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Haynes J, Manogaran P. Mechanisms and Strategies to Overcome Drug Resistance in Colorectal Cancer. Int J Mol Sci 2025; 26:1988. [PMID: 40076613 PMCID: PMC11901061 DOI: 10.3390/ijms26051988] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2025] [Revised: 02/22/2025] [Accepted: 02/24/2025] [Indexed: 03/14/2025] Open
Abstract
Colorectal cancer (CRC) is a major cause of cancer-related mortality worldwide, with a significant impact on public health. Current treatment options include surgery, chemotherapy, radiotherapy, molecular-targeted therapy, and immunotherapy. Despite advancements in these therapeutic modalities, resistance remains a significant challenge, often leading to treatment failure, poor progression-free survival, and cancer recurrence. Mechanisms of resistance in CRC are multifaceted, involving genetic mutations, epigenetic alterations, tumor heterogeneity, and the tumor microenvironment. Understanding these mechanisms at the molecular level is crucial for identifying novel therapeutic targets and developing strategies to overcome resistance. This review provides an overview of the diverse mechanisms driving drug resistance in sporadic CRC and discusses strategies currently under investigation to counteract this resistance. Several promising strategies are being explored, including targeting drug transport, key signaling pathways, DNA damage response, cell death pathways, epigenetic modifications, cancer stem cells, and the tumor microenvironment. The integration of emerging therapeutic approaches that target resistance mechanisms aims to enhance the efficacy of current CRC treatments and improve patient outcomes.
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Affiliation(s)
- Jennifer Haynes
- Department of Clinical and Translational Sciences, Joan C. Edwards School of Medicine, Marshall University, 1600 Medical Center Drive, Huntington, WV 25701, USA;
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Dey S, Ghosh M, Dev A. Signalling and molecular pathways, overexpressed receptors of colorectal cancer and effective therapeutic targeting using biogenic silver nanoparticles. Gene 2025; 936:149099. [PMID: 39557372 DOI: 10.1016/j.gene.2024.149099] [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: 08/15/2024] [Revised: 10/18/2024] [Accepted: 11/13/2024] [Indexed: 11/20/2024]
Abstract
Increasing morbidity and mortality in CRC is a potential threat to human health. The major challenges for better treatment outcomes are the heterogeneity of CRC cases, complicated molecular pathway cross-talks, the influence of gut dysbiosis in CRC, and the lack of multimodal target-specific drug delivery. The overexpression of many receptors in CRC cells may pave the path for targeting them with multiple ligands. The design of a more target-specific drug-delivery device with multiple ligand-functionalized, green-synthesized silver nanoparticles is highly promising and may also deliver other approved chemotherapeutic agents. This review presents the various aspects of colorectal cancer and over-expressed receptors that can be targeted with appropriate ligands to enhance the specific drug delivery potency of green synthesised silver nanoparticles. This review aims to broaden further research into this multi-ligand functionalised, safer and effective silver nano drug delivery system.
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Affiliation(s)
- Sandip Dey
- Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Jharkhand, India
| | - Manik Ghosh
- Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Jharkhand, India
| | - Abhimanyu Dev
- Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Jharkhand, India.
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Liu S, Ren J, Hu Y, Zhou F, Zhang L. TGFβ family signaling in human stem cell self-renewal and differentiation. CELL REGENERATION (LONDON, ENGLAND) 2024; 13:26. [PMID: 39604763 PMCID: PMC11602941 DOI: 10.1186/s13619-024-00207-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/28/2024] [Revised: 10/16/2024] [Accepted: 11/01/2024] [Indexed: 11/29/2024]
Abstract
Human stem cells are undifferentiated cells with the capacity for self-renewal and differentiation into distinct cell lineages, playing important role in the development and maintenance of diverse tissues and organs. The microenvironment of stem cell provides crucial factors and components that exert significant influence over the determination of cell fate. Among these factors, cytokines from the transforming growth factor β (TGFβ) superfamily, including TGFβ, bone morphogenic protein (BMP), Activin and Nodal, have been identified as important regulators governing stem cell maintenance and differentiation. In this review, we present a comprehensive overview of the pivotal roles played by TGFβ superfamily signaling in governing human embryonic stem cells, somatic stem cells, induced pluripotent stem cells, and cancer stem cells. Furthermore, we summarize the latest research and advancements of TGFβ family in various cancer stem cells and stem cell-based therapy, discussing their potential clinical applications in cancer therapy and regeneration medicine.
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Affiliation(s)
- Sijia Liu
- International Biomed-X Research Center, Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Second Affiliated Hospital of Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China
| | - Jiang Ren
- The First Affiliated Hospital, MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors, Institute of Biomedical Innovation, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Yanmei Hu
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Fangfang Zhou
- The First Affiliated Hospital, the Institutes of Biology and Medical Sciences, Suzhou Medical College, Soochow University, Suzhou, China.
| | - Long Zhang
- International Biomed-X Research Center, Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Second Affiliated Hospital of Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China.
- The First Affiliated Hospital, MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors, Institute of Biomedical Innovation, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, China.
- MOE Key Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou, 310058, China.
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Li Q, Geng S, Luo H, Wang W, Mo YQ, Luo Q, Wang L, Song GB, Sheng JP, Xu B. Signaling pathways involved in colorectal cancer: pathogenesis and targeted therapy. Signal Transduct Target Ther 2024; 9:266. [PMID: 39370455 PMCID: PMC11456611 DOI: 10.1038/s41392-024-01953-7] [Citation(s) in RCA: 54] [Impact Index Per Article: 54.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Revised: 07/25/2024] [Accepted: 08/16/2024] [Indexed: 10/08/2024] Open
Abstract
Colorectal cancer (CRC) remains one of the leading causes of cancer-related mortality worldwide. Its complexity is influenced by various signal transduction networks that govern cellular proliferation, survival, differentiation, and apoptosis. The pathogenesis of CRC is a testament to the dysregulation of these signaling cascades, which culminates in the malignant transformation of colonic epithelium. This review aims to dissect the foundational signaling mechanisms implicated in CRC, to elucidate the generalized principles underpinning neoplastic evolution and progression. We discuss the molecular hallmarks of CRC, including the genomic, epigenomic and microbial features of CRC to highlight the role of signal transduction in the orchestration of the tumorigenic process. Concurrently, we review the advent of targeted and immune therapies in CRC, assessing their impact on the current clinical landscape. The development of these therapies has been informed by a deepening understanding of oncogenic signaling, leading to the identification of key nodes within these networks that can be exploited pharmacologically. Furthermore, we explore the potential of integrating AI to enhance the precision of therapeutic targeting and patient stratification, emphasizing their role in personalized medicine. In summary, our review captures the dynamic interplay between aberrant signaling in CRC pathogenesis and the concerted efforts to counteract these changes through targeted therapeutic strategies, ultimately aiming to pave the way for improved prognosis and personalized treatment modalities in colorectal cancer.
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Affiliation(s)
- Qing Li
- The Shapingba Hospital, Chongqing University, Chongqing, China
- Chongqing Key Laboratory of Intelligent Oncology for Breast Cancer, Chongqing University Cancer Hospital and School of Medicine, Chongqing University, Chongqing, China
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, China
| | - Shan Geng
- Central Laboratory, The Affiliated Dazu Hospital of Chongqing Medical University, Chongqing, China
| | - Hao Luo
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, China
- Cancer Center, Daping Hospital, Army Medical University, Chongqing, China
| | - Wei Wang
- Chongqing Municipal Health and Health Committee, Chongqing, China
| | - Ya-Qi Mo
- Chongqing Key Laboratory of Intelligent Oncology for Breast Cancer, Chongqing University Cancer Hospital and School of Medicine, Chongqing University, Chongqing, China
| | - Qing Luo
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, China
| | - Lu Wang
- Chongqing Key Laboratory of Intelligent Oncology for Breast Cancer, Chongqing University Cancer Hospital and School of Medicine, Chongqing University, Chongqing, China
| | - Guan-Bin Song
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, China.
| | - Jian-Peng Sheng
- College of Artificial Intelligence, Nanjing University of Aeronautics and Astronautics, Nanjing, China.
| | - Bo Xu
- Chongqing Key Laboratory of Intelligent Oncology for Breast Cancer, Chongqing University Cancer Hospital and School of Medicine, Chongqing University, Chongqing, China.
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Lun J, Zhang Y, Yu M, Zhai W, Zhu L, Liu H, Guo J, Zhang G, Qiu W, Fang J. Circular RNA circHIPK2 inhibits colon cancer cells through miR-373-3p/RGMA axis. Cancer Lett 2024; 593:216957. [PMID: 38762192 DOI: 10.1016/j.canlet.2024.216957] [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: 03/25/2024] [Revised: 05/08/2024] [Accepted: 05/09/2024] [Indexed: 05/20/2024]
Abstract
Circular RNAs (circRNAs) have been implicated in cancer development. However, their regulation, function, and underlying mechanisms of action remain unclear. We found that circHIPK2 was downregulated in colon cancer, and low expression levels of circHIPK2 were associated with high tumor grade and poor patient survival. The expression of circHIPK2 was observed to be regulated by the transcription factor HOXD10, which was downregulated in colon cancer. Consequently, low circHIPK2 expression promoted colon cancer cell proliferation, migration, and invasion in vitro and tumor growth and metastasis in vivo. Mechanistically, circHIPK2 sponges miR-373-3p to upregulate the expression of the tumor suppressor RGMA, leading to the activation of BMP/Smad signaling and, ultimately, the inhibition of colon cancer cells, indicating that circHIPK2 inhibits colon cancer cells through the miR-373-3p/RGMA/BMP pathway. These findings revealed a previously unknown regulation, function, and underlying mechanism of circHIPK2 in cancer cells. Hence, circHIPK2 may have a prognostic value and serve as a potential target for colon cancer treatment.
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Affiliation(s)
- Jie Lun
- Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao Cancer Institute, Qingdao University, Qingdao, 266071, China; School of Pharmacy, Qingdao University, Qingdao, 266071, China
| | - Yuying Zhang
- School of Public Health, Qingdao University, Qingdao, 266071, China
| | - Mengchao Yu
- Central Laboratories, Qingdao Municipal Hospital, Qingdao, 266071, China
| | - Wenxin Zhai
- Department of Medical Oncology, Changzheng Hospital, Naval Medical University, 64 Hetian Road, Shanghai, 200072, China
| | - Lei Zhu
- Medical College, Qingdao Binhai University, Qingdao, 266071, China
| | - Huizi Liu
- Department of Rehabilitation Medicine, General Hospital of Central Theater Command, Wuhan, 430070, China
| | - Jing Guo
- Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao Cancer Institute, Qingdao University, Qingdao, 266071, China
| | - Gang Zhang
- Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao Cancer Institute, Qingdao University, Qingdao, 266071, China
| | - Wensheng Qiu
- Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao Cancer Institute, Qingdao University, Qingdao, 266071, China.
| | - Jing Fang
- Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao Cancer Institute, Qingdao University, Qingdao, 266071, China.
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Bustamante-Madrid P, Barbáchano A, Albandea-Rodríguez D, Rodríguez-Cobos J, Rodríguez-Salas N, Prieto I, Burgos A, Martínez de Villarreal J, Real FX, González-Sancho JM, Larriba MJ, Lafarga M, Muñoz A, Fernández-Barral A. Vitamin D opposes multilineage cell differentiation induced by Notch inhibition and BMP4 pathway activation in human colon organoids. Cell Death Dis 2024; 15:301. [PMID: 38684650 PMCID: PMC11058856 DOI: 10.1038/s41419-024-06680-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Revised: 04/08/2024] [Accepted: 04/12/2024] [Indexed: 05/02/2024]
Abstract
Understanding the mechanisms involved in colonic epithelial differentiation is key to unraveling the alterations causing inflammatory conditions and cancer. Organoid cultures provide an unique tool to address these questions but studies are scarce. We report a differentiation system toward enterocytes and goblet cells, the two major colonic epithelial cell lineages, using colon organoids generated from healthy tissue of colorectal cancer patients. Culture of these organoids in medium lacking stemness agents resulted in a modest ultrastructural differentiation phenotype with low-level expression of enterocyte (KLF4, KRT20, CA1, FABP2) and goblet cell (TFF2, TFF3, AGR2) lineage markers. BMP pathway activation through depletion of Noggin and addition of BMP4 resulted in enterocyte-biased differentiation. Contrarily, blockade of the Notch pathway using the γ-secretase inhibitor dibenzazepine (DBZ) favored goblet cell differentiation. Combination treatment with BMP4 and DBZ caused a balanced strong induction of both lineages. In contrast, colon tumor organoids responded poorly to BMP4 showing only weak signals of cell differentiation, and were unresponsive to DBZ. We also investigated the effects of 1α,25-dihydroxyvitamin D3 (calcitriol) on differentiation. Calcitriol attenuated the effects of BMP4 and DBZ on colon normal organoids, with reduced expression of differentiation genes and phenotype. Consistently, in normal organoids, calcitriol inhibited early signaling by BMP4 as assessed by reduction of the level of phospho-SMAD1/5/8. Our results show that BMP and Notch signaling play key roles in human colon stem cell differentiation to the enterocytic and goblet cell lineages and that calcitriol modulates these processes favoring stemness features.
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Affiliation(s)
- Pilar Bustamante-Madrid
- Instituto de Investigaciones Biomédicas Sols-Morreale, CSIC-UAM, 28029, Madrid, Spain
- Centro de Investigación Biomédica en Red-Cáncer (CIBERONC), 28029, Madrid, Spain
- Instituto de Investigación Sanitaria Hospital Universitario La Paz (IdiPAZ), 28046, Madrid, Spain
| | - Antonio Barbáchano
- Instituto de Investigaciones Biomédicas Sols-Morreale, CSIC-UAM, 28029, Madrid, Spain
- Centro de Investigación Biomédica en Red-Cáncer (CIBERONC), 28029, Madrid, Spain
- Instituto de Investigación Sanitaria Hospital Universitario La Paz (IdiPAZ), 28046, Madrid, Spain
| | - David Albandea-Rodríguez
- Instituto de Investigaciones Biomédicas Sols-Morreale, CSIC-UAM, 28029, Madrid, Spain
- Centro de Investigación Biomédica en Red-Cáncer (CIBERONC), 28029, Madrid, Spain
- Instituto de Investigación Sanitaria Hospital Universitario La Paz (IdiPAZ), 28046, Madrid, Spain
| | - Javier Rodríguez-Cobos
- Instituto de Investigaciones Biomédicas Sols-Morreale, CSIC-UAM, 28029, Madrid, Spain
- Instituto de Investigación Sanitaria Hospital Universitario La Paz (IdiPAZ), 28046, Madrid, Spain
| | - Nuria Rodríguez-Salas
- Centro de Investigación Biomédica en Red-Cáncer (CIBERONC), 28029, Madrid, Spain
- Instituto de Investigación Sanitaria Hospital Universitario La Paz (IdiPAZ), 28046, Madrid, Spain
- Servicio de Oncología Médica, Hospital Universitario La Paz, 28046, Madrid, Spain
| | - Isabel Prieto
- Instituto de Investigación Sanitaria Hospital Universitario La Paz (IdiPAZ), 28046, Madrid, Spain
- Servicio de Cirugía General, Hospital Universitario La Paz, 28046, Madrid, Spain
| | - Aurora Burgos
- Servicio de Digestivo, Hospital Universitario La Paz, 28046, Madrid, Spain
| | - Jaime Martínez de Villarreal
- Centro de Investigación Biomédica en Red-Cáncer (CIBERONC), 28029, Madrid, Spain
- Centro Nacional de Investigaciones Oncológicas (CNIO), 28029, Madrid, Spain
| | - Francisco X Real
- Centro de Investigación Biomédica en Red-Cáncer (CIBERONC), 28029, Madrid, Spain
- Centro Nacional de Investigaciones Oncológicas (CNIO), 28029, Madrid, Spain
- Department of Medicine and Life Sciences, Universitat Pompeu Fabra, 08003, Barcelona, Spain
| | - José Manuel González-Sancho
- Instituto de Investigaciones Biomédicas Sols-Morreale, CSIC-UAM, 28029, Madrid, Spain
- Centro de Investigación Biomédica en Red-Cáncer (CIBERONC), 28029, Madrid, Spain
- Instituto de Investigación Sanitaria Hospital Universitario La Paz (IdiPAZ), 28046, Madrid, Spain
| | - María Jesús Larriba
- Instituto de Investigaciones Biomédicas Sols-Morreale, CSIC-UAM, 28029, Madrid, Spain
- Centro de Investigación Biomédica en Red-Cáncer (CIBERONC), 28029, Madrid, Spain
- Instituto de Investigación Sanitaria Hospital Universitario La Paz (IdiPAZ), 28046, Madrid, Spain
| | - Miguel Lafarga
- Departamento de Anatomía y Biología Celular, Universidad de Cantabria-IDIVAL, 39008, Santander, Spain
| | - Alberto Muñoz
- Instituto de Investigaciones Biomédicas Sols-Morreale, CSIC-UAM, 28029, Madrid, Spain.
- Centro de Investigación Biomédica en Red-Cáncer (CIBERONC), 28029, Madrid, Spain.
- Instituto de Investigación Sanitaria Hospital Universitario La Paz (IdiPAZ), 28046, Madrid, Spain.
| | - Asunción Fernández-Barral
- Instituto de Investigaciones Biomédicas Sols-Morreale, CSIC-UAM, 28029, Madrid, Spain.
- Centro de Investigación Biomédica en Red-Cáncer (CIBERONC), 28029, Madrid, Spain.
- Instituto de Investigación Sanitaria Hospital Universitario La Paz (IdiPAZ), 28046, Madrid, Spain.
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Dupuy J, Cogo E, Fouché E, Guéraud F, Pierre F, Plaisancié P. Epithelial-mesenchymal interaction protects normal colonocytes from 4-HNE-induced phenotypic transformation. PLoS One 2024; 19:e0302932. [PMID: 38669265 PMCID: PMC11051638 DOI: 10.1371/journal.pone.0302932] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2024] [Accepted: 04/05/2024] [Indexed: 04/28/2024] Open
Abstract
INTRODUCTION Recent studies have shown that epithelial-stromal interactions could play a role in the development of colorectal cancer. Here, we investigated the role of fibroblasts in the transformation of normal colonocytes induced by 4-HNE. METHODS Normal Co colonocytes and nF fibroblasts from the same mouse colon were exposed, in monoculture (m) or coculture (c), to 4-HNE (5 μM) twice weekly for 3 weeks. Gene expression was then analysed and the ability of Co colonocytes to grow in anchorage-independent conditions was tested in soft agar. Fibroblasts previously treated or not with 4-HNE were also seeded in culture inserts positioned above the agar layers to allow paracrine exchanges with colonocytes. RESULTS First, 60% of the genes studied were modulated by coculture in Co colonocytes, with notably increased expression of BMP receptors. Furthermore, while 4-HNE increased the ability of monoculture-treated Co colonocytes to form colonies, this effect was not observed in coculture-treated Co colonocytes. Adding a selective BMPR1 inhibitor during the treatment phase abolished the protective effect of coculture. Conversely, addition of a BMP4 agonist to the medium of monoculture-treated Co colonocytes prevented phenotypic transformation by 4-HNE. Second, the presence of nF(m)-HNE fibroblasts during the soft agar assay increased the number and size of Co(m) colonocyte colonies, regardless of whether these cells had been previously treated with 4-HNE in monoculture. For soft agar assays performed with nF(c) and Co(c) cells initially treated in coculture, only the reassociation between Co(c)-HNE and nF(c)-HNE resulted in a small increase in the number of colonies. CONCLUSIONS During the exposure phase, the epithelial-mesenchymal interaction protected colonocytes from 4-HNE-induced phenotypic transformation via activation of the BMP pathway. This intercellular dialogue also limited the ability of fibroblasts to subsequently promote colonocyte-anchorage-independent growth. In contrast, fibroblasts pre-exposed to 4-HNE in monoculture strongly increased the ability of Co(m) colonocytes to form colonies.
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Affiliation(s)
- Jacques Dupuy
- Toxalim UMR1331 (Research Centre in Food Toxicology), Toulouse University, INRAE, ENVT, INP-Purpan, UPS, Toulouse, France
| | - Emma Cogo
- Toxalim UMR1331 (Research Centre in Food Toxicology), Toulouse University, INRAE, ENVT, INP-Purpan, UPS, Toulouse, France
| | - Edwin Fouché
- Toxalim UMR1331 (Research Centre in Food Toxicology), Toulouse University, INRAE, ENVT, INP-Purpan, UPS, Toulouse, France
| | - Françoise Guéraud
- Toxalim UMR1331 (Research Centre in Food Toxicology), Toulouse University, INRAE, ENVT, INP-Purpan, UPS, Toulouse, France
| | - Fabrice Pierre
- Toxalim UMR1331 (Research Centre in Food Toxicology), Toulouse University, INRAE, ENVT, INP-Purpan, UPS, Toulouse, France
| | - Pascale Plaisancié
- Toxalim UMR1331 (Research Centre in Food Toxicology), Toulouse University, INRAE, ENVT, INP-Purpan, UPS, Toulouse, France
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Golán-Cancela I, Caja L. The TGF-β Family in Glioblastoma. Int J Mol Sci 2024; 25:1067. [PMID: 38256140 PMCID: PMC10816220 DOI: 10.3390/ijms25021067] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Revised: 01/03/2024] [Accepted: 01/09/2024] [Indexed: 01/24/2024] Open
Abstract
Members of the transforming growth factor β (TGF-β) family have been implicated in the biology of several cancers. In this review, we focus on the role of TGFβ and bone morphogenetic protein (BMP) signaling in glioblastoma. Glioblastoma (GBM) is the most common malignant brain tumor in adults; it presents at a median age of 64 years, but can occur at any age, including childhood. Unfortunately, there is no cure, and even patients undergoing current treatments (surgical resection, radiotherapy, and chemotherapy) have a median survival of 15 months. There is a great need to identify new therapeutic targets to improve the treatment of GBM patients. TGF-βs signaling promotes tumorigenesis in glioblastoma, while BMPs suppress tumorigenic potential by inducing tumor cell differentiation. In this review, we discuss the actions of TGF-βs and BMPs on cancer cells as well as in the tumor microenvironment, and their use in potential therapeutic intervention.
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Affiliation(s)
| | - Laia Caja
- Department of Medical Biochemistry and Microbiology, Biomedical Center, Uppsala University, SE-75123 Uppsala, Sweden;
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Zhou W, Yan K, Xi Q. BMP signaling in cancer stemness and differentiation. CELL REGENERATION (LONDON, ENGLAND) 2023; 12:37. [PMID: 38049682 PMCID: PMC10695912 DOI: 10.1186/s13619-023-00181-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Accepted: 11/06/2023] [Indexed: 12/06/2023]
Abstract
The BMP (Bone morphogenetic protein) signaling pathway plays a central role in metazoan biology, intricately shaping embryonic development, maintaining tissue homeostasis, and influencing disease progression. In the context of cancer, BMP signaling exhibits context-dependent dynamics, spanning from tumor suppression to promotion. Cancer stem cells (CSCs), a modest subset of neoplastic cells with stem-like attributes, exert substantial influence by steering tumor growth, orchestrating therapy resistance, and contributing to relapse. A comprehensive grasp of the intricate interplay between CSCs and their microenvironment is pivotal for effective therapeutic strategies. Among the web of signaling pathways orchestrating cellular dynamics within CSCs, BMP signaling emerges as a vital conductor, overseeing CSC self-renewal, differentiation dynamics, and the intricate symphony within the tumor microenvironment. Moreover, BMP signaling's influence in cancer extends beyond CSCs, intricately regulating cellular migration, invasion, and metastasis. This multifaceted role underscores the imperative of comprehending BMP signaling's contributions to cancer, serving as the foundation for crafting precise therapies to navigate multifaceted challenges posed not only by CSCs but also by various dimensions of cancer progression. This article succinctly encapsulates the diverse roles of the BMP signaling pathway across different cancers, spanning glioblastoma multiforme (GBM), diffuse intrinsic pontine glioma (DIPG), colorectal cancer, acute myeloid leukemia (AML), lung cancer, prostate cancer, and osteosarcoma. It underscores the necessity of unraveling underlying mechanisms and molecular interactions. By delving into the intricate tapestry of BMP signaling's engagement in cancers, researchers pave the way for meticulously tailored therapies, adroitly leveraging its dualistic aspects-whether as a suppressor or promoter-to effectively counter the relentless march of tumor progression.
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Affiliation(s)
- Wei Zhou
- State Key Laboratory of Molecular Oncology, MOE Key Laboratory of Protein Sciences, School of Life Sciences, Tsinghua University, Beijing, 100084, China
| | - Kun Yan
- Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, 100084, China
| | - Qiaoran Xi
- State Key Laboratory of Molecular Oncology, MOE Key Laboratory of Protein Sciences, School of Life Sciences, Tsinghua University, Beijing, 100084, China.
- Joint Graduate Program of Peking-Tsinghua-NIBS, Tsinghua University, Beijing, China.
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Shimizu S, Kondo J, Onuma K, Coppo R, Ota K, Kamada M, Harada Y, Tanaka Y, Nakazawa MA, Tamada Y, Okuno Y, Kawada K, Obama K, Coffey RJ, Fujiwara Y, Inoue M. Inhibition of the bone morphogenetic protein pathway suppresses tumor growth through downregulation of epidermal growth factor receptor in MEK/ERK-dependent colorectal cancer. Cancer Sci 2023; 114:3636-3648. [PMID: 37357017 PMCID: PMC10475764 DOI: 10.1111/cas.15882] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Revised: 05/22/2023] [Accepted: 05/27/2023] [Indexed: 06/27/2023] Open
Abstract
The bone morphogenetic protein (BMP) pathway promotes differentiation and induces apoptosis in normal colorectal epithelial cells. However, its role in colorectal cancer (CRC) is controversial, where it can act as context-dependent tumor promoter or tumor suppressor. Here we have found that CRC cells reside in a BMP-rich environment based on curation of two publicly available RNA-sequencing databases. Suppression of BMP using a specific BMP inhibitor, LDN193189, suppresses the growth of select CRC organoids. Colorectal cancer organoids treated with LDN193189 showed a decrease in epidermal growth factor receptor, which was mediated by protein degradation induced by leucine-rich repeats and immunoglobulin-like domains protein 1 (LRIG1) expression. Among 18 molecularly characterized CRC organoids, suppression of growth by BMP inhibition correlated with induction of LRIG1 gene expression. Notably, knockdown of LRIG1 in organoids diminished the growth-suppressive effect of LDN193189. Furthermore, in CRC organoids, which are susceptible to growth suppression by LDN193189, simultaneous treatment with LDN193189 and trametinib, an FDA-approved MEK inhibitor, resulted in cooperative growth inhibition both in vitro and in vivo. Taken together, the simultaneous inhibition of BMP and MEK could be a novel treatment option in CRC cases, and evaluating in vitro growth suppression and LRIG1 induction by BMP inhibition using patient-derived organoids could offer functional biomarkers for predicting potential responders to this regimen.
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Affiliation(s)
- Shota Shimizu
- Department of Clinical Bioresource Research and DevelopmentKyoto University Graduate School of MedicineKyotoJapan
- Division of Gastrointestinal and Pediatric Surgery, Department of Surgery, School of MedicineTottori University Faculty of MedicineTottoriJapan
| | - Jumpei Kondo
- Department of Clinical Bioresource Research and DevelopmentKyoto University Graduate School of MedicineKyotoJapan
- Department of BiochemistryOsaka International Cancer InstituteOsakaJapan
- Department of Molecular Biochemistry and Clinical Investigation, Division of Health ScienceOsaka University Graduate School of MedicineOsakaJapan
- Epithelial Biology CenterVanderbilt University Medical CenterNashvilleTennesseeUSA
| | - Kunishige Onuma
- Department of Clinical Bioresource Research and DevelopmentKyoto University Graduate School of MedicineKyotoJapan
| | - Roberto Coppo
- Department of Clinical Bioresource Research and DevelopmentKyoto University Graduate School of MedicineKyotoJapan
| | - Kasumi Ota
- Graduate School of Medicine and Faculty of MedicineKyoto UniversityKyotoJapan
| | - Mayumi Kamada
- Graduate School of Medicine and Faculty of MedicineKyoto UniversityKyotoJapan
| | - Yohei Harada
- Graduate School of Medicine and Faculty of MedicineKyoto UniversityKyotoJapan
| | - Yoshihisa Tanaka
- Graduate School of Pharmaceutical SciencesKyoto UniversityKyotoJapan
- RIKEN Center for Computational Science(R‐CCS)HPC/HPC‐ and AI‐driven Drug Development Platform DivisionKobeJapan
| | - Mai Adachi Nakazawa
- Graduate School of Medicine and Faculty of MedicineKyoto UniversityKyotoJapan
- Department of Medical Data Intelligence and Data Analysis Division, Innovation Center for Health PromotionHirosaki UniversityHirosakiJapan
| | - Yoshinori Tamada
- Department of Medical Data Intelligence and Data Analysis Division, Innovation Center for Health PromotionHirosaki UniversityHirosakiJapan
| | - Yasushi Okuno
- Graduate School of Medicine and Faculty of MedicineKyoto UniversityKyotoJapan
- RIKEN Center for Computational Science(R‐CCS)HPC/HPC‐ and AI‐driven Drug Development Platform DivisionKobeJapan
| | - Kenji Kawada
- Department of Surgery, Graduate School of MedicineKyoto UniversityKyotoJapan
| | - Kazutaka Obama
- Department of Surgery, Graduate School of MedicineKyoto UniversityKyotoJapan
| | - Robert J. Coffey
- Epithelial Biology CenterVanderbilt University Medical CenterNashvilleTennesseeUSA
| | - Yoshiyuki Fujiwara
- Division of Gastrointestinal and Pediatric Surgery, Department of Surgery, School of MedicineTottori University Faculty of MedicineTottoriJapan
| | - Masahiro Inoue
- Department of Clinical Bioresource Research and DevelopmentKyoto University Graduate School of MedicineKyotoJapan
- Department of BiochemistryOsaka International Cancer InstituteOsakaJapan
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11
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Savino W, Lepletier A. Thymus-derived hormonal and cellular control of cancer. Front Endocrinol (Lausanne) 2023; 14:1168186. [PMID: 37529610 PMCID: PMC10389273 DOI: 10.3389/fendo.2023.1168186] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Accepted: 06/26/2023] [Indexed: 08/03/2023] Open
Abstract
The thymus gland is a central lymphoid organ in which developing T cell precursors, known as thymocytes, undergo differentiation into distinct type of mature T cells, ultimately migrating to the periphery where they exert specialized effector functions and orchestrate the immune responses against tumor cells, pathogens and self-antigens. The mechanisms supporting intrathymic T cell differentiation are pleiotropically regulated by thymic peptide hormones and cytokines produced by stromal cells in the thymic microenvironment and developing thymocytes. Interestingly, in the same way as T cells, thymic hormones (herein exemplified by thymosin, thymulin and thymopoietin), can circulate to impact immune cells and other cellular components in the periphery. Evidence on how thymic function influences tumor cell biology and response of patients with cancer to therapies remains unsatisfactory, although there has been some improvement in the knowledge provided by recent studies. Herein, we summarize research progression in the field of thymus-mediated immunoendocrine control of cancer, providing insights into how manipulation of the thymic microenvironment can influence treatment outcomes, including clinical responses and adverse effects of therapies. We review data obtained from clinical and preclinical cancer research to evidence the complexity of immunoendocrine interactions underpinning anti-tumor immunity.
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Affiliation(s)
- Wilson Savino
- Laboratory on Thymus Research, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil
- Brazilian National Institute of Science and Technology on Neuroimmunomodulation, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil
- Rio de Janeiro Research Network on Neuroinflammation, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil
- INOVA-IOC Network on Neuroimmunomodulation, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil
| | - Ailin Lepletier
- Institute for Glycomics, Griffith University, Gold Coast, QLD, Australia
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12
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Novoa Díaz MB, Carriere P, Gentili C. How the interplay among the tumor microenvironment and the gut microbiota influences the stemness of colorectal cancer cells. World J Stem Cells 2023; 15:281-301. [PMID: 37342226 PMCID: PMC10277969 DOI: 10.4252/wjsc.v15.i5.281] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2022] [Revised: 03/06/2023] [Accepted: 04/17/2023] [Indexed: 05/26/2023] Open
Abstract
Colorectal cancer (CRC) remains the third most prevalent cancer disease and involves a multi-step process in which intestinal cells acquire malignant characteristics. It is well established that the appearance of distal metastasis in CRC patients is the cause of a poor prognosis and treatment failure. Nevertheless, in the last decades, CRC aggressiveness and progression have been attributed to a specific cell population called CRC stem cells (CCSC) with features like tumor initiation capacity, self-renewal capacity, and acquired multidrug resistance. Emerging data highlight the concept of this cell subtype as a plastic entity that has a dynamic status and can be originated from different types of cells through genetic and epigenetic changes. These alterations are modulated by complex and dynamic crosstalk with environmental factors by paracrine signaling. It is known that in the tumor niche, different cell types, structures, and biomolecules coexist and interact with cancer cells favoring cancer growth and development. Together, these components constitute the tumor microenvironment (TME). Most recently, researchers have also deepened the influence of the complex variety of microorganisms that inhabit the intestinal mucosa, collectively known as gut microbiota, on CRC. Both TME and microorganisms participate in inflammatory processes that can drive the initiation and evolution of CRC. Since in the last decade, crucial advances have been made concerning to the synergistic interaction among the TME and gut microorganisms that condition the identity of CCSC, the data exposed in this review could provide valuable insights into the biology of CRC and the development of new targeted therapies.
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Affiliation(s)
- María Belén Novoa Díaz
- Departamento de Biología, Bioquímica y Farmacia, Universidad Nacional del Sur, Bahía Blanca 8000, Buenos Aires, Argentina
- Instituto de Ciencias Biológicas y Biomédicas del Sur, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)- Universidad Nacional del Sur (UNS), Bahía Blanca 8000, Buenos Aires, Argentina
| | - Pedro Carriere
- Departamento de Biología, Bioquímica y Farmacia, Universidad Nacional del Sur, Bahía Blanca 8000, Buenos Aires, Argentina
- Instituto de Ciencias Biológicas y Biomédicas del Sur, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)- Universidad Nacional del Sur (UNS), Bahía Blanca 8000, Buenos Aires, Argentina
| | - Claudia Gentili
- Departamento de Biología, Bioquímica y Farmacia, Universidad Nacional del Sur, Bahía Blanca 8000, Buenos Aires, Argentina
- Instituto de Ciencias Biológicas y Biomédicas del Sur, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)- Universidad Nacional del Sur (UNS), Bahía Blanca 8000, Buenos Aires, Argentina
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13
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Xu K, Zheng S, Li B, Shao Y, Yin X. Molecular characterization of colorectal mucinous adenocarcinoma and adenocarcinoma, not otherwise specified, identified by multiomic data analysis. Front Mol Biosci 2023; 10:1150362. [PMID: 37091868 PMCID: PMC10114614 DOI: 10.3389/fmolb.2023.1150362] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2023] [Accepted: 02/27/2023] [Indexed: 04/08/2023] Open
Abstract
Adenocarcinoma not otherwise specified (AC) and mucinous adenocarcinoma (MC) have different biological behaviors and clinical features. We utilized our previous proteomic data and public transcriptome, single-cell transcriptome, and spatial transcriptome databases to profile the molecular atlas of the tumor microenvironments of MC, AC, and normal colon tissues. By exploring the general and specific molecular features of AC and MC, we found that AC was immune-active but exposed to a hypoxic microenvironment. MC cells could protect against DNA damage, and the microenvironment was unfavorable to leukocyte transendothelial migration. We identified several potential molecular and cellular targets of AC and MC for future research. We also highlighted that the major difference between AC and MC was not the variety of cell types and functions but possibly cell interactions. Stromal and epithelial cell interactions play important roles in both MC and AC, but different regulatory pathways were involved.
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Affiliation(s)
- Kailun Xu
- Department of Breast Surgery and Oncology (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences, Zhejiang Province, China), Cancer Institute, The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Cancer, Cancer Center of Zhejiang University, Hangzhou, Zhejiang, China
| | - Shu Zheng
- Department of Breast Surgery and Oncology (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences, Zhejiang Province, China), Cancer Institute, The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Cancer, Cancer Center of Zhejiang University, Hangzhou, Zhejiang, China
| | - Baosheng Li
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Yingkuan Shao
- Department of Breast Surgery and Oncology (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences, Zhejiang Province, China), Cancer Institute, The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Cancer, Cancer Center of Zhejiang University, Hangzhou, Zhejiang, China
- *Correspondence: Yingkuan Shao, ; Xiaoyang Yin,
| | - Xiaoyang Yin
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
- *Correspondence: Yingkuan Shao, ; Xiaoyang Yin,
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14
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Ebrahimi N, Afshinpour M, Fakhr SS, Kalkhoran PG, Shadman-Manesh V, Adelian S, Beiranvand S, Rezaei-Tazangi F, Khorram R, Hamblin MR, Aref AR. Cancer stem cells in colorectal cancer: Signaling pathways involved in stemness and therapy resistance. Crit Rev Oncol Hematol 2023; 182:103920. [PMID: 36702423 DOI: 10.1016/j.critrevonc.2023.103920] [Citation(s) in RCA: 51] [Impact Index Per Article: 25.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Revised: 12/07/2022] [Accepted: 01/20/2023] [Indexed: 01/24/2023] Open
Abstract
Colorectal cancer (CRC) is the third cause of cancer death worldwide. Although, in some cases, treatment can increase patient survival and reduce cancer recurrence, in many cases, tumors can develop resistance to therapy leading to recurrence. One of the main reasons for recurrence and therapy resistance is the presence of cancer stem cells (CSCs). CSCs possess a self-renewal ability, and their stemness properties lead to the avoidance of apoptosis, and allow a new clone of cancer cells to emerge. Numerous investigations inidicated the involvment of cellular signaling pathways in embryonic development, and growth, repair, and maintenance of tissue homeostasis, also participate in the generation and maintenance of stemness in colorectal CSCs. This review discusses the role of Wnt, NF-κB, PI3K/AKT/mTOR, Sonic hedgehog, and Notch signaling pathways in colorectal CSCs, and the possible modulating drugs that could be used in treatment for resistant CRC.
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Affiliation(s)
- Nasim Ebrahimi
- Division of Genetics, Department of cell and molecular & microbiology, Faculty of Science and technology, University of Isfahan, Isfahan, Iran
| | - Maral Afshinpour
- Department of chemistry and Biochemistry, South Dakota State University (SDSU), Brookings, SD, USA
| | - Siavash Seifollahy Fakhr
- Department of Biotechnology; Faculty of Applied Ecology, Agricultural Sciences and Biotechnology, Campus Hamar, Norway
| | - Paniz Ghasempour Kalkhoran
- Department of Cellular and Molecular Biology_Microbiology, Faculty of Advanced Science and Technology, Tehran Medical science, Islamic Azad University, Tehran, Iran
| | - Vida Shadman-Manesh
- Department of Biomedical Engineering, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Samaneh Adelian
- Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Sheida Beiranvand
- Department of Biotechnology, School of Basic Sciences, Shahrekord Branch, Islamic Azad University, Shahrekord, Iran
| | - Fatemeh Rezaei-Tazangi
- Department of Anatomy, School of Medicine, Fasa University of Medical Sciences, Fasa, Iran
| | - Roya Khorram
- Bone and Joint Diseases Research Center, Department of Orthopedic Surgery, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Michael R Hamblin
- Laser Research Centre, Faculty of Health Science, University of Johannesburg, Doornfontein 2028, South Africa.
| | - Amir Reza Aref
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA; Xsphera Biosciences, Translational Medicine Group, 6 Tide Street, Boston, MA 02210, USA.
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15
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Dijkstra J, Neikes HK, Rezaeifard S, Ma X, Voest EE, Tauriello DVF, Vermeulen M. Multiomics of Colorectal Cancer Organoids Reveals Putative Mediators of Cancer Progression Resulting from SMAD4 Inactivation. J Proteome Res 2023; 22:138-151. [PMID: 36450103 PMCID: PMC9830641 DOI: 10.1021/acs.jproteome.2c00551] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/05/2022]
Abstract
The development of metastasis severely reduces the life expectancy of patients with colorectal cancer (CRC). Although loss of SMAD4 is a key event in CRC progression, the resulting changes in biological processes in advanced disease and metastasis are not fully understood. Here, we applied a multiomics approach to a CRC organoid model that faithfully reflects the metastasis-supporting effects of SMAD4 inactivation. We show that loss of SMAD4 results in decreased differentiation and activation of pro-migratory and cell proliferation processes, which is accompanied by the disruption of several key oncogenic pathways, including the TGFβ, WNT, and VEGF pathways. In addition, SMAD4 inactivation leads to increased secretion of proteins that are known to be involved in a variety of pro-metastatic processes. Finally, we show that one of the factors that is specifically secreted by SMAD4-mutant organoids─DKK3─reduces the antitumor effects of natural killer cells (NK cells). Altogether, our data provide new insights into the role of SMAD4 perturbation in advanced CRC.
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Affiliation(s)
- Jelmer
J. Dijkstra
- Department
of Molecular Biology, Faculty of Science, Radboud Institute for Molecular
Life Sciences (RIMLS), Oncode Institute, Radboud University Nijmegen, Geert Grooteplein 26−28, 6525
GA Nijmegen, The
Netherlands
| | - Hannah K. Neikes
- Department
of Molecular Biology, Faculty of Science, Radboud Institute for Molecular
Life Sciences (RIMLS), Oncode Institute, Radboud University Nijmegen, Geert Grooteplein 26−28, 6525
GA Nijmegen, The
Netherlands
| | - Somayeh Rezaeifard
- Department
of Cell Biology, Radboud University Medical Center/Radboud Institute
for Molecular Life Sciences (RIMLS), Radboud
University Nijmegen, Geert Grooteplein 26−28, 6525
GA Nijmegen, The
Netherlands
| | - Xuhui Ma
- Department
of Molecular Oncology and Immunology, Oncode Institute, The Netherlands Cancer Institute, Antoni van Leeuwenhoek
Hospital, 1066 CX Amsterdam, The Netherlands
| | - Emile E. Voest
- Department
of Molecular Oncology and Immunology, Oncode Institute, The Netherlands Cancer Institute, Antoni van Leeuwenhoek
Hospital, 1066 CX Amsterdam, The Netherlands
| | - Daniele V. F. Tauriello
- Department
of Cell Biology, Radboud University Medical Center/Radboud Institute
for Molecular Life Sciences (RIMLS), Radboud
University Nijmegen, Geert Grooteplein 26−28, 6525
GA Nijmegen, The
Netherlands
| | - Michiel Vermeulen
- Department
of Molecular Biology, Faculty of Science, Radboud Institute for Molecular
Life Sciences (RIMLS), Oncode Institute, Radboud University Nijmegen, Geert Grooteplein 26−28, 6525
GA Nijmegen, The
Netherlands,
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16
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Urh K, Zidar N, Tomažič A, Boštjančič E. Intra‑tumor heterogeneity of cancer stem cell‑related genes and their potential regulatory microRNAs in metastasizing colorectal carcinoma. Oncol Rep 2022; 48:193. [PMID: 36111489 DOI: 10.3892/or.2022.8408] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Accepted: 07/13/2022] [Indexed: 11/06/2022] Open
Abstract
Intra‑tumor heterogeneity (ITH) is related to cancer progression, therapy resistance and recurrences, and is one of the challenging fields in cancerogenesis research. Cancer stem cells (CSC) are thought to be crucially involved in the pathogenesis of several cancer types, including colorectal carcinoma (CRC), and associated with ITH. In the present study, the expression gradient of four genes related to CSC (L1TD1, SLITRK6, ST6GALNAC1 and TCEA3) and their potential regulatory microRNAs (miRNAs) were investigated in the central part and invasive front of the primary tumor, as well as in lymph node and liver metastases. In total, 63 formalin‑fixed paraffin‑embedded biopsy samples of primary tumor (central part, invasive tumor front), as well as lymph node and liver metastases from 19 patients with CRC, were analyzed. The expression of selected genes (L1TD1, SLITRK6, ST6GALNAC1 and TCEA3) and miRNAs (miR‑199a‑3p, miR‑425‑5p, miR‑1225‑3p, miR‑1233‑3p and miR‑1303) was evaluated using reverse transcription‑quantitative PCR. Significant differences in expression were identified for all investigated genes in lymph node metastasis, but not in the liver metastases. All investigated miRNAs were significantly differentially expressed in lymph node metastasis, and miR‑199a‑3p, miR‑425‑5p and miR‑1233‑3p in liver metastasis. Furthermore, a negative correlation between the expression of miR‑199a‑3p and expression of its potential target gene SLITRK6 was confirmed. The present results provide further evidence that expression of CSC‑related genes and their potential regulatory miRNAs contribute to ITH in CRC, lymph node and liver metastasis. The SLITRK6 gene and its regulatory miRNA miR‑199a‑3p are promising for further validation in functional studies to deepen the present understanding of the regulation of CSC‑related genes in CRC.
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Affiliation(s)
- Kristian Urh
- Institute of Pathology, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia
| | - Nina Zidar
- Institute of Pathology, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia
| | - Aleš Tomažič
- Department of Abdominal Surgery, Division of Surgery, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia
| | - Emanuela Boštjančič
- Institute of Pathology, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia
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17
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Urh K, Zidar N, Boštjančič E. Bioinformatics Analysis of RNA-seq Data Reveals Genes Related to Cancer Stem Cells in Colorectal Cancerogenesis. Int J Mol Sci 2022; 23:ijms232113252. [PMID: 36362041 PMCID: PMC9654446 DOI: 10.3390/ijms232113252] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Revised: 10/26/2022] [Accepted: 10/28/2022] [Indexed: 11/06/2022] Open
Abstract
Cancer stem cells (CSC) play one of the crucial roles in the pathogenesis of various cancers, including colorectal cancer (CRC). Although great efforts have been made regarding our understanding of the cancerogenesis of CRC, CSC involvement in CRC development is still poorly understood. Using bioinformatics and RNA-seq data of normal mucosa, colorectal adenoma, and carcinoma (n = 106) from GEO and TCGA, we identified candidate CSC genes and analyzed pathway enrichment analysis (PEI) and protein–protein interaction analysis (PPI). Identified CSC-related genes were validated using qPCR and tissue samples from 47 patients with adenoma, adenoma with early carcinoma, and carcinoma without and with lymph node metastasis and were compared to normal mucosa. Six CSC-related genes were identified: ANLN, CDK1, ECT2, PDGFD, TNC, and TNXB. ANLN, CDK1, ECT2, and TNC were differentially expressed between adenoma and adenoma with early carcinoma. TNC was differentially expressed in CRC without lymph node metastases whereas ANLN, CDK1, and PDGFD were differentially expressed in CRC with lymph node metastases compared to normal mucosa. ANLN and PDGFD were differentially expressed between carcinoma without and with lymph node metastasis. Our study identified and validated CSC-related genes that might be involved in early stages of CRC development (ANLN, CDK1, ECT2, TNC) and in development of metastasis (ANLN, PDGFD).
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18
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Álvarez-Varela A, Novellasdemunt L, Barriga FM, Hernando-Momblona X, Cañellas-Socias A, Cano-Crespo S, Sevillano M, Cortina C, Stork D, Morral C, Turon G, Slebe F, Jiménez-Gracia L, Caratù G, Jung P, Stassi G, Heyn H, Tauriello DVF, Mateo L, Tejpar S, Sancho E, Stephan-Otto Attolini C, Batlle E. Mex3a marks drug-tolerant persister colorectal cancer cells that mediate relapse after chemotherapy. NATURE CANCER 2022; 3:1052-1070. [PMID: 35773527 DOI: 10.1038/s43018-022-00402-0] [Citation(s) in RCA: 63] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Accepted: 05/20/2022] [Indexed: 06/15/2023]
Abstract
Colorectal cancer (CRC) patient-derived organoids predict responses to chemotherapy. Here we used them to investigate relapse after treatment. Patient-derived organoids expand from highly proliferative LGR5+ tumor cells; however, we discovered that lack of optimal growth conditions specifies a latent LGR5+ cell state. This cell population expressed the gene MEX3A, is chemoresistant and regenerated the organoid culture after treatment. In CRC mouse models, Mex3a+ cells contributed marginally to metastatic outgrowth; however, after chemotherapy, Mex3a+ cells produced large cell clones that regenerated the disease. Lineage-tracing analysis showed that persister Mex3a+ cells downregulate the WNT/stem cell gene program immediately after chemotherapy and adopt a transient state reminiscent to that of YAP+ fetal intestinal progenitors. In contrast, Mex3a-deficient cells differentiated toward a goblet cell-like phenotype and were unable to resist chemotherapy. Our findings reveal that adaptation of cancer stem cells to suboptimal niche environments protects them from chemotherapy and identify a candidate cell of origin of relapse after treatment in CRC.
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Affiliation(s)
- Adrián Álvarez-Varela
- Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Barcelona, Spain
| | - Laura Novellasdemunt
- Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain
| | - Francisco M Barriga
- Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain
- Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Xavier Hernando-Momblona
- Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Barcelona, Spain
| | - Adrià Cañellas-Socias
- Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Barcelona, Spain
| | - Sara Cano-Crespo
- Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain
| | - Marta Sevillano
- Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Barcelona, Spain
| | - Carme Cortina
- Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Barcelona, Spain
| | - Diana Stork
- Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain
| | - Clara Morral
- Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain
| | - Gemma Turon
- Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain
| | - Felipe Slebe
- Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain
| | - Laura Jiménez-Gracia
- CNAG-CRG, Centre for Genomic Regulation, Barcelona Institute of Science and Technology, Barcelona, Spain
| | - Ginevra Caratù
- CNAG-CRG, Centre for Genomic Regulation, Barcelona Institute of Science and Technology, Barcelona, Spain
| | - Peter Jung
- German Cancer Research Center (DKFZ), Heidelberg, Germany
- German Cancer Consortium (DKTK), Partner site Munich, Institute of Pathology, Ludwig Maximilian University, Munich, Germany
| | - Giorgio Stassi
- Department of Surgical Oncological and Stomatological Sciences, University of Palermo, Palermo, Italy
| | - Holger Heyn
- CNAG-CRG, Centre for Genomic Regulation, Barcelona Institute of Science and Technology, Barcelona, Spain
- Universitat Pompeu Fabra, Barcelona, Spain
| | - Daniele V F Tauriello
- Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain
- Department of Cell Biology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands
| | - Lidia Mateo
- Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain
| | - Sabine Tejpar
- Molecular Digestive Oncology, Department of Oncology, Katholieke Universiteit Leuven, Leuven, Belgium
| | - Elena Sancho
- Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Barcelona, Spain
| | - Camille Stephan-Otto Attolini
- Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain
| | - Eduard Batlle
- Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain.
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Barcelona, Spain.
- ICREA, Barcelona, Spain.
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19
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Sharma T, Kapoor A, Mandal CC. Duality of bone morphogenetic proteins in cancer: A comprehensive analysis. J Cell Physiol 2022; 237:3127-3163. [DOI: 10.1002/jcp.30785] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Revised: 04/06/2022] [Accepted: 04/29/2022] [Indexed: 11/06/2022]
Affiliation(s)
- Tanu Sharma
- Department of Biochemistry, School of Life Sciences Central University of Rajasthan Ajmer Rajasthan India
| | - Anmol Kapoor
- Department of Biochemistry, School of Life Sciences Central University of Rajasthan Ajmer Rajasthan India
| | - Chandi C. Mandal
- Department of Biochemistry, School of Life Sciences Central University of Rajasthan Ajmer Rajasthan India
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20
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The Protective Role of 4-Acetylarylquinolinol B in Different Pathological Processes. Curr Issues Mol Biol 2022; 44:2362-2373. [PMID: 35678690 PMCID: PMC9164036 DOI: 10.3390/cimb44050161] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Revised: 05/15/2022] [Accepted: 05/20/2022] [Indexed: 12/01/2022] Open
Abstract
Antrodia cinnamomea is a traditional plant and a unique fungus native to Taiwan that has been reported to have many biological functions, including anti-inflammatory and anticancer activities. The compound 4-acetylarylquinolinol B (4-AAQB) is one of the main bioactive compounds in the stamens of Antrodia cinnamomea, and has many biological functions, such as anti-inflammatory, antiproliferative, blood sugar reduction, antimetastasis, and vascular tone relaxation. In recent years, the increasing evidences have shown that 4-AAQB is involved in many diseases; however, the relevant mechanisms have not been fully clarified. This review aimed to clarify the improvement by 4-AAQB in different pathological processes, as well as the compound’s molecular mechanisms, in order to provide a theoretical reference for future related research
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21
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Han Y, Xia L, Wang X, Xiong H, Zeng L, Wang Z, Zhang T, Xia K, Hu X, Su T. Study on the expression and function of chordin like 1 in oral squamous cell carcinoma. Oral Dis 2022. [PMID: 35510812 DOI: 10.1111/odi.14240] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2022] [Revised: 04/30/2022] [Accepted: 05/02/2022] [Indexed: 11/27/2022]
Abstract
OBJECTIVE The aim of this study was to investigate the role and related mechanism of chordin like 1 (CHRDL1) in oral squamous cell carcinoma (OSCC). METHODS The expressions of CHRDL1 were analyzed in both mRNA and protein levels by bioinformatics analysis, immunohistochemistry, and fluorescence in situ hybridization in OSCC. Survival analysis was used to determine the relationship between CHRDL1 and prognosis. In addition, enrichment analysis was used to suggest signal pathways involved in CHRDL1. Besides, the relationships between CHRDL1 and miRNAs, hypoxia, and immune infiltration were explored. RESULTS The mRNA level of CHRDL1 in OSCC was significantly lower than that in normal tissues, while the protein level was significantly higher than that in normal tissues. The high mRNA levels of CHRDL1 suggested a poor prognosis in patients with OSCC. The enrichment results showed that CHRDL1 might be involved in the Calcium signaling pathway, dilated cardiomyopathy, and focal adhesion. 7 immune cells were positively correlated with CHRDL1, while Tgd was negatively correlated with CHRDL1. In addition, we also found that hsa-miR-455-3p directly targeted CHRDL1 and reduced the mRNA levels of CHRDL1. CONCLUSION CHRDL1 plays a vital role in promoting cancer in OSCC and is downregulated at the mRNA levels by hsa-miR-455-3p.
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Affiliation(s)
- Ying Han
- Department of Oral and Maxillofacial Surgery, Center of Stomatology, Xiangya hospital of Central South University, Changsha, Hunan, 410008, China.,Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, 410008, China
| | - Lu Xia
- Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, 410008, China
| | - Xiaomeng Wang
- Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, 410008, China
| | - Haofeng Xiong
- Department of Oral and Maxillofacial Surgery, Center of Stomatology, Xiangya hospital of Central South University, Changsha, Hunan, 410008, China.,Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, 410008, China.,Research Center of Oral and Maxillofacial Tumor, Xiangya hospital of Central South University, Changsha, Hunan, 410008, China.,Institute of Oral Cancer and Precancerous Lesions, Central South University, Changsha, Hunan, 410008, China
| | - Liujun Zeng
- Department of Oral and Maxillofacial Surgery, Center of Stomatology, Xiangya hospital of Central South University, Changsha, Hunan, 410008, China.,Research Center of Oral and Maxillofacial Tumor, Xiangya hospital of Central South University, Changsha, Hunan, 410008, China.,Institute of Oral Cancer and Precancerous Lesions, Central South University, Changsha, Hunan, 410008, China
| | - Zijia Wang
- Department of Oral and Maxillofacial Surgery, Center of Stomatology, Xiangya hospital of Central South University, Changsha, Hunan, 410008, China.,Research Center of Oral and Maxillofacial Tumor, Xiangya hospital of Central South University, Changsha, Hunan, 410008, China.,Institute of Oral Cancer and Precancerous Lesions, Central South University, Changsha, Hunan, 410008, China
| | - Tianyi Zhang
- Department of Oral and Maxillofacial Surgery, Center of Stomatology, Xiangya hospital of Central South University, Changsha, Hunan, 410008, China.,Research Center of Oral and Maxillofacial Tumor, Xiangya hospital of Central South University, Changsha, Hunan, 410008, China.,Institute of Oral Cancer and Precancerous Lesions, Central South University, Changsha, Hunan, 410008, China
| | - Kun Xia
- Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, 410008, China
| | - Xin Hu
- Department of Oral and Maxillofacial Surgery, Center of Stomatology, Xiangya hospital of Central South University, Changsha, Hunan, 410008, China.,Research Center of Oral and Maxillofacial Tumor, Xiangya hospital of Central South University, Changsha, Hunan, 410008, China.,Institute of Oral Cancer and Precancerous Lesions, Central South University, Changsha, Hunan, 410008, China
| | - Tong Su
- Department of Oral and Maxillofacial Surgery, Center of Stomatology, Xiangya hospital of Central South University, Changsha, Hunan, 410008, China.,Research Center of Oral and Maxillofacial Tumor, Xiangya hospital of Central South University, Changsha, Hunan, 410008, China.,Institute of Oral Cancer and Precancerous Lesions, Central South University, Changsha, Hunan, 410008, China
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22
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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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23
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Colorectal Cancer Stem Cells: An Overview of Evolving Methods and Concepts. Cancers (Basel) 2021; 13:cancers13235910. [PMID: 34885020 PMCID: PMC8657142 DOI: 10.3390/cancers13235910] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Revised: 11/18/2021] [Accepted: 11/19/2021] [Indexed: 12/20/2022] Open
Abstract
Simple Summary In recent years, colorectal cancer stem cells (cCSCs) have been the object of intense investigation for their promise to disclose new aspects of colorectal cancer cell biology, as well as to devise new treatment strategies for colorectal cancer (CRC). However, accumulating studies on cCSCs by complementary technologies have progressively disclosed their plastic nature, i.e., their capability to acquire different phenotypes and/or functions under different circumstances in response to both intrinsic and extrinsic signals. In this review, we aim to recapitulate how a progressive methodological development has contributed to deepening and remodeling the concept of cCSCs over time, up to the present. Abstract Colorectal cancer (CRC) represents one of the most deadly cancers worldwide. Colorectal cancer stem cells (cCSCs) are the driving units of CRC initiation and development. After the concept of cCSC was first formulated in 2007, a huge bulk of research has contributed to expanding its definition, from a cell subpopulation defined by a fixed phenotype in a plastic entity modulated by complex interactions with the tumor microenvironment, in which cell position and niche-driven signals hold a prominent role. The wide development of cellular and molecular technologies recent years has been a main driver of advancements in cCSCs research. Here, we will give an overview of the parallel role of technological progress and of theoretical evolution in shaping the concept of cCSCs.
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24
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Pluripotency Stemness and Cancer: More Questions than Answers. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1376:77-100. [PMID: 34725790 DOI: 10.1007/5584_2021_663] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
Embryonic stem cells and induced pluripotent stem cells provided us with fascinating new knowledge in recent years. Mechanistic insight into intricate regulatory circuitry governing pluripotency stemness and disclosing parallels between pluripotency stemness and cancer instigated numerous studies focusing on roles of pluripotency transcription factors, including Oct4, Sox2, Klf4, Nanog, Sall4 and Tfcp2L1, in cancer. Although generally well substantiated as tumour-promoting factors, oncogenic roles of pluripotency transcription factors and their clinical impacts are revealing themselves as increasingly complex. In certain tumours, both Oct4 and Sox2 behave as genuine oncogenes, and reporter genes driven by composite regulatory elements jointly recognized by both the factors can identify stem-like cells in a proportion of tumours. On the other hand, cancer stem cells seem to be biologically very heterogeneous both among different tumour types and among and even within individual tumours. Pluripotency transcription factors are certainly implicated in cancer stemness, but do not seem to encompass its entire spectrum. Certain cancer stem cells maintain their stemness by biological mechanisms completely different from pluripotency stemness, sometimes even by engaging signalling pathways that promote differentiation of pluripotent stem cells. Moreover, while these signalling pathways may well be antithetical to stemness in pluripotent stem cells, they may cooperate with pluripotency factors in cancer stem cells - a paradigmatic example is provided by the MAPK-AP-1 pathway. Unexpectedly, forced expression of pluripotency transcription factors in cancer cells frequently results in loss of their tumour-initiating ability, their phenotypic reversion and partial epigenetic normalization. Besides the very different signalling contexts operating in pluripotent and cancer stem cells, respectively, the pronounced dose dependency of reprogramming pluripotency factors may also contribute to the frequent loss of tumorigenicity observed in induced pluripotent cancer cells. Finally, contradictory cell-autonomous and non-cell-autonomous effects of various signalling molecules operate during pluripotency (cancer) reprogramming. The effects of pluripotency transcription factors in cancer are thus best explained within the concept of cancer stem cell heterogeneity.
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25
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Lampis A, Hahne JC, Gasparini P, Cascione L, Hedayat S, Vlachogiannis G, Murgia C, Fontana E, Edwards J, Horgan PG, Terracciano L, Sansom OJ, Martins CD, Kramer-Marek G, Croce CM, Braconi C, Fassan M, Valeri N. MIR21-induced loss of junctional adhesion molecule A promotes activation of oncogenic pathways, progression and metastasis in colorectal cancer. Cell Death Differ 2021; 28:2970-2982. [PMID: 34226680 PMCID: PMC8481293 DOI: 10.1038/s41418-021-00820-0] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Revised: 06/07/2021] [Accepted: 06/09/2021] [Indexed: 01/02/2023] Open
Abstract
Junctional adhesion molecules (JAMs) play a critical role in cell permeability, polarity and migration. JAM-A, a key protein of the JAM family, is altered in a number of conditions including cancer; however, consequences of JAM-A dysregulation on carcinogenesis appear to be tissue dependent and organ dependent with significant implications for the use of JAM-A as a biomarker or therapeutic target. Here, we test the expression and prognostic role of JAM-A downregulation in primary and metastatic colorectal cancer (CRC) (n = 947). We show that JAM-A downregulation is observed in ~60% of CRC and correlates with poor outcome in four cohorts of stages II and III CRC (n = 1098). Using JAM-A knockdown, re-expression and rescue experiments in cell line monolayers, 3D spheroids, patient-derived organoids and xenotransplants, we demonstrate that JAM-A silencing promotes proliferation and migration in 2D and 3D cell models and increases tumour volume and metastases in vivo. Using gene-expression and proteomic analyses, we show that JAM-A downregulation results in the activation of ERK, AKT and ROCK pathways and leads to decreased bone morphogenetic protein 7 expression. We identify MIR21 upregulation as the cause of JAM-A downregulation and show that JAM-A rescue mitigates the effects of MIR21 overexpression on cancer phenotype. Our results identify a novel molecular loop involving MIR21 dysregulation, JAM-A silencing and activation of multiple oncogenic pathways in promoting invasiveness and metastasis in CRC.
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Affiliation(s)
- Andrea Lampis
- Division of Molecular Pathology, Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK
| | - Jens C Hahne
- Division of Molecular Pathology, Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK
| | - Pierluigi Gasparini
- Department of Cancer Biology and Genetics, Comprehensive Cancer Center, The Ohio State University College of Medicine, Columbus, OH, USA
- School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Newcastle, NSW, Australia
- Hunter Medical Research Institute, New Lambton Heights, NSW, Australia
| | - Luciano Cascione
- Bioinformatics Core Unit, Institute of Oncology Research (IOR), Faculty of Biomedical Sciences, Università della Svizzera italiana, Bellinzona, Switzerland
- Swiss Institute of Bioinformatics, Bellinzona, Switzerland
| | - Somaieh Hedayat
- Division of Molecular Pathology, Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK
| | - Georgios Vlachogiannis
- Division of Molecular Pathology, Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK
| | | | - Elisa Fontana
- Division of Molecular Pathology, Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK
| | - Joanne Edwards
- Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
| | - Paul G Horgan
- Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
| | - Luigi Terracciano
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
- IRCCS Humanitas Research Hospital, Milan, Italy
| | - Owen J Sansom
- Cancer Research UK Beatson Institute, Glasgow, UK
- Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
| | - Carlos D Martins
- Division of Radiotherapy and Imaging, The Institute of Cancer Research, London, UK
| | | | - Carlo M Croce
- Department of Cancer Biology and Genetics, Comprehensive Cancer Center, The Ohio State University College of Medicine, Columbus, OH, USA
| | - Chiara Braconi
- Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
| | - Matteo Fassan
- IRCCS Humanitas Research Hospital, Milan, Italy
- Department of Medicine, Surgical Pathology Unit, University of Padua, Padua, Italy
- Istituto Oncologico Veneto, Istituto di Ricovero e Cura a Carattere Scientifico, Padua, Italy
| | - Nicola Valeri
- Division of Molecular Pathology, Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK.
- Department of Medicine, The Royal Marsden Hospital, London, UK.
- Division of Surgery and Cancer, Imperial College London, London, UK.
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26
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Beyond the Double-Strand Breaks: The Role of DNA Repair Proteins in Cancer Stem-Cell Regulation. Cancers (Basel) 2021; 13:cancers13194818. [PMID: 34638302 PMCID: PMC8508278 DOI: 10.3390/cancers13194818] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Revised: 09/22/2021] [Accepted: 09/22/2021] [Indexed: 12/12/2022] Open
Abstract
Simple Summary Cancer stem cells (CSCs) are a tumor cell population maintaining tumor growth and promoting tumor relapse if not wholly eradicated during treatment. CSCs are often equipped with molecular mechanisms making them resistant to conventional anti-cancer therapies whose curative potential depends on DNA damage-induced cell death. An elevated expression of some key DNA repair proteins is one of such defense mechanisms. However, new research reveals that the role of critical DNA repair proteins is extending far beyond the DNA repair mechanisms. This review discusses the diverse biological functions of DNA repair proteins in CSC maintenance and the adaptation to replication and oxidative stress, anti-cancer immune response, epigenetic reprogramming, and intracellular signaling mechanisms. It also provides an overview of their potential therapeutic targeting. Abstract Cancer stem cells (CSCs) are pluripotent and highly tumorigenic cells that can re-populate a tumor and cause relapses even after initially successful therapy. As with tissue stem cells, CSCs possess enhanced DNA repair mechanisms. An active DNA damage response alleviates the increased oxidative and replicative stress and leads to therapy resistance. On the other hand, mutations in DNA repair genes cause genomic instability, therefore driving tumor evolution and developing highly aggressive CSC phenotypes. However, the role of DNA repair proteins in CSCs extends beyond the level of DNA damage. In recent years, more and more studies have reported the unexpected role of DNA repair proteins in the regulation of transcription, CSC signaling pathways, intracellular levels of reactive oxygen species (ROS), and epithelial–mesenchymal transition (EMT). Moreover, DNA damage signaling plays an essential role in the immune response towards tumor cells. Due to its high importance for the CSC phenotype and treatment resistance, the DNA damage response is a promising target for individualized therapies. Furthermore, understanding the dependence of CSC on DNA repair pathways can be therapeutically exploited to induce synthetic lethality and sensitize CSCs to anti-cancer therapies. This review discusses the different roles of DNA repair proteins in CSC maintenance and their potential as therapeutic targets.
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Adipose stem cell niche reprograms the colorectal cancer stem cell metastatic machinery. Nat Commun 2021; 12:5006. [PMID: 34408135 PMCID: PMC8373975 DOI: 10.1038/s41467-021-25333-9] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2020] [Accepted: 08/03/2021] [Indexed: 12/30/2022] Open
Abstract
Obesity is a strong risk factor for cancer progression, posing obesity-related cancer as one of the leading causes of death. Nevertheless, the molecular mechanisms that endow cancer cells with metastatic properties in patients affected by obesity remain unexplored. Here, we show that IL-6 and HGF, secreted by tumor neighboring visceral adipose stromal cells (V-ASCs), expand the metastatic colorectal (CR) cancer cell compartment (CD44v6 + ), which in turn secretes neurotrophins such as NGF and NT-3, and recruits adipose stem cells within tumor mass. Visceral adipose-derived factors promote vasculogenesis and the onset of metastatic dissemination by activation of STAT3, which inhibits miR-200a and enhances ZEB2 expression, effectively reprogramming CRC cells into a highly metastatic phenotype. Notably, obesity-associated tumor microenvironment provokes a transition in the transcriptomic expression profile of cells derived from the epithelial consensus molecular subtype (CMS2) CRC patients towards a mesenchymal subtype (CMS4). STAT3 pathway inhibition reduces ZEB2 expression and abrogates the metastatic growth sustained by adipose-released proteins. Together, our data suggest that targeting adipose factors in colorectal cancer patients with obesity may represent a therapeutic strategy for preventing metastatic disease. Obesity is a major risk factor for cancer related death. Here, the authors show that visceral adipose-derived factors promote vasculogenesis and metastatic dissemination by activation of STAT3, which inhibits miR-200a and enhances ZEB2 expression, effectively reprogramming colorectal cancer cells into a highly metastatic phenotype.
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28
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McAndrews KM, Vázquez-Arreguín K, Kwak C, Sugimoto H, Zheng X, Li B, Kirtley ML, LeBleu VS, Kalluri R. αSMA + fibroblasts suppress Lgr5 + cancer stem cells and restrain colorectal cancer progression. Oncogene 2021; 40:4440-4452. [PMID: 34108617 DOI: 10.1038/s41388-021-01866-7] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Revised: 05/07/2021] [Accepted: 05/25/2021] [Indexed: 02/07/2023]
Abstract
The development and progression of solid tumors is dependent on cancer cell autonomous drivers and the tumor microenvironment (TME). Cancer-associated fibroblasts (CAFs) in the TME possess both tumor-promoting and tumor-restraining functions. In the current study, we interrogated the role of αSMA+ CAFs in a genetic mouse model of metastatic colorectal cancer (CRC). Selective depletion of αSMA+ CAFs resulted in increased tumor invasiveness, lymph node metastasis, and reduced overall survival. Depletion of αSMA+ CAFs reduced BMP4 and increased TGFβ1 secretion from stromal cells, and was associated with increased Lgr5+ cancer stem-like cells (CSCs) and the generation of an immunosuppressive TME with increased frequency of Foxp3+ regulatory T cells and suppression of CD8+ T cells. This study demonstrates that αSMA+ CAFs in CRC exert tumor-restraining functions via BMP4/TGFβ1 paracrine signaling that serves to suppress Lgr5+ CSCs and promote anti-tumor immunity, ultimately limiting CRC progression.
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Affiliation(s)
- Kathleen M McAndrews
- Metastasis Research Center, Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Karina Vázquez-Arreguín
- Metastasis Research Center, Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Changsoo Kwak
- Metastasis Research Center, Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Hikaru Sugimoto
- Metastasis Research Center, Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Xiaofeng Zheng
- Metastasis Research Center, Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Bingrui Li
- Metastasis Research Center, Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Michelle L Kirtley
- Metastasis Research Center, Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Valerie S LeBleu
- Metastasis Research Center, Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.,Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Raghu Kalluri
- Metastasis Research Center, Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. .,Department of Bioengineering, Rice University, Houston, TX, USA. .,Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
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29
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Kopenhaver J, Crutcher M, Waldman SA, Snook AE. The shifting paradigm of colorectal cancer treatment: a look into emerging cancer stem cell-directed therapeutics to lead the charge toward complete remission. Expert Opin Biol Ther 2021; 21:1335-1345. [PMID: 33977849 DOI: 10.1080/14712598.2021.1929167] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
Introduction: Colorectal cancer (CRC) is one of the most common forms of cancer worldwide and is the second leading cause of cancer-related death in the United States. Despite advances in early detection, ~25% of patients are late stage, and treated patients have <12% chance of survival after five years. Tumor relapse and metastasis are the main causes of patient death. Cancer stem cells (CSCs) are a rare population of cancer cells characterized by properties of self-renewal, chemo- and radio-resistance, tumorigenicity, and high plasticity. These qualities make CSCs particularly important for metastasic seeding, DNA-damage resistance, and tumor repopulating.Areas Covered: The following review article focuses on the role of CRC-SCs in tumor initiation, metastasis, drug resistance, and tumor relapse, as well as on potential therapeutic options for targeting CSCs.Expert Opinion: Current studies are underway to better isolate and discriminate CSCs from normal stem cells and to produce CSC-targeted therapeutics. The intestinal receptor, guanylate cyclase C (GUCY2C) could potentially provide a unique therapeutic target for both non-stem cells and CSCs alike in colorectal cancer through immunotherapies. Indeed, immunotherapies targeting CSCs have the potential to break the treatment-recurrence cycle in the management of advanced malignancies.
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Affiliation(s)
- Jessica Kopenhaver
- Department of Pharmacology & Experimental Therapeutics, Thomas Jefferson University, Philadelphia, United States
| | - Madison Crutcher
- Department of Pharmacology & Experimental Therapeutics, Thomas Jefferson University, Philadelphia, United States.,Department of Surgery, Thomas Jefferson University, Philadelphia, United States
| | - Scott A Waldman
- Department of Pharmacology & Experimental Therapeutics, Thomas Jefferson University, Philadelphia, United States
| | - Adam E Snook
- Department of Pharmacology & Experimental Therapeutics, Thomas Jefferson University, Philadelphia, United States
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30
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Frank MH, Wilson BJ, Gold JS, Frank NY. Clinical Implications of Colorectal Cancer Stem Cells in the Age of Single-Cell Omics and Targeted Therapies. Gastroenterology 2021; 160:1947-1960. [PMID: 33617889 PMCID: PMC8215897 DOI: 10.1053/j.gastro.2020.12.080] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 11/30/2020] [Accepted: 12/10/2020] [Indexed: 02/07/2023]
Abstract
The cancer stem cell (CSC) concept emerged from the recognition of inherent tumor heterogeneity and suggests that within a given tumor, in analogy to normal tissues, there exists a cellular hierarchy composed of a minority of more primitive cells with enhanced longevity (ie, CSCs) that give rise to shorter-lived, more differentiated cells (ie, cancer bulk populations), which on their own are not capable of tumor perpetuation. CSCs can be responsible for cancer therapeutic resistance to conventional, targeted, and immunotherapeutic treatment modalities, and for cancer progression through CSC-intrinsic molecular mechanisms. The existence of CSCs in colorectal cancer (CRC) was first established through demonstration of enhanced clonogenicity and tumor-forming capacity of this cell subset in human-to-mouse tumor xenotransplantation experiments and subsequently confirmed through lineage-tracing studies in mice. Surface markers for CRC CSC identification and their prospective isolation are now established. Therefore, the application of single-cell omics technologies to CSC characterization, including whole-genome sequencing, RNA sequencing, and epigenetic analyses, opens unprecedented opportunities to discover novel targetable molecular pathways and hence to develop novel strategies for CRC eradication. We review recent advances in this field and discuss the potential implications of next-generation CSC analyses for currently approved and experimental targeted CRC therapies.
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Affiliation(s)
- Markus H. Frank
- Transplant Research Program, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts;,Department of Dermatology, Brigham & Women’s Hospital, Harvard Medical School, Boston, Massachusetts;,Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts;,School of Medical and Health Sciences, Edith Cowan University, Perth, Western Australia, Australia
| | - Brian J. Wilson
- Transplant Research Program, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts;,Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts
| | - Jason S. Gold
- Department of Surgery, Veterans Affairs Boston Healthcare System, Boston, Massachusetts;,Department of Surgery, Brigham & Women’s Hospital, Harvard Medical School, Boston, Massachusetts
| | - Natasha Y. Frank
- Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts;,Department of Medicine, Veterans Affairs Boston Healthcare System, Boston, Massachusetts;,Division of Genetics, Brigham & Women’s Hospital, Harvard Medical School, Boston, Massachusetts
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31
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Fernandes S, Fernandez T, Metze S, Balakrishnan PB, Mai BT, Conteh J, De Mei C, Turdo A, Di Franco S, Stassi G, Todaro M, Pellegrino T. Magnetic Nanoparticle-Based Hyperthermia Mediates Drug Delivery and Impairs the Tumorigenic Capacity of Quiescent Colorectal Cancer Stem Cells. ACS APPLIED MATERIALS & INTERFACES 2021; 13:15959-15972. [PMID: 33797220 PMCID: PMC8045020 DOI: 10.1021/acsami.0c21349] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Accepted: 03/15/2021] [Indexed: 05/27/2023]
Abstract
Cancer stem cells (CSCs) are the tumor cell subpopulation responsible for resistance to chemotherapy, tumor recurrence, and metastasis. An efficient therapy must act on low proliferating quiescent-CSCs (q-CSCs). We here investigate the effect of magnetic hyperthermia (MHT) in combination with local chemotherapy as a dual therapy to inhibit patient-derived colorectal qCR-CSCs. We apply iron oxide nanocubes as MHT heat mediators, coated with a thermoresponsive polymer (TR-Cubes) and loaded with DOXO (TR-DOXO) as a chemotherapeutic agent. The thermoresponsive polymer releases DOXO only at a temperature above 44 °C. In colony-forming assays, the cells exposed to TR-Cubes with MHT reveal that qCR-CSCs struggle to survive the heat damage and, with a due delay, restart the division of dormant cells. The eradication of qCR-CSCs with a complete stop of the colony formation was achieved only with TR-DOXO when exposed to MHT. The in vivo tumor formation study confirms the combined effects of MHT with heat-mediated drug release: only the group of animals that received the CR-CSCs pretreated, in vitro, with TR-DOXO and MHT lacked the formation of tumor even after several months. For DOXO-resistant CR-CSCs cells, the same results were shown, in vitro, when choosing the drug oxaliplatin rather than DOXO and applying MHT. These findings emphasize the potential of our nanoplatforms as an effective patient-personalized cancer treatment against qCR-CSCs.
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Affiliation(s)
- Soraia Fernandes
- Istituto
Italiano di Tecnologia (IIT), via Morego 30, 16163 Genova, Italy
| | - Tamara Fernandez
- Istituto
Italiano di Tecnologia (IIT), via Morego 30, 16163 Genova, Italy
| | - Sabrina Metze
- Istituto
Italiano di Tecnologia (IIT), via Morego 30, 16163 Genova, Italy
| | | | - Binh T. Mai
- Istituto
Italiano di Tecnologia (IIT), via Morego 30, 16163 Genova, Italy
| | - John Conteh
- Istituto
Italiano di Tecnologia (IIT), via Morego 30, 16163 Genova, Italy
| | - Claudia De Mei
- Istituto
Italiano di Tecnologia (IIT), via Morego 30, 16163 Genova, Italy
| | - Alice Turdo
- PROMISE
Department,Piazza delle Cliniche 2, University
of Palermo, 90133 Palermo, Italy
| | - Simone Di Franco
- DICHIRONS
Department, University of Palermo, Via del Vespro 129, 90133 Palermo, Italy
| | - Giorgio Stassi
- DICHIRONS
Department, University of Palermo, Via del Vespro 129, 90133 Palermo, Italy
| | - Matilde Todaro
- PROMISE
Department,Piazza delle Cliniche 2, University
of Palermo, 90133 Palermo, Italy
| | - Teresa Pellegrino
- Istituto
Italiano di Tecnologia (IIT), via Morego 30, 16163 Genova, Italy
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Ding R, Ning X, Ye M, Yin Y. Antrodia camphorata extract (ACE)-induced apoptosis is associated with BMP4 expression and p53-dependent ROS generation in human colon cancer cells. JOURNAL OF ETHNOPHARMACOLOGY 2021; 268:113570. [PMID: 33181285 DOI: 10.1016/j.jep.2020.113570] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Revised: 11/02/2020] [Accepted: 11/04/2020] [Indexed: 06/11/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Antrodia camphorata (AC) is a rare functional fungus in Taiwan and is known as traditional Chinese medicine. It has been reported to inhibit proliferation and promote apoptosis in human cancer cells. AIM OF THE STUDY To investigate the potential mechanism of apoptosis induced in colon cancer cells by Antrodia camphorata extract (ACE). MATERIALS AND METHODS The MTT assay and crystal violet staining were used to determine relative cell viability in vitro at 24 and 48 h. The effects of ACE on apoptosis were determined by Hoechst 33342 staining and flow cytometric analysis following Annexin V-FITC/PI staining. The gene expression profile of HCT116 cells was assessed by the RNA sequencing system. In combination with RNA-seq data and qRT-PCR, Western blot analysis was used to evaluate expression of proteins. The intracellular ROS of HCT116 cells were determined using a DCFH-DA fluorescence probe. RESULTS ACE significantly reduces cell viability in a dose-dependent manner and triggers apoptosis. To explore the underlying mechanism, we performed transcriptome analysis of ACE-treated colon cancer HCT116 cells. Bioinformatics analyses showed that ACE treatment is associated with pathways in cancer. We further used Cytoscape to analyze hub genes in this network. Among them, BMP4, which is associated with cancer cell death through regulation of the tumor suppressor p53, was significantly decreased at both mRNA and protein levels in ACE treatment groups. We found that cell death is reversible via inactivation or knockdown of p53 gene and reduction of reactive oxygen species (ROS) generation in response to ACE exposure, indicating that p53 plays an important role in ROS generation induced by ACE. Meanwhile, ROS scavenger NAC was used to verify that cell death is reversible via reduction of ROS. CONCLUSION Our findings demonstrate that ACE has potential as an anticancer agent that induces apoptosis through BMP4 and p53-dependent response to ROS in human colon cancer.
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Affiliation(s)
- Ruqian Ding
- Beijing Advanced Innovation Center for Big-Data Precision Medicine, Beihang University, Beijing, 100083, China
| | - Xianling Ning
- Institute of Systems Biomedicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China
| | - Min Ye
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China
| | - Yuxin Yin
- Institute of Systems Biomedicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China.
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Yan G, Dai M, Zhang C, Poulet S, Moamer A, Wang N, Boudreault J, Ali S, Lebrun JJ. TGFβ/cyclin D1/Smad-mediated inhibition of BMP4 promotes breast cancer stem cell self-renewal activity. Oncogenesis 2021; 10:21. [PMID: 33649296 PMCID: PMC7921419 DOI: 10.1038/s41389-021-00310-5] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2020] [Revised: 02/08/2021] [Accepted: 02/10/2021] [Indexed: 12/31/2022] Open
Abstract
Basal-like triple-negative breast cancers (TNBCs) display poor prognosis, have a high risk of tumor recurrence, and exhibit high resistance to drug treatments. The TNBC aggressive features are largely due to the high proportion of cancer stem cells present within these tumors. In this study, we investigated the interplay and networking pathways occurring between TGFβ family ligands in regulating stemness in TNBCs. We found that TGFβ stimulation of TNBCs resulted in enhanced tumorsphere formation efficiency and an increased proportion of the highly tumorigenic CD44high/CD24low cancer stem cell population. Analysis of the TGFβ transcriptome in TNBC cells revealed bone morphogenetic protein4 (BMP4) as a main TGFβ-repressed target in these tumor cells. We further found that BMP4 opposed TGFβ effects on stemness and potently decreased cancer stem cell numbers, thereby acting as a differentiation factor in TNBC. At the molecular level, we found that TGFβ inhibition of BMP4 gene expression is mediated through the Smad pathway and cyclin D1. In addition, we also found BMP4 to act as a pro-differentiation factor in normal mammary epithelial cells and promote mammary acinar formation in 3D cell culture assays. Finally, and consistent with our in vitro results, in silico patient data analysis defined BMP4 as a potential valuable prognosis marker for TNBC patients.
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Affiliation(s)
- Gang Yan
- McGill University Health Center, Department of Medicine, Cancer Research Program, Montreal, QC, H4A 3J1, Canada
| | - Meiou Dai
- McGill University Health Center, Department of Medicine, Cancer Research Program, Montreal, QC, H4A 3J1, Canada
| | - Chenjing Zhang
- McGill University Health Center, Department of Medicine, Cancer Research Program, Montreal, QC, H4A 3J1, Canada.,Department of Gastroenterology, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Sophie Poulet
- McGill University Health Center, Department of Medicine, Cancer Research Program, Montreal, QC, H4A 3J1, Canada
| | - Alaa Moamer
- McGill University Health Center, Department of Medicine, Cancer Research Program, Montreal, QC, H4A 3J1, Canada
| | - Ni Wang
- McGill University Health Center, Department of Medicine, Cancer Research Program, Montreal, QC, H4A 3J1, Canada
| | - Julien Boudreault
- McGill University Health Center, Department of Medicine, Cancer Research Program, Montreal, QC, H4A 3J1, Canada
| | - Suhad Ali
- McGill University Health Center, Department of Medicine, Cancer Research Program, Montreal, QC, H4A 3J1, Canada
| | - Jean-Jacques Lebrun
- McGill University Health Center, Department of Medicine, Cancer Research Program, Montreal, QC, H4A 3J1, Canada.
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Sphyris N, Hodder MC, Sansom OJ. Subversion of Niche-Signalling Pathways in Colorectal Cancer: What Makes and Breaks the Intestinal Stem Cell. Cancers (Basel) 2021; 13:1000. [PMID: 33673710 PMCID: PMC7957493 DOI: 10.3390/cancers13051000] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 02/15/2021] [Accepted: 02/17/2021] [Indexed: 12/12/2022] Open
Abstract
The intestinal epithelium fulfils pleiotropic functions in nutrient uptake, waste elimination, and immune surveillance while also forming a barrier against luminal toxins and gut-resident microbiota. Incessantly barraged by extraneous stresses, the intestine must continuously replenish its epithelial lining and regenerate the full gamut of specialized cell types that underpin its functions. Homeostatic remodelling is orchestrated by the intestinal stem cell (ISC) niche: a convergence of epithelial- and stromal-derived cues, which maintains ISCs in a multipotent state. Following demise of homeostatic ISCs post injury, plasticity is pervasive among multiple populations of reserve stem-like cells, lineage-committed progenitors, and/or fully differentiated cell types, all of which can contribute to regeneration and repair. Failure to restore the epithelial barrier risks seepage of toxic luminal contents, resulting in inflammation and likely predisposing to tumour formation. Here, we explore how homeostatic niche-signalling pathways are subverted in tumorigenesis, enabling ISCs to gain autonomy from niche restraints ("ISC emancipation") and transform into cancer stem cells capable of driving tumour initiation, progression, and therapy resistance. We further consider the implications of the pervasive plasticity of the intestinal epithelium for the trajectory of colorectal cancer, the emergence of distinct molecular subtypes, the propensity to metastasize, and the development of effective therapeutic strategies.
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Affiliation(s)
- Nathalie Sphyris
- Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK; (N.S.); (M.C.H.)
| | - Michael C. Hodder
- Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK; (N.S.); (M.C.H.)
- Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Glasgow G61 1QH, UK
| | - Owen J. Sansom
- Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK; (N.S.); (M.C.H.)
- Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Glasgow G61 1QH, UK
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Du L, Cheng Q, Zheng H, Liu J, Liu L, Chen Q. Targeting stemness of cancer stem cells to fight colorectal cancers. Semin Cancer Biol 2021; 82:150-161. [PMID: 33631296 DOI: 10.1016/j.semcancer.2021.02.012] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2020] [Revised: 01/12/2021] [Accepted: 02/19/2021] [Indexed: 02/07/2023]
Abstract
Cancer initiating/ stem cells (CSCs) undergo self-renewal and differentiation that contributes to tumor initiation, recurrence and metastasis in colorectal cancer (CRC). Targeting of colorectal cancer stem cells (CCSCs) holds significant promise in eradicating cancer cells and ultimately curing patients with cancer. In this review, we will introduce the current progress of CCSC studies, including the specific surface markers of CCSCs, the intrinsic signaling pathways that regulate the stemness and differentiation characteristics of CCSCs, and the tumor organoid model for CCSC research. We will focus on how these studies will lead to the progress in targeting specific surface markers or signaling pathways on CCSCs by monoclonal antibodies, or by natural or synthetic compounds, or by immunotherapy. As CSCs are highly heterogeneous and plastic, we suggest that combinatory approaches that target the stemness network may represent an important strategy for eradicating cancers.
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Affiliation(s)
- Lei Du
- The State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China; Beijing Institute for Stem Cell and Regenerative Medicine. Beijing, 100101, China.
| | - Qi Cheng
- The State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China; The Graduate University of Chinese Academy of Sciences. Beijing, 100049, China
| | - Hao Zheng
- The State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China; The State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin, 300071, China
| | - Jinming Liu
- The State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin, 300071, China
| | - Lei Liu
- The State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China; Beijing Institute for Stem Cell and Regenerative Medicine. Beijing, 100101, China
| | - Quan Chen
- The State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin, 300071, China.
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Urh K, Žlajpah M, Zidar N, Boštjančič E. Identification and Validation of New Cancer Stem Cell-Related Genes and Their Regulatory microRNAs in Colorectal Cancerogenesis. Biomedicines 2021; 9:biomedicines9020179. [PMID: 33670246 PMCID: PMC7916981 DOI: 10.3390/biomedicines9020179] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Revised: 01/31/2021] [Accepted: 02/04/2021] [Indexed: 12/11/2022] Open
Abstract
Significant progress has been made in the last decade in our understanding of the pathogenetic mechanisms of colorectal cancer (CRC). Cancer stem cells (CSC) have gained much attention and are now believed to play a crucial role in the pathogenesis of various cancers, including CRC. In the current study, we validated gene expression of four genes related to CSC, L1TD1, SLITRK6, ST6GALNAC1 and TCEA3, identified in a previous bioinformatics analysis. Using bioinformatics, potential miRNA-target gene correlations were prioritized. In total, 70 formalin-fixed paraffin-embedded biopsy samples from 47 patients with adenoma, adenoma with early carcinoma and CRC without and with lymph node metastases were included. The expression of selected genes and microRNAs (miRNAs) was evaluated using quantitative PCR. Differential expression of all investigated genes and four of six prioritized miRNAs (hsa-miR-199a-3p, hsa-miR-335-5p, hsa-miR-425-5p, hsa-miR-1225-3p, hsa-miR-1233-3p and hsa-miR-1303) was found in at least one group of CRC cancerogenesis. L1TD1, SLITRK6, miR-1233-3p and miR-1225-3p were correlated to the level of malignancy. A negative correlation between miR-199a-3p and its predicted target SLITRK6 was observed, showing potential for further experimental validation in CRC. Our results provide further evidence that CSC-related genes and their regulatory miRNAs are involved in CRC development and progression and suggest that some them, particularly miR-199a-3p and its SLITRK6 target gene, are promising for further validation in CRC.
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37
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Reddy KB. Stem Cells: Current Status and Therapeutic Implications. Genes (Basel) 2020; 11:E1372. [PMID: 33233552 PMCID: PMC7699792 DOI: 10.3390/genes11111372] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Revised: 11/11/2020] [Accepted: 11/18/2020] [Indexed: 12/14/2022] Open
Abstract
Cancer stem cells (CSCs) are a class of pluripotent cells that have been observed in most types of cancers. Evolving evidence suggests that CSCs, has the ability to self-renew and initiate tumors, may be responsible for promoting therapeutic resistance, tumor recurrence and metastasis. Tumor heterogeneity is originating from CSCs and its progenitors are recognized as major difficulty in efficaciously treating cancer patients. Therefore, understanding the biological mechanisms by which CSCs survive chemo- and-radiation therapy has the potential to identify new therapeutic strategies in the future. In this review, we summarized recent advances in CSC biology and their environment, and discuss about the potential therapies to prevent therapeutic resistance.
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Affiliation(s)
- Kaladhar B. Reddy
- Department of Pathology, Wayne State University, Detroit, MI 48201, USA;
- Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201, USA
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Role of Nrf2 and mitochondria in cancer stem cells; in carcinogenesis, tumor progression, and chemoresistance. Biochimie 2020; 179:32-45. [PMID: 32946993 DOI: 10.1016/j.biochi.2020.09.014] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2020] [Revised: 08/05/2020] [Accepted: 09/04/2020] [Indexed: 02/06/2023]
Abstract
Cancer stem cells (CSCs) are rare sub-population in tumor mass with self-renewal and differentiation abilities; CSCs are considered as the main cells which are responsible for tumor metastasis, cancer recurrence, and chemo/radio-resistance. CSCs are believed to contain low mitochondria in quantity, high concentration of nuclear factor erythroid 2-related factor 2 (Nrf2), and low reactive oxygen species (ROS) levels. Mitochondria regulate certain cellular functions, including controlling of cellular energetics, calcium signaling, cell growth and cell differentiation, cell cycle regulation, and cell death. Also, mitochondria are the main sources of intrinsic ROS production. Dysfunction of CSCs mitochondria due to oxidative phosphorylation is reported in several pathological conditions, including metabolic disorders, age-related diseases, and various types of cancers. ROS levels play a significant role in cellular signal transduction and CSCs' identity and differentiation capability. Nrf2 is a master transcription factor that plays critical functions in maintaining cellular redox hemostasis by regulating several antioxidant and detoxification pathways. Recently, the critical function of Nrf2 in CSCs has been revealed by several studies. Nrf2 is an essential molecule in the maintenance of CSCs' stemness and self-renewal in response to different oxidative stresses such as chemotherapy-induced elevation of ROS. Nrf2 enables these cells to recover from chemotherapy damages, and promotes establishment of invasion and dissemination. In this study, we have summarized the role of Nrf2 and mitochondria function CSCs, which promote cancer development. The significant role of Nrf2 in the regulation of mitochondrial function and ROS levels suggests this molecule as a potential target to eradicate CSCs.
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Dzobo K, Senthebane DA, Ganz C, Thomford NE, Wonkam A, Dandara C. Advances in Therapeutic Targeting of Cancer Stem Cells within the Tumor Microenvironment: An Updated Review. Cells 2020; 9:E1896. [PMID: 32823711 PMCID: PMC7464860 DOI: 10.3390/cells9081896] [Citation(s) in RCA: 71] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Revised: 08/04/2020] [Accepted: 08/11/2020] [Indexed: 12/24/2022] Open
Abstract
Despite great strides being achieved in improving cancer patients' outcomes through better therapies and combinatorial treatment, several hurdles still remain due to therapy resistance, cancer recurrence and metastasis. Drug resistance culminating in relapse continues to be associated with fatal disease. The cancer stem cell theory posits that tumors are driven by specialized cancer cells called cancer stem cells (CSCs). CSCs are a subpopulation of cancer cells known to be resistant to therapy and cause metastasis. Whilst the debate on whether CSCs are the origins of the primary tumor rages on, CSCs have been further characterized in many cancers with data illustrating that CSCs display great abilities to self-renew, resist therapies due to enhanced epithelial to mesenchymal (EMT) properties, enhanced expression of ATP-binding cassette (ABC) membrane transporters, activation of several survival signaling pathways and increased immune evasion as well as DNA repair mechanisms. CSCs also display great heterogeneity with the consequential lack of specific CSC markers presenting a great challenge to their targeting. In this updated review we revisit CSCs within the tumor microenvironment (TME) and present novel treatment strategies targeting CSCs. These promising strategies include targeting CSCs-specific properties using small molecule inhibitors, immunotherapy, microRNA mediated inhibitors, epigenetic methods as well as targeting CSC niche-microenvironmental factors and differentiation. Lastly, we present recent clinical trials undertaken to try to turn the tide against cancer by targeting CSC-associated drug resistance and metastasis.
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Affiliation(s)
- Kevin Dzobo
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Cape Town Component, Wernher and Beit Building (South), UCT Medical Campus, Anzio Road, Observatory, Cape Town 7925, South Africa; (D.A.S.); (C.G.)
- Division of Medical Biochemistry and Institute of Infectious Disease and Molecular Medicine, Department of Integrative Biomedical Sciences, Faculty of Health Sciences, University of Cape Town, Cape Town 7925, South Africa
| | - Dimakatso Alice Senthebane
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Cape Town Component, Wernher and Beit Building (South), UCT Medical Campus, Anzio Road, Observatory, Cape Town 7925, South Africa; (D.A.S.); (C.G.)
- Division of Medical Biochemistry and Institute of Infectious Disease and Molecular Medicine, Department of Integrative Biomedical Sciences, Faculty of Health Sciences, University of Cape Town, Cape Town 7925, South Africa
| | - Chelene Ganz
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Cape Town Component, Wernher and Beit Building (South), UCT Medical Campus, Anzio Road, Observatory, Cape Town 7925, South Africa; (D.A.S.); (C.G.)
- Division of Medical Biochemistry and Institute of Infectious Disease and Molecular Medicine, Department of Integrative Biomedical Sciences, Faculty of Health Sciences, University of Cape Town, Cape Town 7925, South Africa
| | - Nicholas Ekow Thomford
- Division of Human Genetics, Department of Pathology and Institute for Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Anzio Road, Observatory, Cape Town 7925, South Africa; (N.E.T.); (A.W.); (C.D.)
- Department of Medical Biochemistry, School of Medical Sciences, College of Health Sciences, University of Cape Coast, PMB, Cape Coast, Ghana
| | - Ambroise Wonkam
- Division of Human Genetics, Department of Pathology and Institute for Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Anzio Road, Observatory, Cape Town 7925, South Africa; (N.E.T.); (A.W.); (C.D.)
| | - Collet Dandara
- Division of Human Genetics, Department of Pathology and Institute for Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Anzio Road, Observatory, Cape Town 7925, South Africa; (N.E.T.); (A.W.); (C.D.)
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Chen H, Shi Y, Sun L, Ni S. Electrospun composite nanofibers with all-trans retinoic acid and MWCNTs-OH against cancer stem cells. Life Sci 2020; 258:118152. [PMID: 32735881 DOI: 10.1016/j.lfs.2020.118152] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Revised: 07/10/2020] [Accepted: 07/23/2020] [Indexed: 01/22/2023]
Abstract
AIMS Cancer stem cells (CSCs) are the source of tumors and play a key role in the resistance of cancer to therapies. To improve the current therapies against CSCs, in this work we developed a novel system of electrospun polycaprolactone (PCL) nanofibers containing hydroxylated multi-walled carbon nanotubes (MWCNTs-OH) and all-trans retinoic acid (ATRA). MATERIALS AND METHODS The nanofiber membranes were forged by electrospinning, and the physical and chemical properties of the nanofiber membranes were evaluated by scanning electron microscopy, XRD and Raman etc. The photothermal properties of nanofiber membranes and their effects on CSCs differentiation and cytotoxicity were investigated. Finally, the anti-tumor effect of nanofiber membranes in vivo was evaluated. KEY FINDINGS The nanofibers formed under optimal conditions were smooth without beads. The nanofibrous membranes with MWCNTs-OH could increase temperature of the medium under near-infrared (NIR) illumination to suppress the viability of glioma stem cells (GSCs). Meanwhile, the added ATRA could further induce the differentiation of GSCs to destroy their stemness and reduce their resistance to heat treatment. Compared with no NIR irradiation, after 2min NIR irradiation, the membranes reduced the in-vitro viability of GSCs by 13.41%, 14.83%, and 26.71% after 1, 2, and 3 days, respectively. After 3 min daily illumination for 3 days, the viability of GSCs was only 22.75%, and similar results were observed in vivo. SIGNIFICANCE These results showed efficiently cytotoxicity to CSCs by combining heat therapy and differentiation therapy. The nanofiber membranes if inserted at the site after surgical tumor removal, may hinder tumor recurrence.
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Affiliation(s)
- Haijun Chen
- Department of Neurosurgery, Qilu Hospital, Shandong University, Jinan, Shandong, China
| | - Yue Shi
- School of Pharmaceutical Sciences, Shandong University, Jinan, Shandong, China
| | - Lei Sun
- Department of Endocrinology, Qilu Hospital, Shandong University, Jinan, Shandong, China.
| | - Shilei Ni
- Department of Neurosurgery, Qilu Hospital, Shandong University, Jinan, Shandong, China.
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Kostouros A, Koliarakis I, Natsis K, Spandidos DA, Tsatsakis A, Tsiaoussis J. Large intestine embryogenesis: Molecular pathways and related disorders (Review). Int J Mol Med 2020; 46:27-57. [PMID: 32319546 PMCID: PMC7255481 DOI: 10.3892/ijmm.2020.4583] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2020] [Accepted: 04/08/2020] [Indexed: 02/07/2023] Open
Abstract
The large intestine, part of the gastrointestinal tract (GI), is composed of all three germ layers, namely the endoderm, the mesoderm and the ectoderm, forming the epithelium, the smooth muscle layers and the enteric nervous system, respectively. Since gastrulation, these layers develop simultaneously during embryogenesis, signaling to each other continuously until adult age. Two invaginations, the anterior intestinal portal (AIP) and the caudal/posterior intestinal portal (CIP), elongate and fuse, creating the primitive gut tube, which is then patterned along the antero‑posterior (AP) axis and the radial (RAD) axis in the context of left‑right (LR) asymmetry. These events lead to the formation of three distinct regions, the foregut, midgut and hindgut. All the above‑mentioned phenomena are under strict control from various molecular pathways, which are critical for the normal intestinal development and function. Specifically, the intestinal epithelium constitutes a constantly developing tissue, deriving from the progenitor stem cells at the bottom of the intestinal crypt. Epithelial differentiation strongly depends on the crosstalk with the adjacent mesoderm. Major molecular pathways that are implicated in the embryogenesis of the large intestine include the canonical and non‑canonical wingless‑related integration site (Wnt), bone morphogenetic protein (BMP), Notch and hedgehog systems. The aberrant regulation of these pathways inevitably leads to several intestinal malformation syndromes, such as atresia, stenosis, or agangliosis. Novel theories, involving the regulation and homeostasis of intestinal stem cells, suggest an embryological basis for the pathogenesis of colorectal cancer (CRC). Thus, the present review article summarizes the diverse roles of these molecular factors in intestinal embryogenesis and related disorders.
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Affiliation(s)
- Antonios Kostouros
- Laboratory of Anatomy-Histology-Embryology, Medical School, University of Crete, 71110 Heraklion
| | - Ioannis Koliarakis
- Laboratory of Anatomy-Histology-Embryology, Medical School, University of Crete, 71110 Heraklion
| | - Konstantinos Natsis
- Department of Anatomy and Surgical Anatomy, Medical School, Aristotle University of Thessaloniki, 54124 Thessaloniki
| | | | - Aristidis Tsatsakis
- Laboratory of Toxicology, Medical School, University of Crete, 71409 Heraklion, Greece
| | - John Tsiaoussis
- Laboratory of Anatomy-Histology-Embryology, Medical School, University of Crete, 71110 Heraklion
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Das PK, Islam F, Lam AK. The Roles of Cancer Stem Cells and Therapy Resistance in Colorectal Carcinoma. Cells 2020; 9:1392. [PMID: 32503256 PMCID: PMC7348976 DOI: 10.3390/cells9061392] [Citation(s) in RCA: 145] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2020] [Revised: 05/29/2020] [Accepted: 06/02/2020] [Indexed: 12/22/2022] Open
Abstract
Cancer stem cells (CSCs) are the main culprits involved in therapy resistance and disease recurrence in colorectal carcinoma (CRC). Results using cell culture, animal models and tissues from patients with CRC suggest the indispensable roles of colorectal CSCs in therapeutic failure. Conventional therapies target proliferating and mature cancer cells, while CSCs are mostly quiescent and poorly differentiated, thereby they can easily survive chemotherapeutic insults. The aberrant activation of Wnt/β-catenin, Notch, Hedgehog, Hippo/YAP (Yes-associated protein) and phosphatidylinositol 3-kinase/protein kinase B facilitates CSCs with excessive self-renewal and therapy resistance property in CRC. CSCs survive the chemo-radiotherapies by escaping therapy mediated DNA damage via altering the cell cycle checkpoints, increasing DNA damage repair capacity and by an efficient scavenging of reactive oxygen species. Furthermore, dysregulations of miRNAs e.g., miR-21, miR-93, miR-203, miR-215, miR-497 etc., modulate the therapeutic sensitivity of colorectal CSCs by regulating growth and survival signalling. In addition, a reversible quiescent G0 state and the re-entering cell cycle capacity of colorectal CSCs can accelerate tumour regeneration after treatment. Moreover, switching to favourable metabolic signatures during a therapeutic regimen will add more complexity in therapeutic outcomes against CSCs. Therapeutic strategies targeting these underlying mechanisms of CSCs' therapy resistance could provide a promising outcome, however, deep understanding and concerted research are necessary to design novel therapies targeting CSCs. To conclude, the understanding of these mechanisms of CSC in CRC could lead to the improved management of patients with CRC.
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Affiliation(s)
- Plabon Kumar Das
- Department of Biochemistry and Molecular Biology, University of Rajshahi, Rajshahi 6205, Bangladesh;
| | - Farhadul Islam
- Department of Biochemistry and Molecular Biology, University of Rajshahi, Rajshahi 6205, Bangladesh;
- Institute for Glycomics, Griffith University, Gold Coast, QLD 4222, Australia
| | - Alfred K. Lam
- Cancer Molecular Pathology, School of Medicine, Griffith University, Gold Coast, QLD 4222, Australia
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Morral C, Stanisavljevic J, Hernando-Momblona X, Mereu E, Álvarez-Varela A, Cortina C, Stork D, Slebe F, Turon G, Whissell G, Sevillano M, Merlos-Suárez A, Casanova-Martí À, Moutinho C, Lowe SW, Dow LE, Villanueva A, Sancho E, Heyn H, Batlle E. Zonation of Ribosomal DNA Transcription Defines a Stem Cell Hierarchy in Colorectal Cancer. Cell Stem Cell 2020; 26:845-861.e12. [PMID: 32396863 DOI: 10.1016/j.stem.2020.04.012] [Citation(s) in RCA: 63] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2019] [Revised: 02/20/2020] [Accepted: 04/19/2020] [Indexed: 01/12/2023]
Abstract
Colorectal cancers (CRCs) are composed of an amalgam of cells with distinct genotypes and phenotypes. Here, we reveal a previously unappreciated heterogeneity in the biosynthetic capacities of CRC cells. We discover that the majority of ribosomal DNA transcription and protein synthesis in CRCs occurs in a limited subset of tumor cells that localize in defined niches. The rest of the tumor cells undergo an irreversible loss of their biosynthetic capacities as a consequence of differentiation. Cancer cells within the biosynthetic domains are characterized by elevated levels of the RNA polymerase I subunit A (POLR1A). Genetic ablation of POLR1A-high cell population imposes an irreversible growth arrest on CRCs. We show that elevated biosynthesis defines stemness in both LGR5+ and LGR5- tumor cells. Therefore, a common architecture in CRCs is a simple cell hierarchy based on the differential capacity to transcribe ribosomal DNA and synthesize proteins.
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Affiliation(s)
- Clara Morral
- Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology (BIST), Baldiri i Reixac 10, 08028 Barcelona, Spain
| | - Jelena Stanisavljevic
- Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology (BIST), Baldiri i Reixac 10, 08028 Barcelona, Spain
| | - Xavier Hernando-Momblona
- Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology (BIST), Baldiri i Reixac 10, 08028 Barcelona, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), 08028 Barcelona, Spain
| | - Elisabetta Mereu
- CNAG-Centre for Genomic Regulation (CRG), BIST, Baldiri i Reixac 4, 08028 Barcelona, Spain
| | - Adrián Álvarez-Varela
- Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology (BIST), Baldiri i Reixac 10, 08028 Barcelona, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), 08028 Barcelona, Spain
| | - Carme Cortina
- Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology (BIST), Baldiri i Reixac 10, 08028 Barcelona, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), 08028 Barcelona, Spain
| | - Diana Stork
- Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology (BIST), Baldiri i Reixac 10, 08028 Barcelona, Spain
| | - Felipe Slebe
- Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology (BIST), Baldiri i Reixac 10, 08028 Barcelona, Spain
| | - Gemma Turon
- Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology (BIST), Baldiri i Reixac 10, 08028 Barcelona, Spain
| | - Gavin Whissell
- Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology (BIST), Baldiri i Reixac 10, 08028 Barcelona, Spain
| | - Marta Sevillano
- Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology (BIST), Baldiri i Reixac 10, 08028 Barcelona, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), 08028 Barcelona, Spain
| | - Anna Merlos-Suárez
- Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology (BIST), Baldiri i Reixac 10, 08028 Barcelona, Spain
| | - Àngela Casanova-Martí
- Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology (BIST), Baldiri i Reixac 10, 08028 Barcelona, Spain
| | - Catia Moutinho
- CNAG-Centre for Genomic Regulation (CRG), BIST, Baldiri i Reixac 4, 08028 Barcelona, Spain
| | - Scott W Lowe
- Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA
| | - Lukas E Dow
- Department of Medicine, Weill-Cornell Medical College, New York, NY 10021, USA
| | - Alberto Villanueva
- Group of Chemoresistance and Predictive Factors, Subprogram Against Cancer Therapeutic Resistance (ProCURE), ICO, Oncobell Program, IDIBELL, L'Hospitalet del Llobregat, 08908 Barcelona, Spain
| | - Elena Sancho
- Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology (BIST), Baldiri i Reixac 10, 08028 Barcelona, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), 08028 Barcelona, Spain
| | - Holger Heyn
- CNAG-Centre for Genomic Regulation (CRG), BIST, Baldiri i Reixac 4, 08028 Barcelona, Spain; Universitat Pompeu Fabra (UPF), Barcelona, Spain
| | - Eduard Batlle
- Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology (BIST), Baldiri i Reixac 10, 08028 Barcelona, Spain; ICREA, Passeig Lluís Companys 23, 08010 Barcelona, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), 08028 Barcelona, Spain.
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Wan ML, Wang Y, Zeng Z, Deng B, Zhu BS, Cao T, Li YK, Xiao J, Han Q, Wu Q. Colorectal cancer (CRC) as a multifactorial disease and its causal correlations with multiple signaling pathways. Biosci Rep 2020; 40:BSR20200265. [PMID: 32149326 PMCID: PMC7087324 DOI: 10.1042/bsr20200265] [Citation(s) in RCA: 77] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Revised: 02/21/2020] [Accepted: 02/25/2020] [Indexed: 12/12/2022] Open
Abstract
Colorectal cancer (CRC) is the third most common malignancy and one of the leading causes of cancer-related death among men worldwide. CRC is a multifactor digestive pathology, which is a huge problem faced not only by clinicians but also by researchers. Importantly, a unique feature of CRC is the dysregulation of molecular signaling pathways. To date, a series of reviews have indicated that different signaling pathways are disordered and have potential as therapeutic targets in CRC. Nevertheless, an overview of the function and interaction of multiple signaling pathways in CRC is needed. Therefore, we summarized the pathways, biological functions and important interactions involved in CRC. First, we investigated the involvement of signaling pathways, including Wnt, PI3K/Akt, Hedgehog, ErbB, RHOA, Notch, BMP, Hippo, AMPK, NF-κB, MAPK and JNK. Subsequently, we discussed the biological function of these pathways in pathophysiological aspects of CRC, such as proliferation, apoptosis and metastasis. Finally, we summarized important interactions among these pathways in CRC. We believe that the interaction of these pathways could provide new strategies for the treatment of CRC.
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Affiliation(s)
- Mao-lin Wan
- Department of Hepatobiliary and Pancreatic Surgery, Xianning Central Hospital, the First Affiliated Hospital of Hubei University of Science and Technology, Xianning, 437000, P.R. China
| | - Yu Wang
- Department of Laboratory Medicine, The Second Affiliated Hospital of University of South China, Hengyang, 421001, P.R. China
| | - Zhi Zeng
- Department of Pathology, Xianning Central Hospital, the First Affiliated Hospital of Hubei University of Science and Technology, Xianning, 437000, P.R. China
| | - Bo Deng
- Department of Oncology, Xianning Central Hospital, the First Affiliated Hospital of Hubei University of Science and Technology, Xianning, 437000, P.R. China
| | - Bi-sheng Zhu
- Department of Oncology, Xianning Central Hospital, the First Affiliated Hospital of Hubei University of Science and Technology, Xianning, 437000, P.R. China
| | - Ting Cao
- Department of Digestive Medical, The Affiliated Nanhua Hospital, University of South China, Hengyang, 421002, P.R. China
| | - Yu-kun Li
- Key Laboratory of Tumor Cellular and Molecular Pathology, College of Hunan Province, Cancer Research Institute, University of South China, Hengyang, Hunan, 421001, P.R. China
| | - Jiao Xiao
- Department of Endocrinology, The Affiliated Nanhua Hospital, University of South China, Hengyang, 421002, P.R. China
| | - Qi Han
- Department of Oncology, Xianning Central Hospital, the First Affiliated Hospital of Hubei University of Science and Technology, Xianning, 437000, P.R. China
| | - Qing Wu
- Department of Digestive Medical, The Affiliated Nanhua Hospital, University of South China, Hengyang, 421002, P.R. China
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45
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Wu G, Huang F, Chen Y, Zhuang Y, Huang Y, Xie Y. High Levels of BMP2 Promote Liver Cancer Growth via the Activation of Myeloid-Derived Suppressor Cells. Front Oncol 2020; 10:194. [PMID: 32195173 PMCID: PMC7064622 DOI: 10.3389/fonc.2020.00194] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2019] [Accepted: 02/05/2020] [Indexed: 12/16/2022] Open
Abstract
Bone morphogenetic protein 2 (BMP2) signaling had significant roles in diverse pathological processes, such as cancer. Nevertheless, the interaction between BMP2 and carcinoma development remained largely unknown. In particular, the roles that BMP2 play in the development of liver cancer remained controversial, and mechanisms were unclear. BMP2 with strong osteogenic potential had been manufactured into various bone materials. However, cancer risk concerns were raised in recent years. Thus, we focused on analyzing the effects of exogenous BMP2 on the growth of liver cancer and the detailed mechanisms. We found that both intravenous injection of rhBMP2 and in vivo implantation of rhBMP2 materials could lead to the expansion of myeloid-derived suppressor cells (MDSCs) in peripheral blood and subsequently enhanced the infiltration of MDSCs into tumor in vivo. Furthermore, BMP2 signaling-activated MDSCs could secrete IL6 to enhance cell proliferation of liver cancer cells in vitro and facilitate liver cancer growth in vivo. Our study indicated that increased concentration of BMP2 within the peripheral blood could enhance liver cancer growth via the activation of MDSCs. In this study, the roles that BMP2 played in liver cancer growth were further confirmed and the detailed mechanisms about how BMP2 enhanced liver cancer growth were also elucidated.
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Affiliation(s)
- Gui Wu
- Department of Orthopedics, First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Fei Huang
- Central Lab, First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Yaoqing Chen
- Department of Orthopedics, First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Yuehong Zhuang
- Department of Human Anatomy and Embryology, Institute of Neuroscientific Study, Fujian Medical University, Fuzhou, China
| | - Yunpeng Huang
- Department of Orthopedics, First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Yun Xie
- Department of Orthopedics, First Affiliated Hospital, Fujian Medical University, Fuzhou, China
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46
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Targeting chemoresistant colorectal cancer via systemic administration of a BMP7 variant. Oncogene 2019; 39:987-1003. [PMID: 31591478 PMCID: PMC6989400 DOI: 10.1038/s41388-019-1047-4] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2019] [Revised: 09/23/2019] [Accepted: 09/25/2019] [Indexed: 12/15/2022]
Abstract
Despite intense research and clinical efforts, patients affected by advanced colorectal cancer (CRC) have still a poor prognosis. The discovery of colorectal (CR) cancer stem cell (CSC) as the cell compartment responsible for tumor initiation and propagation may provide new opportunities for the development of new therapeutic strategies. Given the reduced sensitivity of CR-CSCs to chemotherapy and the ability of bone morphogenetic proteins (BMP) to promote colonic stem cell differentiation, we aimed to investigate whether an enhanced variant of BMP7 (BMP7v) could sensitize to chemotherapy-resistant CRC cells and tumors. Thirty-five primary human cultures enriched in CR-CSCs, including four from chemoresistant metastatic lesions, were used for in vitro studies and to generate CR-CSC-based mouse avatars to evaluate tumor growth and progression upon treatment with BMP7v alone or in combination with standard therapy or PI3K inhibitors. BMP7v treatment promotes CR-CSC differentiation and recapitulates the cell differentiation-related gene expression profile by suppressing Wnt pathway activity and reducing mesenchymal traits and survival of CR-CSCs. Moreover, in CR-CSC-based mouse avatars, BMP7v exerts an antiangiogenic effect and sensitizes tumor cells to standard chemotherapy regardless of the mutational, MSI, and CMS profiles. Of note, tumor harboring PIK3CA mutations were affected to a lower extent by the combination of BMP7v and chemotherapy. However, the addition of a PI3K inhibitor to the BMP7v-based combination potentiates PIK3CA-mutant tumor drug response and reduces the metastatic lesion size. These data suggest that BMP7v treatment may represent a useful antiangiogenic and prodifferentiation agent, which renders CSCs sensitive to both standard and targeted therapies.
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47
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Sánchez-de-Diego C, Valer JA, Pimenta-Lopes C, Rosa JL, Ventura F. Interplay between BMPs and Reactive Oxygen Species in Cell Signaling and Pathology. Biomolecules 2019; 9:E534. [PMID: 31561501 PMCID: PMC6843432 DOI: 10.3390/biom9100534] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2019] [Revised: 09/12/2019] [Accepted: 09/24/2019] [Indexed: 12/12/2022] Open
Abstract
The integration of cell extrinsic and intrinsic signals is required to maintain appropriate cell physiology and homeostasis. Bone morphogenetic proteins (BMPs) are cytokines that belong to the transforming growth factor-β (TGF-β) superfamily, which play a key role in embryogenesis, organogenesis and regulation of whole-body homeostasis. BMPs interact with membrane receptors that transduce information to the nucleus through SMAD-dependent and independent pathways, including PI3K-AKT and MAPKs. Reactive oxygen species (ROS) are intracellular molecules derived from the partial reduction of oxygen. ROS are highly reactive and govern cellular processes by their capacity to regulate signaling pathways (e.g., NF-κB, MAPKs, KEAP1-NRF2 and PI3K-AKT). Emerging evidence indicates that BMPs and ROS interplay in a number of ways. BMPs stimulate ROS production by inducing NOX expression, while ROS regulate the expression of several BMPs. Moreover, BMPs and ROS influence common signaling pathways, including PI3K/AKT and MAPK. Additionally, dysregulation of BMPs and ROS occurs in several pathologies, including vascular and musculoskeletal diseases, obesity, diabetes and kidney injury. Here, we review the current knowledge on the integration between BMP and ROS signals and its potential applications in the development of new therapeutic strategies.
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Affiliation(s)
- Cristina Sánchez-de-Diego
- Departament de Ciències Fisiològiques, Universitat de Barcelona, Carrer Feixa Llarga s/n, 08907 L'Hospitalet Llobregat, Spain.
| | - José Antonio Valer
- Departament de Ciències Fisiològiques, Universitat de Barcelona, Carrer Feixa Llarga s/n, 08907 L'Hospitalet Llobregat, Spain.
| | - Carolina Pimenta-Lopes
- Departament de Ciències Fisiològiques, Universitat de Barcelona, Carrer Feixa Llarga s/n, 08907 L'Hospitalet Llobregat, Spain.
| | - José Luis Rosa
- Departament de Ciències Fisiològiques, Universitat de Barcelona, Carrer Feixa Llarga s/n, 08907 L'Hospitalet Llobregat, Spain.
- IDIBELL, Avinguda Granvia de l'Hospitalet 199, 08908 L'Hospitalet de Llobregat, Spain.
| | - Francesc Ventura
- Departament de Ciències Fisiològiques, Universitat de Barcelona, Carrer Feixa Llarga s/n, 08907 L'Hospitalet Llobregat, Spain.
- IDIBELL, Avinguda Granvia de l'Hospitalet 199, 08908 L'Hospitalet de Llobregat, Spain.
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48
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Iyer DN, Sin WY, Ng L. Linking stemness with colorectal cancer initiation, progression, and therapy. World J Stem Cells 2019; 11:519-534. [PMID: 31523371 PMCID: PMC6716088 DOI: 10.4252/wjsc.v11.i8.519] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2019] [Revised: 06/12/2019] [Accepted: 06/20/2019] [Indexed: 02/06/2023] Open
Abstract
The discovery of cancer stem cells caused a paradigm shift in the concepts of origin and development of colorectal cancer. Several unresolved questions remain in this field though. Are colorectal cancer stem cells the cause or an effect of the disease? How do cancer stem cells assist in colorectal tumor dissemination to distant organs? What are the molecular or environmental factors affecting the roles of these cells in colorectal cancer? Through this review, we investigate the key findings until now and attempt to elucidate the origins, physical properties, microenvironmental niches, as well as the molecular signaling network that support the existence, self-renewal, plasticity, quiescence, and the overall maintenance of cancer stem cells in colorectal cancer. Increasing data show that the cancer stem cells play a crucial role not only in the establishment of the primary colorectal tumor but also in the distant spread of the disease. Hence, we will also look at the mechanisms adopted by cancer stem cells to influence the development of metastasis and evade therapeutic targeting and its role in the overall disease prognosis. Finally, we will illustrate the importance of understanding the biology of these cells to develop improved clinical strategies to tackle colorectal cancer.
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Affiliation(s)
- Deepak Narayanan Iyer
- Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Wai-Yan Sin
- Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Lui Ng
- Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
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49
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Bianco AC, Dumitrescu A, Gereben B, Ribeiro MO, Fonseca TL, Fernandes GW, Bocco BMLC. Paradigms of Dynamic Control of Thyroid Hormone Signaling. Endocr Rev 2019; 40:1000-1047. [PMID: 31033998 PMCID: PMC6596318 DOI: 10.1210/er.2018-00275] [Citation(s) in RCA: 181] [Impact Index Per Article: 30.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2018] [Accepted: 03/15/2019] [Indexed: 12/17/2022]
Abstract
Thyroid hormone (TH) molecules enter cells via membrane transporters and, depending on the cell type, can be activated (i.e., T4 to T3 conversion) or inactivated (i.e., T3 to 3,3'-diiodo-l-thyronine or T4 to reverse T3 conversion). These reactions are catalyzed by the deiodinases. The biologically active hormone, T3, eventually binds to intracellular TH receptors (TRs), TRα and TRβ, and initiate TH signaling, that is, regulation of target genes and other metabolic pathways. At least three families of transmembrane transporters, MCT, OATP, and LAT, facilitate the entry of TH into cells, which follow the gradient of free hormone between the extracellular fluid and the cytoplasm. Inactivation or marked downregulation of TH transporters can dampen TH signaling. At the same time, dynamic modifications in the expression or activity of TRs and transcriptional coregulators can affect positively or negatively the intensity of TH signaling. However, the deiodinases are the element that provides greatest amplitude in dynamic control of TH signaling. Cells that express the activating deiodinase DIO2 can rapidly enhance TH signaling due to intracellular buildup of T3. In contrast, TH signaling is dampened in cells that express the inactivating deiodinase DIO3. This explains how THs can regulate pathways in development, metabolism, and growth, despite rather stable levels in the circulation. As a consequence, TH signaling is unique for each cell (tissue or organ), depending on circulating TH levels and on the exclusive blend of transporters, deiodinases, and TRs present in each cell. In this review we explore the key mechanisms underlying customization of TH signaling during development, in health and in disease states.
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Affiliation(s)
- Antonio C Bianco
- Section of Endocrinology, Diabetes, and Metabolism, University of Chicago Medical Center, Chicago, Illinois
| | - Alexandra Dumitrescu
- Section of Endocrinology, Diabetes, and Metabolism, University of Chicago Medical Center, Chicago, Illinois
| | - Balázs Gereben
- Department of Endocrine Neurobiology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary
| | - Miriam O Ribeiro
- Developmental Disorders Program, Center of Biologic Sciences and Health, Mackenzie Presbyterian University, São Paulo, São Paulo, Brazil
| | - Tatiana L Fonseca
- Section of Endocrinology, Diabetes, and Metabolism, University of Chicago Medical Center, Chicago, Illinois
| | - Gustavo W Fernandes
- Section of Endocrinology, Diabetes, and Metabolism, University of Chicago Medical Center, Chicago, Illinois
| | - Barbara M L C Bocco
- Section of Endocrinology, Diabetes, and Metabolism, University of Chicago Medical Center, Chicago, Illinois
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50
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Luongo F, Colonna F, Calapà F, Vitale S, Fiori ME, De Maria R. PTEN Tumor-Suppressor: The Dam of Stemness in Cancer. Cancers (Basel) 2019; 11:E1076. [PMID: 31366089 PMCID: PMC6721423 DOI: 10.3390/cancers11081076] [Citation(s) in RCA: 120] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2019] [Revised: 07/24/2019] [Accepted: 07/26/2019] [Indexed: 12/11/2022] Open
Abstract
PTEN is one of the most frequently inactivated tumor suppressor genes in cancer. Loss or variation in PTEN gene/protein levels is commonly observed in a broad spectrum of human cancers, while germline PTEN mutations cause inherited syndromes that lead to increased risk of tumors. PTEN restrains tumorigenesis through different mechanisms ranging from phosphatase-dependent and independent activities, subcellular localization and protein interaction, modulating a broad array of cellular functions including growth, proliferation, survival, DNA repair, and cell motility. The main target of PTEN phosphatase activity is one of the most significant cell growth and pro-survival signaling pathway in cancer: PI3K/AKT/mTOR. Several shreds of evidence shed light on the critical role of PTEN in normal and cancer stem cells (CSCs) homeostasis, with its loss fostering the CSC compartment in both solid and hematologic malignancies. CSCs are responsible for tumor propagation, metastatic spread, resistance to therapy, and relapse. Thus, understanding how alterations of PTEN levels affect CSC hallmarks could be crucial for the development of successful therapeutic approaches. Here, we discuss the most significant findings on PTEN-mediated control of CSC state. We aim to unravel the role of PTEN in the regulation of key mechanisms specific for CSCs, such as self-renewal, quiescence/cell cycle, Epithelial-to-Mesenchymal-Transition (EMT), with a particular focus on PTEN-based therapy resistance mechanisms and their exploitation for novel therapeutic approaches in cancer treatment.
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Affiliation(s)
- Francesca Luongo
- Istituto di Patologia Generale, Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168 Rome, Italy
| | - Francesca Colonna
- Istituto di Patologia Generale, Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168 Rome, Italy
| | - Federica Calapà
- Istituto di Patologia Generale, Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168 Rome, Italy
| | - Sara Vitale
- Istituto di Patologia Generale, Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168 Rome, Italy
| | - Micol E Fiori
- Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, 00161 Rome, Italy.
| | - Ruggero De Maria
- Istituto di Patologia Generale, Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168 Rome, Italy.
- Scientific Vice-Direction, Fondazione Policlinico Universitario "A. Gemelli"-I.R.C.C.S., Largo Francesco Vito 1-8, 00168 Rome, Italy.
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