medical Science, Tehran, Iran
| | | | - Vahid Marmari
- Department of Biology, Damghan Branch, Islamic Azad University, Damghan, Iran
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Trosko JE. Cancer Prevention and Therapy of Two Types of Gap Junctional Intercellular Communication⁻Deficient "Cancer Stem Cell". Cancers (Basel) 2019; 11:cancers11010087. [PMID: 30646567 PMCID: PMC6356618 DOI: 10.3390/cancers11010087] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2018] [Revised: 12/23/2018] [Accepted: 01/08/2019] [Indexed: 12/21/2022] Open
Abstract
Early observations showed a lack of growth control and terminal differentiation with a lack of gap junctional intercellular communication (GJIC). Subsequent observations showed that epigenetic tumor promoters and activated oncogenes, which block gap junction function, provide insights into the multi-stage, multi-mechanism carcinogenic process. With the isolation of embryonic induced pluri-potent stem cells and organ-specific adult stem cells, gap junctions were linked to early development. While tumors and tumor cell lines are a heterogeneous mixture of "cancer stem cells" and "cancer non-stem cells", the cancer stem cells seem to be of two types, namely, they express (a) no connexin genes or (b) connexin genes, but do not have functional GJIC. These observations suggest that these "cancer stem cells" originate from normal adult stem cells or from the de-differentiation or re-programming of somatic differentiated cells. This "Concept Paper" provides a hypothesis that "cancer stem cells" either originate from (a) organ-specific adult stem cells before the expression of the connexin genes or (b) organ-specific adult stem cells that just express gap junction genes but that the connexin proteins are rendered dysfunctional by activated oncogenes. Therefore, cancer prevention and therapeutic strategies must account for these two different types of "cancer stem cell".
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Affiliation(s)
- James E Trosko
- Department Pediatrics & Human Development, College of Human Medicine, Michigan State University, East Lansing, MI 48824, USA.
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Ye J, Yuan K, Dai W, Sun K, Li G, Tan M, Song W, Yuan Y. The mTORC1 signaling modulated by intracellular C3 activation in Paneth cells promotes intestinal epithelial regeneration during acute injury. Int Immunopharmacol 2018; 67:54-61. [PMID: 30530169 DOI: 10.1016/j.intimp.2018.12.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2018] [Revised: 11/25/2018] [Accepted: 12/01/2018] [Indexed: 02/06/2023]
Abstract
Complement activation is associated with regional inflammation during acute gastrointestinal injury (AGI). This study is designed to explore how intracellular C3 activation in Paneth cells (PCs) affects regeneration of intestinal epithelium during AGI. AGI was induced in wildtype C57BL/6 mice, with sham operation employed as control. Exogenous C3 (1 mg, I.P.) was applied at 6 h post-surgery. Intestinal crypts harvested from ileum were cultured with presence or absence of C3 (20 μg/ml), with small interfering RNA against BST1 and complement activation inhibitor selectively applied in vitro. The intestinal integrity, percentage of PCs and intestinal stem cells (ISCs) were evaluated. Importantly, cADPR, C3 fragments, and S6-related proteins were detected in PCs to inspect the mammalian target of rapamycin complex 1 (mTORC1) signaling. AGI caused breakdown of intestinal mucosa integrity and regional inflammation. Exogenous C3 by itself failed to promote the growth of intestinal epithelium, but distinctly enhanced the activity of PCs via intracellular activation, which subsequently supported the expansion of ISCs inside of intestinal crypts. Inhibition of C3 activation was associated with decreased expressions of S6, S6K1 and cADPR, with blocking BST1 found to depress cADPR only. Collectively, these data confirmed intracellular activation of C3 in PCs enhanced expansion of ISCs in response to acute injury. The mTORC1 signaling pathway in PCs contributed to this crosstalk during exogenous C3 treatment.
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Affiliation(s)
- Jinning Ye
- Center of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-Sen University, 58 2nd Zhongshan Road, Guangzhou 510080, PR China; Center of Gastric Cancer, Sun Yat-Sen University, 58 2nd Zhongshan Road, Guangzhou 510080, PR China.
| | - Kaitao Yuan
- Center of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-Sen University, 58 2nd Zhongshan Road, Guangzhou 510080, PR China; Center of Gastric Cancer, Sun Yat-Sen University, 58 2nd Zhongshan Road, Guangzhou 510080, PR China
| | - Weigang Dai
- Center of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-Sen University, 58 2nd Zhongshan Road, Guangzhou 510080, PR China; Center of Gastric Cancer, Sun Yat-Sen University, 58 2nd Zhongshan Road, Guangzhou 510080, PR China
| | - Kaiyu Sun
- Center of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-Sen University, 58 2nd Zhongshan Road, Guangzhou 510080, PR China; Center of Gastric Cancer, Sun Yat-Sen University, 58 2nd Zhongshan Road, Guangzhou 510080, PR China
| | - Guanghua Li
- Center of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-Sen University, 58 2nd Zhongshan Road, Guangzhou 510080, PR China; Center of Gastric Cancer, Sun Yat-Sen University, 58 2nd Zhongshan Road, Guangzhou 510080, PR China
| | - Min Tan
- Center of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-Sen University, 58 2nd Zhongshan Road, Guangzhou 510080, PR China; Center of Gastric Cancer, Sun Yat-Sen University, 58 2nd Zhongshan Road, Guangzhou 510080, PR China
| | - Wu Song
- Center of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-Sen University, 58 2nd Zhongshan Road, Guangzhou 510080, PR China; Center of Gastric Cancer, Sun Yat-Sen University, 58 2nd Zhongshan Road, Guangzhou 510080, PR China.
| | - Yujie Yuan
- Center of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-Sen University, 58 2nd Zhongshan Road, Guangzhou 510080, PR China; Center of Gastric Cancer, Sun Yat-Sen University, 58 2nd Zhongshan Road, Guangzhou 510080, PR China.
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Yu S, Yang M, Lim KM, Cho Y, Kim H, Lee K, Jeong SH, Coffey RJ, Goldenring JR, Nam KT. Expression of LRIG1, a Negative Regulator of EGFR, Is Dynamically Altered during Different Stages of Gastric Carcinogenesis. THE AMERICAN JOURNAL OF PATHOLOGY 2018; 188:2912-2923. [PMID: 30248341 DOI: 10.1016/j.ajpath.2018.08.006] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/23/2018] [Revised: 08/07/2018] [Accepted: 08/14/2018] [Indexed: 12/12/2022]
Abstract
Leucine-rich repeats and immunoglobulin-like domains (LRIG)-1 is a transmembrane protein that antagonizes epidermal growth factor receptor signaling in epithelial tissues. LRIG1 is down-regulated in various epithelial cancers, including bladder, breast, and colorectal cancer, suggesting that it functions as a tumor suppressor. However, its role in gastric carcinogenesis is not well understood. Here, we investigated the changes in LRIG1 expression during the stages of gastric cancer. We used a DMP-777-induced spasmolytic polypeptide-expressing metaplasia mouse model and a tissue array of human gastric cancer lesions. The effects of LRIG1 knockdown were also assessed using the human gastric cancer cell line SNU638 in a xenograft model. LRIG1 expression varied over the course of gastric carcinogenesis, increasing in spasmolytic polypeptide-expressing metaplasia lesions but disappearing in intestinal metaplasia and cancer lesions, and the increase was concurrent with the up-regulation of epidermal growth factor receptor. In addition, LRIG1 knockdown promoted the tumorigenic potential in vitro, which was manifested as increased proliferation, invasiveness, and migration as well as increased tumor size in vivo in the xenograft model. Furthermore, LRIG1 expression was determined to be a positive prognostic biomarker for the survival of gastric cancer patients. Collectively, our findings indicate that LRIG1 expression is closely related wto gastric carcinogenesis and may play a vital role as a tumor suppressor through the modulation of epidermal growth factor receptor activity.
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Affiliation(s)
- Sungsook Yu
- Severance Biomedical Science Institute, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Mijeong Yang
- Severance Biomedical Science Institute, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Kyung-Min Lim
- College of Pharmacy, Ewha Womans University, Seoul, Republic of Korea
| | - Yejin Cho
- Severance Biomedical Science Institute, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Hyunji Kim
- Severance Biomedical Science Institute, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Keunwook Lee
- Department of Biomedical Science, Hallym University, Chuncheon, Republic of Korea
| | - Sang-Ho Jeong
- Department of Surgery, Gyeongsang National University Changwon Hospital, Gyeongsang National University, Changwon, Republic of Korea
| | - Robert J Coffey
- Epithelial Biology Center, Vanderbilt University School of Medicine, Nashville, Tennessee; Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - James R Goldenring
- Epithelial Biology Center, Vanderbilt University School of Medicine, Nashville, Tennessee; Section of Surgical Science, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Ki Taek Nam
- Severance Biomedical Science Institute, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea.
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Dhar D, Antonucci L, Nakagawa H, Kim JY, Glitzner E, Caruso S, Shalapour S, Yang L, Valasek MA, Lee S, Minnich K, Seki E, Tuckermann J, Sibilia M, Zucman-Rossi J, Karin M. Liver Cancer Initiation Requires p53 Inhibition by CD44-Enhanced Growth Factor Signaling. Cancer Cell 2018; 33:1061-1077.e6. [PMID: 29894692 PMCID: PMC6005359 DOI: 10.1016/j.ccell.2018.05.003] [Citation(s) in RCA: 143] [Impact Index Per Article: 20.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2017] [Revised: 02/28/2018] [Accepted: 05/06/2018] [Indexed: 02/06/2023]
Abstract
How fully differentiated cells that experience carcinogenic insults become proliferative cancer progenitors that acquire multiple initiating mutations is not clear. This question is of particular relevance to hepatocellular carcinoma (HCC), which arises from differentiated hepatocytes. Here we show that one solution to this problem is provided by CD44, a hyaluronic acid receptor whose expression is rapidly induced in carcinogen-exposed hepatocytes in a STAT3-dependent manner. Once expressed, CD44 potentiates AKT activation to induce the phosphorylation and nuclear translocation of Mdm2, which terminates the p53 genomic surveillance response. This allows DNA-damaged hepatocytes to escape p53-induced death and senescence and respond to proliferative signals that promote fixation of mutations and their transmission to daughter cells that go on to become HCC progenitors.
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Affiliation(s)
- Debanjan Dhar
- Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, University of California San Diego, School of Medicine, 9500 Gilman Drive, San Diego, CA 92093, USA
| | - Laura Antonucci
- Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, University of California San Diego, School of Medicine, 9500 Gilman Drive, San Diego, CA 92093, USA
| | - Hayato Nakagawa
- Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, University of California San Diego, School of Medicine, 9500 Gilman Drive, San Diego, CA 92093, USA; Department of Gastroenterology, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
| | - Ju Youn Kim
- Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, University of California San Diego, School of Medicine, 9500 Gilman Drive, San Diego, CA 92093, USA
| | - Elisabeth Glitzner
- Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8a, 1090 Vienna, Austria
| | - Stefano Caruso
- Inserm UMR-1162, Génomique Fonctionnelle des Tumeurs Solides, Université Paris Descartes, Université Paris Diderot, Université Paris 13, Labex Immuno-Oncology, 75010 Paris, France
| | - Shabnam Shalapour
- Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, University of California San Diego, School of Medicine, 9500 Gilman Drive, San Diego, CA 92093, USA
| | - Ling Yang
- Department of Medicine, University of California San Diego, School of Medicine, 9500 Gilman Drive, San Diego, CA 92093, USA; Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Mark A Valasek
- Department of Pathology, University of California San Diego, School of Medicine, 9500 Gilman Drive, San Diego, CA 92093, USA
| | - Sooyeon Lee
- Institute for Comparative Molecular Endocrinology (CME), University of Ulm, Helmholtzstrasse 8/1, 89081 Ulm, Germany
| | - Kerstin Minnich
- Leibniz Institute of Age Research-Fritz Lipmann Institute, Beutenbergstrasse 11, 07745 Jena, Germany
| | - Ekihiro Seki
- Department of Medicine, University of California San Diego, School of Medicine, 9500 Gilman Drive, San Diego, CA 92093, USA; Department of Medicine, Cedars-Sinai, 8700 Beverly Boulevard, Davis Building, Los Angeles, CA 90048, USA
| | - Jan Tuckermann
- Institute for Comparative Molecular Endocrinology (CME), University of Ulm, Helmholtzstrasse 8/1, 89081 Ulm, Germany; Leibniz Institute of Age Research-Fritz Lipmann Institute, Beutenbergstrasse 11, 07745 Jena, Germany
| | - Maria Sibilia
- Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8a, 1090 Vienna, Austria
| | - Jessica Zucman-Rossi
- Inserm UMR-1162, Génomique Fonctionnelle des Tumeurs Solides, Université Paris Descartes, Université Paris Diderot, Université Paris 13, Labex Immuno-Oncology, 75010 Paris, France
| | - Michael Karin
- Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, University of California San Diego, School of Medicine, 9500 Gilman Drive, San Diego, CA 92093, USA; Department of Pathology, University of California San Diego, School of Medicine, 9500 Gilman Drive, San Diego, CA 92093, USA; Moores Cancer Center, University of California San Diego, School of Medicine, 9500 Gilman Drive, La Jolla, CA 92093-0723, USA.
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Zhang H, Wong E. Identification of cells expressing OLFM4 and LGR5 mRNA by in situ hybridization in the yolk sac and small intestine of embryonic and early post-hatch chicks. Poult Sci 2018; 97:628-633. [DOI: 10.3382/ps/pex328] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2017] [Accepted: 10/10/2017] [Indexed: 12/24/2022] Open
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Abstract
Organoids have extensive applications in many fields ranging from modelling human development and disease, personalised medicine, drug screening, etc. Moreover, in the last few years, several studies have evaluated the capacity of organoids as transplantation sources for therapeutic approaches and regenerative medicine. Nevertheless, depending on the origin of the cells and anatomical complications, an organoid transplant may make tissue regeneration difficult. However, some essential aspects of organoids including the morphological alterations and the growth pattern of the matched tumour and their healthy derived organoids have received less attention. Therefore, the current work focused on culturing matched healthy and tumour organoids from the same patient with colorectal cancer (CRC) and assessed their timed growth and structural differences on a daily basis. The healthy organoids underwent proliferation and branching morphogenesis, while the tumour organoids did not follow the same pattern, and the majority of them developed cystic structures instead. However, the number and size of tumour organoids were different from one patient to another. The differential morphological changes of the healthy versus human colonic tumour organoids likely linked to distinct molecular and cellular events during each day. Thus, while their specific structural features provide valuable in vitro models to study various aspects of human intestinal/colon tissue homeostasis and CRC which avoid or replace the use of animals in research, this model may also hold a great promise for the transplantation and regenerative medicine applications.
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34
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Emerick B, Schleiniger G, Boman BM. Multi-scale modeling of APC and [Formula: see text]-catenin regulation in the human colonic crypt. J Math Biol 2018; 76:1797-1830. [PMID: 29302705 DOI: 10.1007/s00285-017-1204-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2017] [Revised: 12/22/2017] [Indexed: 10/18/2022]
Abstract
Stem cell renewal and differentiation in the human colonic crypt are linked to the [Formula: see text]-catenin pathway. The spatial balance of Wnt factors in proliferative cells within the crypt maintain an appropriate level of cellular reproduction needed for normal crypt homeostasis. Mutational events at the gene level are responsible for deregulating the balance of Wnt factors along the crypt, causing an overpopulation of proliferative cells, a loss of structure of the crypt domain, and the initiation of colorectal carcinomas. We formulate a PDE model describing cell movement and reproduction in a static crypt domain. We consider a single cell population whose proliferative capabilities are determined by stemness, a quantity defined by intracellular levels of adenomatous polyposis coli (APC) scaffold protein and [Formula: see text]-catenin. We fit APC regulation parameters to biological data that describe normal protein gradients in the crypt. We also fit cell movement and protein flux parameters to normal crypt characteristics such as renewal time, total cell count, and proportion of proliferating cells. The model is used to investigate abnormal crypt dynamics when subjected to a diminished APC gradient, a scenario synonymous to mutations in the APC gene. We find that a 25% decrease in APC synthesis leads to a fraction of 0.88 proliferative, which is reflective of normal-appearing FAP crypts. A 50% drop in APC activity yields a fully proliferative crypt showing a doubling of the level of stemness, which characterizes the initial stages of colorectal cancer development. A sensitivity analysis of APC regulation parameters shows the perturbation of factors that is required to restore crypt dynamics to normal in the case of APC mutations.
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Affiliation(s)
- Brooks Emerick
- Department of Mathematics, Kutztown University, Kutztown, PA, 19530, USA.
| | - Gilberto Schleiniger
- Department of Mathematical Sciences, University of Delaware, Newark, DE, 19711, USA
| | - Bruce M Boman
- Department of Biological Sciences, University of Delaware, Newark, DE, 19711, USA.,Center for Translational Cancer Research, Helen F. Graham Cancer Center and Research Institute, Newark, DE, 19713, USA
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Intestinal Stem Cell Niche Insights Gathered from Both In Vivo and Novel In Vitro Models. Stem Cells Int 2017; 2017:8387297. [PMID: 29081810 PMCID: PMC5610807 DOI: 10.1155/2017/8387297] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2017] [Accepted: 07/03/2017] [Indexed: 12/12/2022] Open
Abstract
Intestinal stem cells are located at the base of the crypts and are surrounded by a complex structure called niche. This environment is composed mainly of epithelial cells and stroma which provides signals that govern cell maintenance, proliferation, and differentiation. Understanding how the niche regulates stem cell fate by controlling developmental signaling pathways will help us to define how stem cells choose between self-renewal and differentiation and how they maintain their undifferentiated state. Tractable in vitro assay systems, which reflect the complexity of the in vivo situation but provide higher level of control, would likely be crucial in identifying new players and mechanisms controlling stem cell function. Knowledge of the intestinal stem cell niche gathered from both in vivo and novel in vitro models may help us improve therapies for tumorigenesis and intestinal damage and make autologous intestinal transplants a feasible clinical practice.
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36
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Phosphorylated mTOR Expression Profiles in Human Normal and Carcinoma Tissues. DISEASE MARKERS 2017; 2017:1397063. [PMID: 28831205 PMCID: PMC5555007 DOI: 10.1155/2017/1397063] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/20/2017] [Revised: 06/21/2017] [Accepted: 06/28/2017] [Indexed: 11/18/2022]
Abstract
Mammalian target of rapamycin (mTOR) is a key controller of cell growth and proliferation in normal tissues and solid tumors. In the present study, an immunohistochemical analysis of the expression pattern of phosphorylated mTOR (p-mTOR) was performed in human normal fetal and adult tissues and various carcinoma tissues. p-mTOR expression showed tissue and cell type specificity in normal and cancer tissues. In normal fetal and adult tissues, p-mTOR staining was observed in the intestinal crypt, intrahepatic bile ductule, pancreatic duct, distal nephron of the kidney, umbrella cell of urothelium, mesothelial cell, and choroid plexus. In cancer tissues, p-mTOR expression was higher in adenocarcinoma than in other types of cancers, in metastatic cancer than in primary cancer, and in the forefront of the infiltrating cancer cells. These results suggest that p-mTOR is implicated not only in cell proliferation but also in tubular morphogenesis in normal and cancer tissues. In addition, mTOR activation appears to be associated with cancer cell invasion and migration in solid tumors.
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Abstract
PURPOSE OF REVIEW The purpose of the review is to delineate novel approaches for biology-based treatment in advanced gastric cancer. We reviewed the latest translational and clinical research articles and congress presentations. RECENT FINDINGS A new molecular classification of gastric cancer based on histology, genetic and proteomic alterations has evolved. It provides a roadmap for development of new drugs and combinations and for patient stratification. Anti-HER2 treatment, which is an effective strategy in metastatic gastric cancer, is now also being studied in the perioperative setting. However, resistance mechanisms in advanced disease are poorly understood and optimal patient selection remains challenging. Targeting angiogenesis is an emerging concept in the management of advanced gastric cancer, and ramucirumab has prolonged survival in the second line either as a monotherapy or in combination with paclitaxel. Biomarkers for selecting patients who benefit from ramucirumab are still lacking. Immune checkpoint blockade and inhibition of cancer stemness targets are other emerging directions for the medical treatment of gastric cancer. Large-scale international studies are ongoing. SUMMARY Promising biology-based treatment strategies are evolving. But tumor heterogeneity which is an inherent feature of gastric cancer challenges the development of molecularly targeted and personalized treatment strategies.
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Antagonistic Interactions between Extracellular Signal-Regulated Kinase Mitogen-Activated Protein Kinase and Retinoic Acid Receptor Signaling in Colorectal Cancer Cells. Mol Cell Biol 2017; 37:MCB.00012-17. [PMID: 28483913 DOI: 10.1128/mcb.00012-17] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2017] [Accepted: 05/02/2017] [Indexed: 01/08/2023] Open
Abstract
Deregulated activation of RAS/extracellular signal-regulated kinase (ERK) signaling and defects in retinoic acid receptor (RAR) signaling are both implicated in many types of cancers. However, interrelationships between these alterations in regulating cancer cell fates have not been fully elucidated. Here, we show that RAS/ERK and RAR signaling pathways antagonistically interact with each other to regulate colorectal cancer (CRC) cell fates. We show that RAR signaling activation promotes spontaneous differentiation of CRC cells, while ERK activation suppresses it. Our microarray analyses identify genes whose expression levels are upregulated by RAR signaling. Notably, one of these genes, MKP4, encoding a member of dual-specificity phosphatases for mitogen-activated protein (MAP) kinases, mediates ERK inactivation upon RAR activation, thereby promoting the differentiation of CRC cells. Moreover, our results also show that RA induction of RAR target genes is suppressed by the ERK pathway activation. This suppression results from the inhibition of RAR transcriptional activity, which is shown to be mediated through an RIP140/histone deacetylase (HDAC)-mediated mechanism. These results identify antagonistic interactions between RAS/ERK and RAR signaling in the cell fate decision of CRC cells and define their underlying molecular mechanisms.
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39
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Contribution of the Microenvironmental Niche to Glioblastoma Heterogeneity. BIOMED RESEARCH INTERNATIONAL 2017. [PMID: 28630875 PMCID: PMC5467280 DOI: 10.1155/2017/9634172] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Glioblastoma is the most aggressive cancer of the brain. The dismal prognosis is largely attributed to the heterogeneous nature of the tumor, which in addition to intrinsic molecular and genetic changes is also influenced by the microenvironmental niche in which the glioma cells reside. The cancer stem cells (CSCs) hypothesis suggests that all cancers arise from CSCs that possess the ability to self-renew and initiate tumor formation. CSCs reside in specialized niches where interaction with the microenvironment regulates their stem cell behavior. The reciprocal interaction between glioma stem cells (GSCs) and cells from the microenvironment, such as endothelial cells, immune cells, and other parenchymal cells, may also promote angiogenesis, invasion, proliferation, and stemness of the GSCs and be likely to have an underappreciated role in their responsiveness to therapy. This crosstalk may also promote molecular transition of GSCs. Hence the inherent plasticity of GSCs can be seen as an adaptive response, changing according to the signaling cue from the niche. Given the association of GSCs with tumor recurrence and treatment sensitivity, understanding this bidirectional crosstalk between GSCs and its niche may provide a framework to identify more effective therapeutic targets and improve treatment outcome.
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40
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Suh JS, Lee HJ, Nam H, Jo BS, Lee DW, Kim JH, Lee JY, Chung CP, Lee G, Park YJ. Control of cancer stem cell like population by intracellular target identification followed by the treatment with peptide-siRNA complex. Biochem Biophys Res Commun 2017; 491:827-833. [PMID: 28554844 DOI: 10.1016/j.bbrc.2017.05.148] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2017] [Accepted: 05/25/2017] [Indexed: 01/06/2023]
Abstract
Cancer stem cells (CSCs) are a subpopulation of cancer cells and have been known to create cancer reoccurrence during cancer therapy due to their stem cell-like characteristics. However, exact target to control the CSC has not been fully established. Here, we enriched CD44High population of MDA-MB-231 cells by CD44 antibody as a CSC marker. By Phospho Antibody Array, CD44High population of MDA-MB-231 cells reveals Feline sarcoma-related tyrosine kinase (FER) protein was highly activated. When FER siRNA and low molecular weight protamine (LMWP) as cell penetrating peptides are applied to this population, cancer migration and colony forming ability are inhibited. Moreover, silencing FER using FER siRNA and LMWP conjugates enhances anti-metastasis related factors including E-cadherin, p75 and p63. Taken together, FER is a new marker for targeting breast CSCs and peptide-mediated siRNA method could be an effective and safe way of delivery and be a new therapeutic strategy for targeting breast cancer.
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Affiliation(s)
- Jin Sook Suh
- Dental Regenerative Biotechnology Major, Dental Research Institute, School of Dentistry, Seoul National University, Seoul, Republic of Korea
| | - Hyun Jung Lee
- Dental Regenerative Biotechnology Major, Dental Research Institute, School of Dentistry, Seoul National University, Seoul, Republic of Korea
| | - Hyun Nam
- Dental Genetics Major, Dental Research Institute, School of Dentistry, Seoul National University, Seoul, Republic of Korea
| | - Beom Soo Jo
- Dental Regenerative Biotechnology Major, Dental Research Institute, School of Dentistry, Seoul National University, Seoul, Republic of Korea
| | - Dong Woo Lee
- Dental Regenerative Biotechnology Major, Dental Research Institute, School of Dentistry, Seoul National University, Seoul, Republic of Korea
| | - Ji-Hye Kim
- Dental Genetics Major, Dental Research Institute, School of Dentistry, Seoul National University, Seoul, Republic of Korea
| | - Jue Yeon Lee
- Central Research Institute, Nano Intelligent Biomedical Engineering Corporation (NIBEC), Seoul, Republic of Korea
| | - Chong Pyoung Chung
- Central Research Institute, Nano Intelligent Biomedical Engineering Corporation (NIBEC), Seoul, Republic of Korea
| | - Gene Lee
- Dental Genetics Major, Dental Research Institute, School of Dentistry, Seoul National University, Seoul, Republic of Korea
| | - Yoon Jeong Park
- Dental Regenerative Biotechnology Major, Dental Research Institute, School of Dentistry, Seoul National University, Seoul, Republic of Korea; Central Research Institute, Nano Intelligent Biomedical Engineering Corporation (NIBEC), Seoul, Republic of Korea.
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41
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Colorectal Cancer: From the Genetic Model to Posttranscriptional Regulation by Noncoding RNAs. BIOMED RESEARCH INTERNATIONAL 2017; 2017:7354260. [PMID: 28573140 PMCID: PMC5442347 DOI: 10.1155/2017/7354260] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/05/2016] [Accepted: 02/16/2017] [Indexed: 12/11/2022]
Abstract
Colorectal cancer is the third most common form of cancer in developed countries and, despite the improvements achieved in its treatment options, remains as one of the main causes of cancer-related death. In this review, we first focus on colorectal carcinogenesis and on the genetic and epigenetic alterations involved. In addition, noncoding RNAs have been shown to be important regulators of gene expression. We present a general overview of what is known about these molecules and their role and dysregulation in cancer, with a special focus on the biogenesis, characteristics, and function of microRNAs. These molecules are important regulators of carcinogenesis, progression, invasion, angiogenesis, and metastases in cancer, including colorectal cancer. For this reason, miRNAs can be used as potential biomarkers for diagnosis, prognosis, and efficacy of chemotherapeutic treatments, or even as therapeutic agents, or as targets by themselves. Thus, this review highlights the importance of miRNAs in the development, progression, diagnosis, and therapy of colorectal cancer and summarizes current therapeutic approaches for the treatment of colorectal cancer.
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42
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Demitrack ES, Samuelson LC. Notch as a Driver of Gastric Epithelial Cell Proliferation. Cell Mol Gastroenterol Hepatol 2017; 3:323-330. [PMID: 28462374 PMCID: PMC5404025 DOI: 10.1016/j.jcmgh.2017.01.012] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2016] [Accepted: 01/28/2017] [Indexed: 02/08/2023]
Abstract
The gastric epithelium is sustained by a population of stem cells that replenish the various mature epithelial lineages throughout adulthood. Regulation of stem and progenitor cell proliferation occurs via basic developmental signaling pathways, including the Notch pathway, which recently was described to promote gastric stem cell proliferation in both mice and human beings. Current cancer theory proposes that adult stem cells that maintain gastrointestinal tissues accumulate mutations that promote cancerous growth, and that basic signaling pathways, such as Notch, which stimulate stem cell proliferation, can promote tumorigenesis. Accordingly, constitutive Notch activation leads to unchecked cellular proliferation and gastric tumors in genetic mouse models. Furthermore, there is emerging evidence suggesting that the Notch pathway may be activated in some human gastric cancers, supporting a potential role for Notch in gastric tumorigenesis. In this review, we first summarize the current understanding of gastric stem cells defined by genetic mouse studies, followed by discussion of the literature regarding Notch pathway regulation of gastric stem cell function in the mouse and human beings. Notch action to maintain gastric epithelial cell homeostasis and the cellular consequences of dysregulated signaling to promote tumorigenesis are discussed, including studies associating Notch activation with human gastric cancer. Finally, we compare and contrast Notch function in the stomach with other gastrointestinal tissues, including the intestine, to highlight the sensitivity of the stomach to Notch-induced tumors.
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Affiliation(s)
- Elise S. Demitrack
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan
| | - Linda C. Samuelson
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan
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43
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Suijkerbuijk SJE, van Rheenen J. From good to bad: Intravital imaging of the hijack of physiological processes by cancer cells. Dev Biol 2017; 428:328-337. [PMID: 28473106 DOI: 10.1016/j.ydbio.2017.04.015] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2017] [Revised: 04/21/2017] [Accepted: 04/23/2017] [Indexed: 12/23/2022]
Abstract
Homeostasis of tissues is tightly regulated at the cellular, tissue and organismal level. Interestingly, tumor cells have found ways to hijack many of these physiological processes at all the different levels. Here we review how intravital microscopy techniques have provided new insights into our understanding of tissue homeostasis and cancer progression. In addition, we highlight the different strategies that tumor cells have adopted to use these physiological processes for their own benefit. We describe how visualization of these dynamic processes in living mice has broadened to our view on cancer initiation and progression.
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Affiliation(s)
- Saskia J E Suijkerbuijk
- Hubrecht Institute - KNAW (Royal Netherlands Academy of Arts and Sciences) and University Medical Center Utrecht, 3584 CT Utrecht, The Netherlands; Cancer Genomics Netherlands, 3584 CG Utrecht, The Netherlands
| | - Jacco van Rheenen
- Hubrecht Institute - KNAW (Royal Netherlands Academy of Arts and Sciences) and University Medical Center Utrecht, 3584 CT Utrecht, The Netherlands; Cancer Genomics Netherlands, 3584 CG Utrecht, The Netherlands.
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44
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Li J, Yu B, Deng P, Cheng Y, Yu Y, Kevork K, Ramadoss S, Ding X, Li X, Wang CY. KDM3 epigenetically controls tumorigenic potentials of human colorectal cancer stem cells through Wnt/β-catenin signalling. Nat Commun 2017; 8:15146. [PMID: 28440295 PMCID: PMC5414094 DOI: 10.1038/ncomms15146] [Citation(s) in RCA: 99] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2016] [Accepted: 03/02/2017] [Indexed: 02/07/2023] Open
Abstract
Human colorectal cancer stem cells (CSCs) are tumour initiating cells that can self-renew and are highly tumorigenic and chemoresistant. While genetic mutations associated with human colorectal cancer development are well-known, little is known about how and whether epigenetic factors specifically contribute to the functional properties of human colorectal CSCs. Here we report that the KDM3 family of histone demethylases plays an important role in tumorigenic potential and survival of human colorectal CSCs by epigenetically activating Wnt target gene transcription. The depletion of KDM3 inhibits tumorigenic growth and chemoresistance of human colorectal CSCs. Mechanistically, KDM3 not only directly erases repressive H3K9me2 marks, but also helps to recruit histone methyltransferase MLL1 to promote H3K4 methylation, thereby promoting Wnt target gene transcription. Our results suggest that KDM3 is a critical epigenetic factor in Wnt signalling that orchestrates chromatin changes and transcription in human colorectal CSCs, identifying potential therapeutic targets for effective elimination of CSCs.
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Affiliation(s)
- Jiong Li
- Laboratory of Molecular Signaling, Division of Oral Biology and Medicine, School of Dentistry and Broad Stem Cell Research Center, UCLA, Los Angeles, California 90095, USA
| | - Bo Yu
- Laboratory of Molecular Signaling, Division of Oral Biology and Medicine, School of Dentistry and Broad Stem Cell Research Center, UCLA, Los Angeles, California 90095, USA
| | - Peng Deng
- Laboratory of Molecular Signaling, Division of Oral Biology and Medicine, School of Dentistry and Broad Stem Cell Research Center, UCLA, Los Angeles, California 90095, USA
| | - Yingduan Cheng
- Laboratory of Molecular Signaling, Division of Oral Biology and Medicine, School of Dentistry and Broad Stem Cell Research Center, UCLA, Los Angeles, California 90095, USA
| | - Yongxin Yu
- Laboratory of Molecular Signaling, Division of Oral Biology and Medicine, School of Dentistry and Broad Stem Cell Research Center, UCLA, Los Angeles, California 90095, USA
| | - Kareena Kevork
- Laboratory of Molecular Signaling, Division of Oral Biology and Medicine, School of Dentistry and Broad Stem Cell Research Center, UCLA, Los Angeles, California 90095, USA
| | - Sivakumar Ramadoss
- Laboratory of Molecular Signaling, Division of Oral Biology and Medicine, School of Dentistry and Broad Stem Cell Research Center, UCLA, Los Angeles, California 90095, USA
| | - Xiangming Ding
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, UCLA, Los Angeles, California 90095, USA
| | - Xinmin Li
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, UCLA, Los Angeles, California 90095, USA
| | - Cun-Yu Wang
- Laboratory of Molecular Signaling, Division of Oral Biology and Medicine, School of Dentistry and Broad Stem Cell Research Center, UCLA, Los Angeles, California 90095, USA.,Department of Bioengineering, Henry Samueli School of Engineering and Applied Science, UCLA, Los Angeles, California 90095, USA
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45
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Garcia M, Chomel JC, Mustapha P, Tran CT, Garnier M, Paris I, Quellard N, Godet J, Cremniter J, Bennaceur-Griscelli A, Lecron JC, Turhan AG, Burucoa C, Bodet C. In vitro culture and phenotypic and molecular characterization of gastric stem cells from human stomach. Helicobacter 2017; 22. [PMID: 27592706 DOI: 10.1111/hel.12351] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
BACKGROUND Human gastric mucosa shows continuous self-renewal via differentiation from stem cells that remain poorly characterized. METHODS We describe an original protocol for culture of gastric stem/progenitor cells from adult human stomach. The molecular characteristics of cells were studied using TaqMan low-density array and qRT-PCR analyses using the well-characterized H1 and H9 embryonic stem cells as reference. Epithelial progenitor cells were challenged with H. pylori to characterize their inflammatory response. RESULTS Resident gastric stem cells expressed specific molecular markers of embryonic stem cells (SOX2, NANOG, and OCT4), as well as others specific to adult stem cells, particularly LGR5 and CD44. We show that gastric stem cells spontaneously differentiate into epithelial progenitor cells that can be challenged with H. pylori. The epithelial progenitor response to H. pylori showed a cag pathogenicity island-dependent induction of matrix metalloproteinases 1 and 3, chemokine (CXCL1, CXCL5, CXCL8, CCL20) and interleukine 33 expression. CONCLUSION This study opens new outlooks for investigation of gastric stem cell biology and pathobiology as well as host-H. pylori interactions.
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Affiliation(s)
- Magali Garcia
- Laboratoire Inflammation, Tissus Epithéliaux et Cytokines, Université de Poitiers, Poitiers, France.,Centre Hospitalier Universitaire de Poitiers, Poitiers, France
| | - Jean-Claude Chomel
- Centre Hospitalier Universitaire de Poitiers, Poitiers, France.,Inserm U935, Université de Poitiers, Poitiers, France
| | - Pascale Mustapha
- Laboratoire Inflammation, Tissus Epithéliaux et Cytokines, Université de Poitiers, Poitiers, France
| | - Cong Tri Tran
- Laboratoire Inflammation, Tissus Epithéliaux et Cytokines, Université de Poitiers, Poitiers, France.,Centre Hospitalier Universitaire de Poitiers, Poitiers, France
| | - Martine Garnier
- Laboratoire Inflammation, Tissus Epithéliaux et Cytokines, Université de Poitiers, Poitiers, France.,Centre Hospitalier Universitaire de Poitiers, Poitiers, France
| | - Isabelle Paris
- Laboratoire Inflammation, Tissus Epithéliaux et Cytokines, Université de Poitiers, Poitiers, France.,Centre Hospitalier Universitaire de Poitiers, Poitiers, France
| | | | - Julie Godet
- Centre Hospitalier Universitaire de Poitiers, Poitiers, France
| | - Julie Cremniter
- Laboratoire Inflammation, Tissus Epithéliaux et Cytokines, Université de Poitiers, Poitiers, France.,Centre Hospitalier Universitaire de Poitiers, Poitiers, France
| | - Annelise Bennaceur-Griscelli
- Inserm U935, Université de Poitiers, Poitiers, France.,Inserm U935, Hôpitaux Universitaires Paris Sud, Hôpital Bicêtre & Paul Brousse, Université Paris-Sud, Villejuif, France
| | - Jean-Claude Lecron
- Laboratoire Inflammation, Tissus Epithéliaux et Cytokines, Université de Poitiers, Poitiers, France.,Centre Hospitalier Universitaire de Poitiers, Poitiers, France
| | - Ali G Turhan
- Inserm U935, Université de Poitiers, Poitiers, France.,Inserm U935, Hôpitaux Universitaires Paris Sud, Hôpital Bicêtre & Paul Brousse, Université Paris-Sud, Villejuif, France
| | - Christophe Burucoa
- Laboratoire Inflammation, Tissus Epithéliaux et Cytokines, Université de Poitiers, Poitiers, France.,Centre Hospitalier Universitaire de Poitiers, Poitiers, France
| | - Charles Bodet
- Laboratoire Inflammation, Tissus Epithéliaux et Cytokines, Université de Poitiers, Poitiers, France
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46
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Emerick B, Schleiniger G, Boman BM. A kinetic model to study the regulation of β-catenin, APC, and Axin in the human colonic crypt. J Math Biol 2017; 75:1171-1202. [PMID: 28271271 DOI: 10.1007/s00285-017-1112-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2016] [Revised: 01/18/2017] [Indexed: 12/17/2022]
Abstract
The Wnt/[Formula: see text]-catenin pathway plays a crucial role in stem cell renewal and differentiation in the normal human colonic crypt. The balance between [Formula: see text]-catenin and APC along the crypt axis determines its normal functionality. The mechanism that deregulates this balance may give insight into the initiation of colorectal cancer. This is significant because the spatial dysregulation of [Formula: see text]-catenin by the mutated tumor suppressor gene/protein APC in human colonic crypts is responsible for the initiation and growth of colorectal cancer. We consider a regulatory function that promotes APC synthesis within the cell and its effect on the accumulation of the Wnt target protein, [Formula: see text]-catenin. It is evident that an APC gradient exists along the crypt axis; however, the mechanism by which APC expression is regulated within the cell is not well known. We investigate the dynamics of an APC regulatory mechanism with an increased level of Axin at the subcellular level. Model output shows an increase of APC for a diminished Wnt signal, which explains the APC gradient along the crypt. We find that the dynamic interplay between [Formula: see text]-catenin, APC, and Axin produces oscillatory behavior, which is controlled by the Wnt stimulus. In the presence of reduced functional APC, the oscillations are amplified, which suggests that the cell remains in a more proliferative state for longer periods of time. Increased Axin levels (typical of mammalian cells) reduce oscillatory behavior and minimize the levels of [Formula: see text]-catenin within the cell while raising the levels of APC.
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Affiliation(s)
- Brooks Emerick
- Department of Mathematics, Trinity College, Hartford, CT, 06106, USA.
| | - Gilberto Schleiniger
- Department of Mathematical Sciences, University of Delaware, Newark, DE, 19711, USA
| | - Bruce M Boman
- Department of Biological Sciences, University of Delaware, Newark, DE, 19711, USA
- Center for Translational Cancer Research, Helen F. Graham Cancer Center and Research Institute, Newark, DE, 19713, USA
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47
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Nanovesicle-mediated systemic delivery of microRNA-34a for CD44 overexpressing gastric cancer stem cell therapy. Biomaterials 2016; 105:12-24. [DOI: 10.1016/j.biomaterials.2016.07.036] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2016] [Revised: 07/24/2016] [Accepted: 07/29/2016] [Indexed: 12/22/2022]
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48
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Goyal S, Nangia-Makker P, Farhana L, Yu Y, Majumdar APN. Racial disparity in colorectal cancer: Gut microbiome and cancer stem cells. World J Stem Cells 2016; 8:279-287. [PMID: 27679684 PMCID: PMC5031889 DOI: 10.4252/wjsc.v8.i9.279] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2016] [Revised: 06/28/2016] [Accepted: 07/22/2016] [Indexed: 02/06/2023] Open
Abstract
Over the past two decades there has been remarkable progress in cancer diagnosis, treatment and screening. The basic mechanisms leading to pathogenesis of various types of cancers are also understood better and some patients, if diagnosed at a particular stage go on to lead a normal pre-diagnosis life. Despite these achievements, racial disparity in some cancers remains a mystery. The higher incidence, aggressiveness and mortality of breast, prostate and colorectal cancers (CRCs) in African-Americans as compared to Caucasian-Americans are now well documented. The polyp-carcinoma sequence in CRC and easy access to colonic epithelia or colonic epithelial cells through colonoscopy/colonic effluent provides the opportunity to study colonic stem cells early in course of natural history of the disease. With the advent of metagenomic sequencing, uncultivable organisms can now be identified in stool and their numbers correlated with the effects on colonic epithelia. It would be expected that these techniques would revolutionize our understanding of the racial disparity in CRC and pave a way for the same in other cancers as well. Unfortunately, this has not happened. Our understanding of the underlying factors responsible in African-Americans for higher incidence and mortality from colorectal carcinoma remains minimal. In this review, we aim to summarize the available data on role of microbiome and cancer stem cells in racial disparity in CRC. This will provide a platform for further research on this topic.
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Sailaja BS, He XC, Li L. The regulatory niche of intestinal stem cells. J Physiol 2016; 594:4827-36. [PMID: 27060879 DOI: 10.1113/jp271931] [Citation(s) in RCA: 75] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2015] [Accepted: 03/29/2016] [Indexed: 12/14/2022] Open
Abstract
The niche constitutes a unique category of cells that support the microenvironment for the maintenance and self-renewal of stem cells. Intestinal stem cells reside at the base of the crypt, which contains adjacent epithelial cells, stromal cells and smooth muscle cells, and soluble and cell-associated growth and differentiation factors. We summarize here recent advances in our understanding of the crucial role of the niche in regulating stem cells. The stem cell niche maintains a balance among quiescence, proliferation and regeneration of intestinal stem cells after injury. Mesenchymal cells, Paneth cells, immune cells, endothelial cells and neural cells are important regulatory components that secrete niche ligands, growth factors and cytokines. Intestinal homeostasis is regulated by niche signalling pathways, specifically Wnt, bone morphogenetic protein, Notch and epidermal growth factor. These insights into the regulatory stem cell niche during homeostasis and post-injury regeneration offer the potential to accelerate development of therapies for intestine-related disorders.
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Affiliation(s)
- Badi Sri Sailaja
- Stowers Institute for Medical Research, Kansas City, MO, 64110, USA
| | - Xi C He
- Stowers Institute for Medical Research, Kansas City, MO, 64110, USA
| | - Linheng Li
- Stowers Institute for Medical Research, Kansas City, MO, 64110, USA.,Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, 66101, USA
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ALIZADEH-NAVAEI REZA, RAFIEI ALIREZA, ABEDIAN-KENARI SAEID, ASGARIAN-OMRAN HOSSEIN, VALADAN REZA, HEDAYATIZADEH-OMRAN AKBAR. Comparison of leucine-rich repeat-containing G protein-coupled receptor 5 expression in different cancer and normal cell lines. Biomed Rep 2016; 5:130-132. [PMID: 27347416 PMCID: PMC4907073 DOI: 10.3892/br.2016.684] [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: 02/18/2016] [Accepted: 05/04/2016] [Indexed: 02/05/2023] Open
Abstract
Evaluating the expression of leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5) may be useful for predicting the best models and achieving more accurate results in cancer research. Therefore, the aim of the present study was to analyze the LGR5 expression levels in different cell lines. Eight commonly used cell lines were assessed (COS-7, NIH3T3, HEK293, VERO, HeLa, BHK, HepG2 and AGS). All the cell lines were cultured in RPMI-1640 medium contain 10% fetal calf serum at 37°C in humidified conditions with 5% CO2. According to the western blotting results, LGR5 was expressed in all cell lines. Densitometry results of LGR5 expression in the different cell lines showed that high LGR5 expression levels were apparent in BHK, AGS, VERO and NIH3T3 cell lines compared with the other cell lines. The results indicate that for the normal and cancer cell lines, BNK and AGS may be a better choice, respectively, for in vitro cancer studies.
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Affiliation(s)
- REZA ALIZADEH-NAVAEI
- Molecular and Cell Biology Research Center, Mazandaran University of Medical Sciences, Sari 48175-861, Iran
| | - ALIREZA RAFIEI
- Molecular and Cell Biology Research Center, Mazandaran University of Medical Sciences, Sari 48175-861, Iran
| | - SAEID ABEDIAN-KENARI
- Immunogenetic Research Center, Mazandaran University of Medical Sciences, Sari 48175-861, Iran
| | - HOSSEIN ASGARIAN-OMRAN
- Molecular and Cell Biology Research Center, Mazandaran University of Medical Sciences, Sari 48175-861, Iran
| | - REZA VALADAN
- Molecular and Cell Biology Research Center, Mazandaran University of Medical Sciences, Sari 48175-861, Iran
| | - AKBAR HEDAYATIZADEH-OMRAN
- Molecular and Cell Biology Research Center, Mazandaran University of Medical Sciences, Sari 48175-861, Iran
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