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1
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Wu L, de Perrot M. Omics Overview of the SPARC Gene in Mesothelioma. Biomolecules 2023; 13:1103. [PMID: 37509139 PMCID: PMC10377476 DOI: 10.3390/biom13071103] [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: 05/29/2023] [Revised: 07/06/2023] [Accepted: 07/08/2023] [Indexed: 07/30/2023] Open
Abstract
The SPARC gene plays multiple roles in extracellular matrix synthesis and cell shaping, associated with tumor cell migration, invasion, and metastasis. The SPARC gene is also involved in the epithelial-mesenchymal transition (EMT) process, which is a critical phenomenon leading to a more aggressive cancer cell phenotype. SPARC gene overexpression has shown to be associated with poor survival in the mesothelioma (MESO) cohort from the TCGA database, indicating that this gene may be a powerful prognostic factor in MESO. Its overexpression is correlated with the immunosuppressive tumor microenvironment. Here, we summarize the omics advances of the SPARC gene, including the summary of SPARC gene expression associated with prognosis in pancancer and MESO, the immunosuppressive microenvironment, and cancer cell stemness. In addition, SPARC might be targeted by microRNAs. Notably, despite the controversial functions on angiogenesis, SPARC may directly or indirectly contribute to tumor angiogenesis in MESO. In conclusion, SPARC is involved in tumor invasion, metastasis, immunosuppression, cancer cell stemness, and tumor angiogenesis, eventually impacting patient survival. Strategies targeting this gene may provide novel therapeutic approaches to the treatment of MESO.
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Affiliation(s)
- Licun Wu
- Latner Thoracic Surgery Research Laboratories, Division of Thoracic Surgery, Toronto General Hospital, Toronto General Hospital Research Institute, University Health Network (UHN), 9N-961, 200 Elizabeth Street, Toronto, ON M5G 2C4, Canada;
| | - Marc de Perrot
- Latner Thoracic Surgery Research Laboratories, Division of Thoracic Surgery, Toronto General Hospital, Toronto General Hospital Research Institute, University Health Network (UHN), 9N-961, 200 Elizabeth Street, Toronto, ON M5G 2C4, Canada;
- Division of Thoracic Surgery, Princess Margaret Hospital, University Health Network (UHN), Toronto, ON M5G 1L7, Canada
- Department of Immunology, University of Toronto, Toronto, ON M5S 1A1, Canada
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2
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Sergi CM. The role of SPARC/ON in human osteosarcoma. ADVANCES IN PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY 2023; 133:181-192. [PMID: 36707201 DOI: 10.1016/bs.apcsb.2022.10.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
The human osteosarcoma is a malignant tumor of the arthro-skeletal system. It has been recognized that it is the most common malignancy followed by the Ewing sarcoma or primitive neuroectodermal tumor. The prognosis is worrisome and is not preserved by the use of classical chemotherapy drugs. High rates of recurrence and metastases often accompany this malignant tumor. Chemotherapy often fails because of the onset of multidrug resistance, even though the mechanism to reach chemotherapy resistance is still intriguing and contains unclear pathways. The secreted protein acidic and rich in cysteine (SPARC) or osteonectin (ON) (SPARC/ON) has been associated with poor prognosis in several malignant neoplasms. In this mini-review, we are going to highlight the role of SPARC/ON in human osteosarcoma. Extracellular vesicles are fundamental in cell-to-cell communication. We suggest that a liquid biopsy targeting SPARC/ON may be critical to implement in the surveillance of patients with this malignant bony neoplasm.
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Affiliation(s)
- Consolato M Sergi
- Anatomic Pathology Division, Children's Hospital of Eastern Ontario (CHEO), Ottawa, ON, Canada; Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB, Canada; Department of Orthopedics, Tianyou Hospital, Wuhan University of Science and Technology, Wuhan, Hubei, China.
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3
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The extracellular matrix of hematopoietic stem cell niches. Adv Drug Deliv Rev 2022; 181:114069. [PMID: 34838648 PMCID: PMC8860232 DOI: 10.1016/j.addr.2021.114069] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Revised: 11/18/2021] [Accepted: 11/21/2021] [Indexed: 12/21/2022]
Abstract
Comprehensive overview of different classes of ECM molecules in the HSC niche. Overview of current knowledge on role of biophysics of the HSC niche. Description of approaches to create artificial stem cell niches for several application. Importance of considering ECM in drug development and testing. Hematopoietic stem cells (HSCs) are the life-long source of all types of blood cells. Their function is controlled by their direct microenvironment, the HSC niche in the bone marrow. Although the importance of the extracellular matrix (ECM) in the niche by orchestrating niche architecture and cellular function is widely acknowledged, it is still underexplored. In this review, we provide a comprehensive overview of the ECM in HSC niches. For this purpose, we first briefly outline HSC niche biology and then review the role of the different classes of ECM molecules in the niche one by one and how they are perceived by cells. Matrix remodeling and the emerging importance of biophysics in HSC niche function are discussed. Finally, the application of the current knowledge of ECM in the niche in form of artificial HSC niches for HSC expansion or targeted differentiation as well as drug testing is reviewed.
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4
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Pan Y, Zuo H, Wen F, Huang F, Zhu Y, Cao L, Sha QQ, Li Y, Zhang H, Shi M, Liang C, Huang J, Zou L, Fan HY, Ju Z, Wang H, Shen L. HMCES safeguards genome integrity and long-term self-renewal of hematopoietic stem cells during stress responses. Leukemia 2022; 36:1123-1131. [PMID: 35039639 DOI: 10.1038/s41375-021-01499-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Revised: 12/04/2021] [Accepted: 12/10/2021] [Indexed: 12/28/2022]
Abstract
Hematopoietic stress drives quiescent hematopoietic stem cells (HSCs) to proliferate, generating reactive oxygen species (ROS) and oxidative DNA damage including abasic sites. Such a coupling between rapid DNA replication and a burst of abasic site formation during HSC stress responses, however, presents a challenge to accurately repair abasic sites located in replication-associated single-stranded DNA. Here we show that HMCES, a novel shield of abasic sites, plays pivotal roles in overcoming this challenge upon HSC activation. While HMCES was dispensable for steady-state hematopoiesis, Hmces-deficient HSCs exhibited compromised long-term self-renewal capacity in response to hematopoietic stress such as myeloablation and transplantation. Loss of HMCES resulted in accumulation of DNA lesions due to impaired resolution of abasic sites generated by activation-induced ROS in activated HSCs and broad downregulation of DNA damage response and repair pathways. Moreover, Hmces-deficient mice died from bone marrow failure after exposure to sublethal irradiation, which also produces ROS. Notably, dysregulation of HMCES occurs frequently in acute lymphocytic leukemia (ALL) and is associated with poor clinical outcomes. Together, our findings not only highlighted HMCES as a novel genome protector in activated HSCs, but also position it as a potential selective target against ALL while sparing normal hematopoiesis.
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Affiliation(s)
- Yinghao Pan
- MOE Key Laboratory of Biosystems Homeostasis & Protection and Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, China
| | - Hongna Zuo
- MOE Key Laboratory of Regenerative Medicine, Institute of Aging and Regenerative Medicine, Jinan University, Guangzhou, China
| | - Fei Wen
- MOE Key Laboratory of Regenerative Medicine, Institute of Aging and Regenerative Medicine, Jinan University, Guangzhou, China
| | - Fei Huang
- MOE Key Laboratory of Biosystems Homeostasis & Protection and Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, China
| | - Yezhang Zhu
- MOE Key Laboratory of Biosystems Homeostasis & Protection and Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, China
| | - Lanrui Cao
- MOE Key Laboratory of Biosystems Homeostasis & Protection and Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, China
| | - Qian-Qian Sha
- MOE Key Laboratory of Biosystems Homeostasis & Protection and Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, China
| | - Yang Li
- MOE Key Laboratory of Biosystems Homeostasis & Protection and Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, China
| | - Huiying Zhang
- MOE Key Laboratory of Biosystems Homeostasis & Protection and Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, China
| | - Miao Shi
- MOE Key Laboratory of Biosystems Homeostasis & Protection and Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, China
| | - Chengzhen Liang
- Department of Orthopedics Surgery, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Jun Huang
- MOE Key Laboratory of Biosystems Homeostasis & Protection and Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, China
| | - Lin Zou
- Clinical Research Unit, Children's Hospital of Shanghai Jiaotong University, Shanghai, China
| | - Heng-Yu Fan
- MOE Key Laboratory of Biosystems Homeostasis & Protection and Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, China
| | - Zhenyu Ju
- MOE Key Laboratory of Regenerative Medicine, Institute of Aging and Regenerative Medicine, Jinan University, Guangzhou, China.
| | - Hu Wang
- Key Laboratory of Aging and Cancer Biology of Zhejiang Province, Institute of Ageing Research, School of Basic Medical Sciences, Hangzhou Normal University, Hangzhou, China.
| | - Li Shen
- MOE Key Laboratory of Biosystems Homeostasis & Protection and Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, China. .,Department of Orthopedics Surgery, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China. .,Hangzhou Innovation Center, Zhejiang University, Hangzhou, China.
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5
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Xu L, Liu X, Peng F, Zhang W, Zheng L, Ding Y, Gu T, Lv K, Wang J, Ortinau L, Hu T, Shi X, Shi G, Shang G, Sun S, Iwawaki T, Ji Y, Li W, Rosen JM, Zhang XHF, Park D, Adoro S, Catic A, Tong W, Qi L, Nakada D, Chen X. Protein quality control through endoplasmic reticulum-associated degradation maintains haematopoietic stem cell identity and niche interactions. Nat Cell Biol 2020; 22:1162-1169. [PMID: 32958856 PMCID: PMC7888538 DOI: 10.1038/s41556-020-00581-x] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2019] [Accepted: 08/21/2020] [Indexed: 12/19/2022]
Abstract
Stem cells need to be protected from genotoxic and proteotoxic stress to maintain a healthy pool throughout life1–3. Little is known about the proteostasis mechanism that safeguards the stem cells. Here, we report Endoplasmic Reticulum-Associated Degradation (ERAD) as a protein quality checkpoint that controls hematopoietic stem cell (HSC)-niche interaction and determines the fate of HSC. SEL1L-HRD1 complex, the most conserved branch of ERAD4, is highly expressed in HSC. Deletion of Sel1l led to niche displacement of HSC, complete loss of HSC identity, and allowed highly efficient donor-HSC engraftment without irradiation. Mechanistic studies identified MPL, the master regulator of HSC identity5, as a bona-fide ERAD substrate that became aggregated in the ER upon ERAD deficiency. Restoration of MPL signaling with an agonist partially rescued the number and reconstitution capacity of Sel1l-deficient HSCs. Our study defines ERAD as an essential proteostasis mechanism to safeguard a healthy stem cell pool through regulating the stem cell-niche interaction.
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Affiliation(s)
- Longyong Xu
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.,Lester and Sue Smith Breast Center and Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA
| | - Xia Liu
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.,Lester and Sue Smith Breast Center and Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA
| | - Fanglue Peng
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.,Lester and Sue Smith Breast Center and Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA
| | - Weijie Zhang
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.,Lester and Sue Smith Breast Center and Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA
| | - Liting Zheng
- Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX, USA
| | - Yao Ding
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.,Lester and Sue Smith Breast Center and Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA
| | - Tianpeng Gu
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.,Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, Houston, TX, USA
| | - Kaosheng Lv
- Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.,Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Jin Wang
- Department of Pharmacology and Chemical Biology, Baylor College of Medicine, Houston, TX, USA
| | - Laura Ortinau
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
| | - Tianyuan Hu
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
| | - Xiangguo Shi
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
| | - Guojun Shi
- Department of Molecular and Integrative Physiology and Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Ge Shang
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA
| | - Shengyi Sun
- Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI, USA
| | - Takao Iwawaki
- Division of Cell Medicine, Department of Life Science, Medical Research Institute, Kanazawa Medical University, Uchinada, Japan
| | - Yewei Ji
- Department of Molecular and Integrative Physiology and Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Wei Li
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.,Lester and Sue Smith Breast Center and Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA
| | - Jeffrey M Rosen
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.,Lester and Sue Smith Breast Center and Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA
| | - Xiang H-F Zhang
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.,Lester and Sue Smith Breast Center and Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA
| | - Dongsu Park
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
| | - Stanley Adoro
- Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH, USA
| | - Andre Catic
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.,Lester and Sue Smith Breast Center and Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA
| | - Wei Tong
- Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.,Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Ling Qi
- Department of Molecular and Integrative Physiology and Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Daisuke Nakada
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
| | - Xi Chen
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA. .,Lester and Sue Smith Breast Center and Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA.
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6
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Yu R, Zhang J, Zang Y, Zeng L, Zuo W, Bai Y, Liu Y, Sun K, Liu Y. iTRAQ-based quantitative protein expression profiling of biomarkers in childhood B-cell and T-cell acute lymphoblastic leukemia. Cancer Manag Res 2019; 11:7047-7063. [PMID: 31440093 PMCID: PMC6664257 DOI: 10.2147/cmar.s210093] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2019] [Accepted: 06/18/2019] [Indexed: 01/01/2023] Open
Abstract
Purpose This study screened serum proteins to identify potential biomarkers for childhood B-cell and T-cell acute lymphoblastic leukemia (ALL). Patients and methods Serum collected from 20 newly diagnosed B-cell ALL, 20 T-cell ALL and 20 healthy children. The peptides from these samples were subjected to iTRAQ. Differentially expressed proteins (DEPs) were further validated by ELISA in 24 B-ALL, 24 T-ALL, and 24 healthy children. Results Bioinformatics analysis revealed several pathways, including atherosclerosis signaling, interleukin signaling and production in macrophages and clathrin-mediated endocytosis signaling, that were closely related to childhood T-cell ALL. Furthermore, four selected proteins, namely LRG1, S100A8, SPARC and sL-selectin, were verified by ELISA. These results were consistent with the results of the proteomics analysis. Conclusion Serum S100A8 may serve as new diagnostic biomarkers in childhood B-cell ALL and T-cell ALL.
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Affiliation(s)
- Runhong Yu
- Department of Hematology, People's Hospital of Zhengzhou University/Henan Provincial People's Hospital, Zhengzhou 450003, Henan, People's Republic of China
| | - Jingyu Zhang
- Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, People's Republic of China
| | - Yuzhu Zang
- Department of Hematology, People's Hospital of Zhengzhou University/Henan Provincial People's Hospital, Zhengzhou 450003, Henan, People's Republic of China
| | - Li Zeng
- Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, People's Republic of China
| | - Wenli Zuo
- Department of Hematology, Affiliated Cancer Hospital of Zhengzhou University/Henan Cancer Hospital, Zhengzhou 450008, Henan, People's Republic of China
| | - Yanliang Bai
- Department of Hematology, People's Hospital of Zhengzhou University/Henan Provincial People's Hospital, Zhengzhou 450003, Henan, People's Republic of China
| | - Yanhui Liu
- Department of Hematology, People's Hospital of Zhengzhou University/Henan Provincial People's Hospital, Zhengzhou 450003, Henan, People's Republic of China
| | - Kai Sun
- Department of Hematology, People's Hospital of Zhengzhou University/Henan Provincial People's Hospital, Zhengzhou 450003, Henan, People's Republic of China
| | - Yufeng Liu
- Department of Pediatrics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, People's Republic of China
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7
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Nallanthighal S, Heiserman JP, Cheon DJ. The Role of the Extracellular Matrix in Cancer Stemness. Front Cell Dev Biol 2019; 7:86. [PMID: 31334229 PMCID: PMC6624409 DOI: 10.3389/fcell.2019.00086] [Citation(s) in RCA: 233] [Impact Index Per Article: 38.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2018] [Accepted: 05/03/2019] [Indexed: 12/12/2022] Open
Abstract
As our understanding of cancer cell biology progresses, it has become clear that tumors are a heterogenous mixture of different cell populations, some of which contain so called "cancer stem cells" (CSCs). Hallmarks of CSCs include self-renewing capability, tumor-initiating capacity and chemoresistance. The extracellular matrix (ECM), a major structural component of the tumor microenvironment, is a highly dynamic structure and increasing evidence suggests that ECM proteins establish a physical and biochemical niche for CSCs. In cancer, abnormal ECM dynamics occur due to disrupted balance between ECM synthesis and secretion and altered expression of matrix-remodeling enzymes. Tumor-derived ECM is biochemically distinct in its composition and is stiffer compared to normal ECM. In this review, we will provide a brief overview of how different components of the ECM modulate CSC properties then discuss how physical, mechanical, and biochemical cues from the ECM drive cancer stemness. Given the fact that current CSC targeting therapies face many challenges, a better understanding of CSC-ECM interactions will be crucial to identify more effective therapeutic strategies to eliminate CSCs.
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Affiliation(s)
| | | | - Dong-Joo Cheon
- Department of Regenerative and Cancer Cell Biology, Albany Medical College, Albany, NY, United States
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8
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Rao TN, Gupta MK, Softic S, Wang LD, Jang YC, Thomou T, Bezy O, Kulkarni RN, Kahn CR, Wagers AJ. Attenuation of PKCδ enhances metabolic activity and promotes expansion of blood progenitors. EMBO J 2018; 37:embj.2018100409. [PMID: 30446598 PMCID: PMC6293338 DOI: 10.15252/embj.2018100409] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2018] [Revised: 09/08/2018] [Accepted: 09/12/2018] [Indexed: 12/21/2022] Open
Abstract
A finely tuned balance of self‐renewal, differentiation, proliferation, and survival governs the pool size and regenerative capacity of blood‐forming hematopoietic stem and progenitor cells (HSPCs). Here, we report that protein kinase C delta (PKCδ) is a critical regulator of adult HSPC number and function that couples the proliferative and metabolic activities of HSPCs. PKCδ‐deficient mice showed a pronounced increase in HSPC numbers, increased competence in reconstituting lethally irradiated recipients, enhanced long‐term competitive advantage in serial transplantation studies, and an augmented HSPC recovery during stress. PKCδ‐deficient HSPCs also showed accelerated proliferation and reduced apoptosis, but did not exhaust in serial transplant assays or induce leukemia. Using inducible knockout and transplantation models, we further found that PKCδ acts in a hematopoietic cell‐intrinsic manner to restrict HSPC number and bone marrow regenerative function. Mechanistically, PKCδ regulates HSPC energy metabolism and coordinately governs multiple regulators within signaling pathways implicated in HSPC homeostasis. Together, these data identify PKCδ as a critical regulator of HSPC signaling and metabolism that acts to limit HSPC expansion in response to physiological and regenerative demands.
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Affiliation(s)
- Tata Nageswara Rao
- Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA .,Section on Islet Cell and Regenerative Biology, Joslin Diabetes Center, Boston, MA, USA
| | - Manoj K Gupta
- Section on Islet Cell and Regenerative Biology, Joslin Diabetes Center, Boston, MA, USA
| | - Samir Softic
- Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Boston, MA, USA.,Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, MA, USA
| | - Leo D Wang
- Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA.,Section on Islet Cell and Regenerative Biology, Joslin Diabetes Center, Boston, MA, USA.,Division of Pediatric Hematology/Oncology/Stem Cell Transplantation, Dana-Farber/Boston Children's Center for Cancer and Blood Disorders, Boston, MA, USA
| | - Young C Jang
- Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA.,Section on Islet Cell and Regenerative Biology, Joslin Diabetes Center, Boston, MA, USA
| | - Thomas Thomou
- Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Boston, MA, USA
| | - Olivier Bezy
- Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Boston, MA, USA
| | - Rohit N Kulkarni
- Section on Islet Cell and Regenerative Biology, Joslin Diabetes Center, Boston, MA, USA
| | - C Ronald Kahn
- Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Boston, MA, USA
| | - Amy J Wagers
- Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA .,Section on Islet Cell and Regenerative Biology, Joslin Diabetes Center, Boston, MA, USA
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9
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Taylor SJ, Duyvestyn JM, Dagger SA, Dishington EJ, Rinaldi CA, Dovey OM, Vassiliou GS, Grove CS, Langdon WY. Preventing chemotherapy-induced myelosuppression by repurposing the FLT3 inhibitor quizartinib. Sci Transl Med 2018; 9:9/402/eaam8060. [PMID: 28794285 DOI: 10.1126/scitranslmed.aam8060] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2017] [Revised: 04/19/2017] [Accepted: 06/29/2017] [Indexed: 02/06/2023]
Abstract
We describe an approach to inhibit chemotherapy-induced myelosuppression. We found that short-term exposure of mice to the FLT3 inhibitor quizartinib induced the transient quiescence of multipotent progenitors (MPPs). This property of quizartinib conferred marked protection to MPPs in mice receiving fluorouracil or gemcitabine. The protection resulted in the rapid recovery of bone marrow and blood cellularity, thus preventing otherwise lethal myelosuppression. A treatment strategy involving quizartinib priming that protected wild-type bone marrow progenitors, but not leukemic cells, from fluorouracil provided a more effective treatment than conventional induction therapy in mouse models of acute myeloid leukemia. This strategy has the potential to be extended for use in other cancers where FLT3 inhibition does not adversely affect the effectiveness of chemotherapy. Thus, the addition of quizartinib to cancer treatment regimens could markedly improve cancer patient survival and quality of life.
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Affiliation(s)
- Samuel J Taylor
- School of Pathology and Laboratory Medicine, University of Western Australia, Crawley, Western Australia 6009, Australia
| | - Johanna M Duyvestyn
- School of Pathology and Laboratory Medicine, University of Western Australia, Crawley, Western Australia 6009, Australia
| | - Samantha A Dagger
- School of Pathology and Laboratory Medicine, University of Western Australia, Crawley, Western Australia 6009, Australia
| | - Emma J Dishington
- School of Pathology and Laboratory Medicine, University of Western Australia, Crawley, Western Australia 6009, Australia
| | - Catherine A Rinaldi
- School of Pathology and Laboratory Medicine, University of Western Australia, Crawley, Western Australia 6009, Australia
| | - Oliver M Dovey
- Department of Haematology, Cambridge University Hospitals NHS Trust, Cambridge CB2 0QQ, UK
| | - George S Vassiliou
- Department of Haematology, Cambridge University Hospitals NHS Trust, Cambridge CB2 0QQ, UK.,Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK
| | - Carolyn S Grove
- School of Pathology and Laboratory Medicine, University of Western Australia, Crawley, Western Australia 6009, Australia.,PathWest Department of Haematology, Queen Elizabeth II Medical Centre, Nedlands, Western Australia 6009, Australia.,Department of Haematology, Sir Charles Gairdner Hospital, Nedlands, Western Australia 6009, Australia
| | - Wallace Y Langdon
- School of Pathology and Laboratory Medicine, University of Western Australia, Crawley, Western Australia 6009, Australia.
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10
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He S, Roberts PJ, Sorrentino JA, Bisi JE, Storrie-White H, Tiessen RG, Makhuli KM, Wargin WA, Tadema H, van Hoogdalem EJ, Strum JC, Malik R, Sharpless NE. Transient CDK4/6 inhibition protects hematopoietic stem cells from chemotherapy-induced exhaustion. Sci Transl Med 2018; 9:9/387/eaal3986. [PMID: 28446688 DOI: 10.1126/scitranslmed.aal3986] [Citation(s) in RCA: 113] [Impact Index Per Article: 16.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2016] [Revised: 11/14/2016] [Accepted: 01/27/2017] [Indexed: 12/11/2022]
Abstract
Conventional cytotoxic chemotherapy is highly effective in certain cancers but causes dose-limiting damage to normal proliferating cells, especially hematopoietic stem and progenitor cells (HSPCs). Serial exposure to cytotoxics causes a long-term hematopoietic compromise ("exhaustion"), which limits the use of chemotherapy and success of cancer therapy. We show that the coadministration of G1T28 (trilaciclib), which is a small-molecule inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6), contemporaneously with cytotoxic chemotherapy protects murine hematopoietic stem cells (HSCs) from chemotherapy-induced exhaustion in a serial 5-fluorouracil treatment model. Consistent with a cell-intrinsic effect, we show directly preserved HSC function resulting in a more rapid recovery of peripheral blood counts, enhanced serial transplantation capacity, and reduced myeloid skewing. When administered to healthy human volunteers, G1T28 demonstrated excellent in vivo pharmacology and transiently inhibited bone marrow (BM) HSPC proliferation. These findings suggest that the combination of CDK4/6 inhibitors with cytotoxic chemotherapy should provide a means to attenuate therapy-induced BM exhaustion in patients with cancer.
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Affiliation(s)
- Shenghui He
- Departments of Genetics and Medicine, University of North Carolina School of Medicine, Chapel Hill, NC 27599-7295, USA.,Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599-7295, USA
| | | | | | - John E Bisi
- G1 Therapeutics Inc., Research Triangle Park, NC 27709, USA
| | | | - Renger G Tiessen
- PRA Health Sciences, P.O. Box 200, 9470 AE Zuidlaren, Netherlands
| | | | | | - Henko Tadema
- PRA Health Sciences, P.O. Box 200, 9470 AE Zuidlaren, Netherlands
| | | | - Jay C Strum
- G1 Therapeutics Inc., Research Triangle Park, NC 27709, USA
| | - Rajesh Malik
- G1 Therapeutics Inc., Research Triangle Park, NC 27709, USA
| | - Norman E Sharpless
- Departments of Genetics and Medicine, University of North Carolina School of Medicine, Chapel Hill, NC 27599-7295, USA. .,Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599-7295, USA
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11
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Jia C, Zhang F, Zhu Y, Qi X, Wang Y. Public data mining plus domestic experimental study defined involvement of the old-yet-uncharacterized gene matrix-remodeling associated 7 (MXRA7) in physiopathology of the eye. Gene 2017; 632:43-49. [PMID: 28847716 DOI: 10.1016/j.gene.2017.08.018] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2017] [Revised: 07/12/2017] [Accepted: 08/23/2017] [Indexed: 12/22/2022]
Abstract
Matrix-remodeling associated 7 (MXRA7) gene was first reported in 2002 and named so for its co-expression with several genes known to relate with matrix-remodeling. However, not any studies had been intentionally performed to characterize this gene. We started defining the functions of MXRA7 by integrating bioinformatics analysis and experimental study. Data mining of MXRA7 expression in BioGPS, Gene Expression Omnibus and EurExpress platforms highlighted high level expression of Mxra7 in murine ocular tissues. Real-time PCR was employed to measure Mxra7 mRNA in tissues of adult C57BL/6 mice and demonstrated that Mxra7 was preferentially expressed at higher level in retina, corneas and lens than in other tissues. Then the inflammatory corneal neovascularization (CorNV) model and fungal corneal infections were induced in Balb/c mice, and mRNA levels of Mxra7 as well as several matrix-remodeling related genes (Mmp3, Mmp13, Ecm1, Timp1) were monitored with RT-PCR. The results demonstrated a time-dependent Mxra7 under-expression pattern (U-shape curve along timeline), while all other matrix-remodeling related genes manifested an opposite changes pattern (dome-shape curve). When limited data from BioGPS concerning human MXRA7 gene expression in human tissues were looked at, it was found that ocular tissue was also the one expressing highest level of MXRA7. To conclude, integrative assay of MXRA7 gene expression in public databank as well as domestic animal models revealed a selective high expression MXRA7 in murine and human ocular tissues, and its change patterns in two corneal disease models implied that MXRA7 might play a role in pathological processes or diseases involving injury, neovascularization and would healing.
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Affiliation(s)
- Changkai Jia
- Shandong Provincial Key Lab of Ophthalmology, Shandong Eye Institute, Shandong Academy of Medical Sciences, Qingdao, China
| | - Feng Zhang
- Eye Clinic, Linyi People's Hospital, Linyi, China
| | - Ying Zhu
- Eye Hospital, Institute & School of Optometry and Ophthalmology, Tianjin Medical University, Tianjin, China
| | - Xia Qi
- Shandong Provincial Key Lab of Ophthalmology, Shandong Eye Institute, Shandong Academy of Medical Sciences, Qingdao, China
| | - Yiqiang Wang
- Shandong Provincial Key Lab of Ophthalmology, Shandong Eye Institute, Shandong Academy of Medical Sciences, Qingdao, China; Collaborative Innovation Center of Hematology, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou, China.
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12
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Sangaletti S, Chiodoni C, Tripodo C, Colombo MP. Common extracellular matrix regulation of myeloid cell activity in the bone marrow and tumor microenvironments. Cancer Immunol Immunother 2017; 66:1059-1067. [PMID: 28501940 PMCID: PMC11029001 DOI: 10.1007/s00262-017-2014-y] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2016] [Accepted: 05/06/2017] [Indexed: 01/09/2023]
Abstract
The complex interaction between cells undergoing transformation and the various stromal and immunological cell components of the tumor microenvironment (TME) crucially influences cancer progression and diversification, as well as endowing clinical and prognostic significance. The immunosuppression characterizing the TME depends on the recruitment and activation of different cell types including regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages. Less considered is the non-cellular component of the TME. Here, we focus on the extracellular matrix (ECM) regulatory activities that, within the TME, actively contribute to many aspects of tumor progression, acting on both tumor and immune cells. Particularly, ECM-mediated regulation of tumor-associated immunosuppression occurs through the modulation of myeloid cell expansion, localization, and functional activities. Such regulation is not limited to the TME but occurs also within the bone marrow, wherein matricellular proteins contribute to the maintenance of specialized hematopoietic stem cell niches thereby regulating their homeostasis as well as the generation and expansion of myeloid cells under both physiological and pathological conditions. Highlighting the commonalities among ECM-myeloid cell interactions in bone marrow and TME, in this review we present a picture in which myeloid cells might sense and respond to ECM modifications, providing different ECM-myeloid cell interfaces that may be useful to define prognostic groups and to tailor therapeutic interventions.
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Affiliation(s)
- Sabina Sangaletti
- Molecular Immunology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Amadeo, 42, 20133, Milan, Italy
| | - Claudia Chiodoni
- Molecular Immunology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Amadeo, 42, 20133, Milan, Italy
| | - Claudio Tripodo
- Tumor Immunology Unit, University of Palermo, Palermo, Italy
| | - Mario P Colombo
- Molecular Immunology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Amadeo, 42, 20133, Milan, Italy.
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13
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Masamoto Y, Arai S, Sato T, Kubota N, Takamoto I, Kadowaki T, Kurokawa M. Adiponectin Enhances Quiescence Exit of Murine Hematopoietic Stem Cells and Hematopoietic Recovery Through mTORC1 Potentiation. Stem Cells 2017; 35:1835-1848. [PMID: 28480607 DOI: 10.1002/stem.2640] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2016] [Revised: 04/11/2017] [Accepted: 04/25/2017] [Indexed: 01/19/2023]
Abstract
Myelotoxic injury, such as chemotherapeutic agents and ionizing radiation, unlocks the vigorous power of hematopoietic stem cells (HSCs) to replenish the hematopoietic system, making quiescent HSCs enter the cell cycle. Considering that both HSC-intrinsic and -extrinsic mechanisms enforce quiescence of HSCs, the drastic change in bone marrow (BM) environment after injury, represented by massive expansion of BM adipocytes, might trigger HSC activation. BM adipocytes, the major cellular component in the ablated marrow, however, reportedly suppress proliferation of hematopoietic cells, which may indicate the BM adipocytogenesis is an irrational response of injured organism. Given that adipose tissue is an endocrine organ with pleiotropic functions, we hypothesized that adipocyte-derived factors, especially adiponectin, an anti-inflammatory adipokine involved in regulation of granulopoiesis, are implicated in HSC activation. Myeloablative intervention increased BM adiponectin by multiple mechanisms, including adipocyte expansion and increased diffusion from the blood. Adiponectin-null (Adipoq -/- ) mice showed delayed hematopoietic recovery after BM injury, with Adipoq-/- HSCs more quiescent and defective in mammalian target of rapamycin complex 1 (mTORC1) activation. Recombinant adiponectin promoted not only HSC activation in vivo but cytokine-induced activation in vitro, and shortened the time for exit from quiescence in an mTORC1-dependent manner. These data illustrate a scarcely-reported example of a cell-extrinsic factor, adiponectin, enhancing quiescence exit of HSCs, and subsequent hematopoietic recovery. Our findings also highlight adipocytes as a source of adiponectin to ensure the proliferative burst of hematopoietic cells in ablated marrow. Stem Cells 2017;35:1835-1848.
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Affiliation(s)
- Yosuke Masamoto
- Department of Hematology & Oncology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.,Department of Transfusion Medicine, The University of Tokyo Hospital, Tokyo, Japan
| | - Shunya Arai
- Department of Hematology & Oncology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Tomohiko Sato
- Department of Hematology & Oncology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.,Department of Transfusion Medicine, The University of Tokyo Hospital, Tokyo, Japan
| | - Naoto Kubota
- Department of Diabetes & Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Iseki Takamoto
- Department of Diabetes & Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Takashi Kadowaki
- Department of Diabetes & Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Mineo Kurokawa
- Department of Hematology & Oncology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
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14
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p190-B RhoGAP and intracellular cytokine signals balance hematopoietic stem and progenitor cell self-renewal and differentiation. Nat Commun 2017; 8:14382. [PMID: 28176763 PMCID: PMC5309857 DOI: 10.1038/ncomms14382] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2015] [Accepted: 12/22/2016] [Indexed: 12/17/2022] Open
Abstract
The mechanisms regulating hematopoietic stem and progenitor cell (HSPC) fate choices remain ill-defined. Here, we show that a signalling network of p190-B RhoGAP-ROS-TGF-β-p38MAPK balances HSPC self-renewal and differentiation. Upon transplantation, HSPCs express high amounts of bioactive TGF-β1 protein, which is associated with high levels of p38MAPK activity and loss of HSC self-renewal in vivo. Elevated levels of bioactive TGF-β1 are associated with asymmetric fate choice in vitro in single HSPCs via p38MAPK activity and this is correlated with the asymmetric distribution of activated p38MAPK. In contrast, loss of p190-B, a RhoGTPase inhibitor, normalizes TGF-β levels and p38MAPK activity in HSPCs and is correlated with increased HSC self-renewal in vivo. Loss of p190-B also promotes symmetric retention of multi-lineage capacity in single HSPC myeloid cell cultures, further suggesting a link between p190-B-RhoGAP and non-canonical TGF-β signalling in HSPC differentiation. Thus, intracellular cytokine signalling may serve as ‘fate determinants' used by HSPCs to modulate their activity. The success of hematopoietic stem cell (HSC) transplantation relies on understanding what regulates the fate decision to self-renew. Here, the authors show using both in vitro assays and in vivo transplantation that loss of the RhoGAP p190-B enhances self-renewal by inhibiting TGFβ/p38 signalling.
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15
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Jung H, Kim DO, Byun JE, Kim WS, Kim MJ, Song HY, Kim YK, Kang DK, Park YJ, Kim TD, Yoon SR, Lee HG, Choi EJ, Min SH, Choi I. Thioredoxin-interacting protein regulates haematopoietic stem cell ageing and rejuvenation by inhibiting p38 kinase activity. Nat Commun 2016; 7:13674. [PMID: 27929088 PMCID: PMC5155146 DOI: 10.1038/ncomms13674] [Citation(s) in RCA: 56] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2016] [Accepted: 10/25/2016] [Indexed: 01/11/2023] Open
Abstract
Ageing is a natural process in living organisms throughout their lifetime, and most elderly people suffer from ageing-associated diseases. One suggested way to tackle such diseases is to rejuvenate stem cells, which also undergo ageing. Here we report that the thioredoxin-interacting protein (TXNIP)-p38 mitogen-activated protein kinase (p38) axis regulates the ageing of haematopoietic stem cells (HSCs), by causing a higher frequency of long-term HSCs, lineage skewing, a decrease in engraftment, an increase in reactive oxygen species and loss of Cdc42 polarity. TXNIP inhibits p38 activity via direct interaction in HSCs. Furthermore, cell-penetrating peptide (CPP)-conjugated peptide derived from the TXNIP-p38 interaction motif inhibits p38 activity via this docking interaction. This peptide dramatically rejuvenates aged HSCs in vitro and in vivo. Our findings suggest that the TXNIP-p38 axis acts as a regulatory mechanism in HSC ageing and indicate the potent therapeutic potential of using CPP-conjugated peptide to rejuvenate aged HSCs.
The processes regulating the ageing of stem cells are not clearly defined. Here, the authors report that in haematopoietic stem cells (HSC) thioredoxin-interacting protein, known to regulate the cell cycle, binds to p38 mitogen-activated protein kinase and regulates HSC ageing and rejuvenation.
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Affiliation(s)
- Haiyoung Jung
- Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Yuseong-gu, Daejeon 34141, Republic of Korea.,Department of Functional Genomics, University of Science and Technology, Yuseong-gu, Daejeon 34113, Republic of Korea
| | - Dong Oh Kim
- Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Yuseong-gu, Daejeon 34141, Republic of Korea.,Department of Functional Genomics, University of Science and Technology, Yuseong-gu, Daejeon 34113, Republic of Korea
| | - Jae-Eun Byun
- Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Yuseong-gu, Daejeon 34141, Republic of Korea.,Department of Biochemistry, School of Life Sciences, Chungbuk National University, Cheongju 28644, Republic of Korea
| | - Won Sam Kim
- Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Yuseong-gu, Daejeon 34141, Republic of Korea.,Department of Functional Genomics, University of Science and Technology, Yuseong-gu, Daejeon 34113, Republic of Korea
| | - Mi Jeong Kim
- Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Yuseong-gu, Daejeon 34141, Republic of Korea.,Department of Functional Genomics, University of Science and Technology, Yuseong-gu, Daejeon 34113, Republic of Korea
| | - Hae Young Song
- Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Yuseong-gu, Daejeon 34141, Republic of Korea
| | - Young Kwan Kim
- Scripps Korea Antibody Institute, 1 Kangwondaehak-gil, Chuncheon 24341, Republic of Korea
| | - Du-Kyeong Kang
- Bioenergy and Biochemical Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Republic of Korea
| | - Young-Jun Park
- Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Yuseong-gu, Daejeon 34141, Republic of Korea.,Department of Functional Genomics, University of Science and Technology, Yuseong-gu, Daejeon 34113, Republic of Korea
| | - Tae-Don Kim
- Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Yuseong-gu, Daejeon 34141, Republic of Korea.,Department of Functional Genomics, University of Science and Technology, Yuseong-gu, Daejeon 34113, Republic of Korea
| | - Suk Ran Yoon
- Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Yuseong-gu, Daejeon 34141, Republic of Korea.,Department of Functional Genomics, University of Science and Technology, Yuseong-gu, Daejeon 34113, Republic of Korea
| | - Hee Gu Lee
- Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Yuseong-gu, Daejeon 34141, Republic of Korea.,Department of Biomolecular Science, University of Science and Technology, Yuseong-gu, Daejeon 34113, Republic of Korea
| | - Eun-Ji Choi
- Department of Hematology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea
| | - Sang-Hyun Min
- New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation (DGMIF), 80 Chumbokro Dong-gu 41061, Daegu, Republic of Korea
| | - Inpyo Choi
- Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Yuseong-gu, Daejeon 34141, Republic of Korea.,Department of Functional Genomics, University of Science and Technology, Yuseong-gu, Daejeon 34113, Republic of Korea
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16
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Su JR, Kuai JH, Li YQ. Smoc2 potentiates proliferation of hepatocellular carcinoma cells via promotion of cell cycle progression. World J Gastroenterol 2016; 22:10053-10063. [PMID: 28018113 PMCID: PMC5143752 DOI: 10.3748/wjg.v22.i45.10053] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2016] [Revised: 09/07/2016] [Accepted: 10/26/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To determine the influence of Smoc2 on hepatocellular carcinoma (HCC) cell proliferation and to find a possible new therapeutic target for preventing HCC progression. METHODS We detected expression of Smoc2 in HCC tissues and corresponding non-tumor liver (CNL) tissues using PCR, western blot, and immunohistochemistry methods. Subsequently, we down-regulated and up-regulated Smoc2 expression using siRNA and lentivirus transfection assay, respectively. Then, we identified the effect of Smoc2 on cell proliferation and cell cycle using CCK-8 and flow cytometry, respectively. The common cell growth signaling influenced by Smoc2 was detected by western blot assay. RESULTS The expression of Smoc2 was significantly higher in HCC tissues compared with CNL tissues. Overexpression of Smoc2 promoted HCC cell proliferation and cell cycle progression. Down-regulation of Smoc2 led to inhibition of cell proliferation and cell cycle progression. Smoc2 had positive effect on ERK and AKT signaling. CONCLUSION Smoc2 promotes the proliferation of HCC cells through accelerating cell cycle progression and might act as an anti-cancer therapeutic target in the future.
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17
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Yi GZ, Liu YW, Xiang W, Wang H, Chen ZY, Xie SD, Qi ST. Akt and β-catenin contribute to TMZ resistance and EMT of MGMT negative malignant glioma cell line. J Neurol Sci 2016; 367:101-6. [PMID: 27423571 DOI: 10.1016/j.jns.2016.05.054] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2016] [Revised: 05/05/2016] [Accepted: 05/30/2016] [Indexed: 10/21/2022]
Abstract
Glioblastoma is one of the most lethal cancers in central nervous system, and some individual cells that cannot be isolated for surgical resection and also show treatment-resistance induce poor prognosis. Hence, in order to research these cells, we treated temozolomide (TMZ)-sensitive U87MG cells with 400μM TMZ in culture media for over 6months and established TMZ-resistant cell line designated as U87/TR. We detected the MGMT status through pyrosequencing and western blotting, and we also assessed the proliferation, migration, EMT-like changes and possible activated signaling pathways in U87/TR cells. Our results demonstrated that U87/TR was MGMT negative, which indicated that MGMT made no contribution for TMZ-resistance of U87/TR. And U87/TR cells displayed cell cycle arrest, higher capacity for migration and EMT-like changes including both phenotype and characteristic proteins. We also revealed that both β-catenin and the phosphorylation level of Akt and PRAS40 were increased in U87/TR, while we did not observe the phosphorylation of mTOR in U87/TR. It indicated that activation of Akt and Wnt/β-catenin pathways may be response for the chemo-resistance and increased invasion of U87/TR cells, and the phosphorylation of PRAS40 and inactivated mTOR may be related to cell cycle arrest in U87/TR cells.
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Affiliation(s)
- Guo-Zhong Yi
- Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Ya-Wei Liu
- Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; The Laboratory of Precision Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Wei Xiang
- Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Hai Wang
- Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Zi-Yang Chen
- Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Si-di Xie
- Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Song-Tao Qi
- Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; The Laboratory of Precision Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; Nanfang Glioma Center, Guangzhou 510515, China.
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18
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Figueiredo LM, Costa EBO, Orellana MD, Picanço-Castro V, Covas DT. OP9 Stromal Cells Proteins Involved in Hematoendothelial Differentiation from Human Embryonic Stem Cells. Cell Reprogram 2015; 17:338-46. [PMID: 26295456 DOI: 10.1089/cell.2015.0014] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Abstract
Hematopoietic cells (HCs) and endothelial cells (ECs) can be produced in vitro from human embryonic stem cells (hESCs), but the differentiation systems used are still inefficient. To overcome this obstacle, it is necessary to understand the differentiation process. One of the methods used to obtain HCs and ECs from hESCs is their co-culture with stromal cells. The soluble factors secreted by these cells and cell-cell contact have a great impact on the differentiation process. Here, we performed comparative proteomic analyses of proteins obtained from the total extract of OP9 stromal cells and secreted by these cells before and during in vitro generation of HCs and ECs (hematoendothelial) from hESCs. We identified a total of 83 secreted and 759 intracellular proteins during differentiation. Twenty-five secreted and 181 proteins from the total extract were more abundant. Some secreted proteins are involved in cell-matrix interactions and HC and/or EC development. Moreover, 13 proteins of the total extract from OP9 cells that were exclusive/or more abundant during differentiation are involved in the Nrf2/Nfe2l2 gene pathway, that is, they are described to have a key role in oxidative stress and in hematopoietic development and maturation. Our proteomic profiles provide valuable insight about the proteins involved in in vitro hematoendothelial cell generation and in the future they might be used to optimize the differentiation process and produce both cell types in vitro.
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Affiliation(s)
- Lilian M Figueiredo
- 1 Department of Clinical Medicine/Ribeirão Preto Medical School, University of São Paulo , Brazil , 14040-900.,2 Center for Cell-based Therapy and Regional Blood Center , Ribeirão Preto, Brazil , 14051-140
| | - Everton B O Costa
- 1 Department of Clinical Medicine/Ribeirão Preto Medical School, University of São Paulo , Brazil , 14040-900.,2 Center for Cell-based Therapy and Regional Blood Center , Ribeirão Preto, Brazil , 14051-140
| | - Maristela D Orellana
- 1 Department of Clinical Medicine/Ribeirão Preto Medical School, University of São Paulo , Brazil , 14040-900.,2 Center for Cell-based Therapy and Regional Blood Center , Ribeirão Preto, Brazil , 14051-140
| | - Virginia Picanço-Castro
- 1 Department of Clinical Medicine/Ribeirão Preto Medical School, University of São Paulo , Brazil , 14040-900.,2 Center for Cell-based Therapy and Regional Blood Center , Ribeirão Preto, Brazil , 14051-140
| | - Dimas T Covas
- 1 Department of Clinical Medicine/Ribeirão Preto Medical School, University of São Paulo , Brazil , 14040-900.,2 Center for Cell-based Therapy and Regional Blood Center , Ribeirão Preto, Brazil , 14051-140
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19
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Blogowski W, Dolegowska K, Deskur A, Dolegowska B, Starzyńska T. An Attempt to Evaluate Selected Aspects of "Bone-Fat Axis" Function in Healthy Individuals and Patients With Pancreatic Cancer. Medicine (Baltimore) 2015; 94:e1303. [PMID: 26266370 PMCID: PMC4616689 DOI: 10.1097/md.0000000000001303] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Abstract
Recently, much attention has been paid to a potential biochemical cross-talk between the metabolism of the adipose tissue (AT) and bone (marrow), termed "bone-fat axis." We hypothesized that selected substances, participating in this "dialog," are associated with body mass and peripheral trafficking of bone marrow-derived stem cells (BMSCs) in both healthy individuals and patients with obesity-associated malignancies such as pancreatic adenocarcinoma.We performed an analysis of the systemic levels of selected substances involved in the regulation of bone (marrow) homeostasis (parathormone, calcitonin, osteopontin, osteonectin, stem cell factor [SCF], and fibroblast growth factor-23) in 35 generally healthy volunteers and 35 patients with pancreatic cancer. Results were correlated with the absolute number of circulating BMSCs and body mass values. Additionally, subcutaneous and visceral/omental AT levels of the aforementioned molecules were analyzed in lean and overweight/obese individuals.Intensified steady-state trafficking of only Lin-CD45 + CD133 + hematopoietic stem/progenitor cells was observed in overweight/obese individuals and this was associated with BMI values and elevated levels of both osteonectin and SCF, which also correlated with BMI. In comparison to healthy individuals, patients with cancer had significantly higher osteopontin levels and lower values of both osteonectin and osteonectin/osteopontin ratio. While no significant correlation was observed between BMI and the number of circulating BMSCs in patients with cancer, peripheral trafficking of CD34 + KDR + CD31 + CD45-endothelial progenitor cells and CD105 + STRO-1 + CD45-mesenchymal stem cells was associated with the osteonectin/osteopontin ratio, which also correlated with BMI (r = 0.52; P < 0.05). AT levels of the examined substances were similar to those measured in the plasma, except for osteonectin, which was about 10 times lower.Our study highlights the potential role of osteonectin, osteopontin, and SCF as communication signals between the bone (marrow) and AT in both healthy individuals and patients with pancreatic cancer. We postulate that these molecules may be overlooked biochemical players linking body mass and BMSCs with obesity-associated cancer development and/or progression in humans.
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Affiliation(s)
- Wojciech Blogowski
- From the Department of Internal Medicine, University of Zielona Góra, Zielona Góra, Poland (WB); Department of Laboratory Diagnostics and Molecular Medicine, Pomeranian Medical University, Szczecin, Poland (KD); Department of Gastroenterology, Pomeranian Medical University, Szczecin, Poland (AD); Department of Microbiology and Immunological Diagnostics, Pomeranian Medical University in Szczecin, Szczecin, Poland (BD); and Department of Gastroenterology and Internal Medicine, Warsaw Medical University, Warsaw, Poland (TS)
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Abstract
PURPOSE OF REVIEW Much effort has been devoted to determining how cellular and noncellular components of the tumoral niche initiate and promote cancer development. Cancer cells perceive biochemical signals from components of the extracellular matrix (ECM) and sense physical features, such as matrix stiffness and cell confinement. The past decade has seen a better understanding of the biophysics and mechanobiology associated with cancer cells. Indeed, loss of mechanisms controlling the production, the degradation, and the remodeling of ECM contributes to tumor growth or cell dissemination by affecting cell contractility in response to ECM stiffness and by stimulating mechanical dependence of growth factor activation. RESULTS Cell plasticity allows adaptative strategies for cancer cells to survive or eventually escape from tumoral environment through modification of the microenvironment-cell interface, internal tension increase, and nuclear deformation partly leading to intratumoral heterogeneity. However, although alteration of the biomechanical properties of the ECM are sufficient to promote cell migration and invasion in cancer cells, this microenvironment can also provide a hospitable niche for tumor dormancy and resistance to cancer therapy. CONCLUSION The review will focus on how physicochemical properties of ECM might promote tumor growth or cell dissemination or on the contrary maintain quiescent state of cancer cells. It is crucial to clarify the molecular basis of mechanotransduction in the development and progression of tumors to identify new potential biomarkers and anticancer therapeutic targets.
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21
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Maguire G, Friedman P. Systems biology approach to developing S 2RM-based “systems therapeutics” and naturally induced pluripotent stem cells. World J Stem Cells 2015; 7:745-756. [PMID: 26029345 PMCID: PMC4444614 DOI: 10.4252/wjsc.v7.i4.745] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2014] [Revised: 11/25/2014] [Accepted: 03/18/2015] [Indexed: 02/06/2023] Open
Abstract
The degree to, and the mechanisms through, which stem cells are able to build, maintain, and heal the body have only recently begun to be understood. Much of the stem cell’s power resides in the release of a multitude of molecules, called stem cell released molecules (SRM). A fundamentally new type of therapeutic, namely “systems therapeutic”, can be realized by reverse engineering the mechanisms of the SRM processes. Recent data demonstrates that the composition of the SRM is different for each type of stem cell, as well as for different states of each cell type. Although systems biology has been successfully used to analyze multiple pathways, the approach is often used to develop a small molecule interacting at only one pathway in the system. A new model is emerging in biology where systems biology is used to develop a new technology acting at multiple pathways called “systems therapeutics”. A natural set of healing pathways in the human that uses SRM is instructive and of practical use in developing systems therapeutics. Endogenous SRM processes in the human body use a combination of SRM from two or more stem cell types, designated as S2RM, doing so under various state dependent conditions for each cell type. Here we describe our approach in using state-dependent SRM from two or more stem cell types, S2RM technology, to develop a new class of therapeutics called “systems therapeutics.” Given the ubiquitous and powerful nature of innate S2RM-based healing in the human body, this “systems therapeutic” approach using S2RM technology will be important for the development of anti-cancer therapeutics, antimicrobials, wound care products and procedures, and a number of other therapeutics for many indications.
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Brenet F, Scandura JM. Cutting the brakes on hematopoietic regeneration by blocking TGFβ to limit chemotherapy-induced myelosuppression. Mol Cell Oncol 2015; 2:e978703. [PMID: 27308454 PMCID: PMC4905289 DOI: 10.4161/23723556.2014.978703] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2014] [Revised: 10/14/2014] [Accepted: 10/15/2014] [Indexed: 01/17/2023]
Abstract
Hematopoietic stressors such as infection, bleeding, or toxic injury trigger a hematopoietic adaptation that sacrifices hematopoietic stem and progenitor cell (HSPC) quiescence to meet an urgent need for new blood cell production. Once the hematopoietic demands are adequately met, homeostasis must be restored. Transforming growth factor β (TGFβ) signaling is a central mediator mandating the return of HSPCs to quiescence after stress. Blockade of TGFβ signaling after hematopoietic stress delays the return of cycling HSPCs to quiescence and in so doing promotes hematopoietic stem cell (HSC) self-renewal and accelerates hematopoietic reconstitution. These findings open the door to new therapeutics that modulate the hematopoietic adaptation to stress. In this review, we will discuss the complex context-dependent activities of TGFβ in hematopoiesis and the potential benefits and limitations of using TGFβ pathway inhibitors to promote multilineage hematopoietic reconstitution after myelosuppressive chemotherapy.
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Affiliation(s)
- Fabienne Brenet
- Inserm U1068, Centre de Recherche en Cancérologie de Marseille (CRCM), Signaling, Hematopoiesis and Mechanisms of Oncogenesis; Institut Paoli-Calmettes; Aix-Marseille Université UM 105, CNRS UMR 7258 ; Marseille, France
| | - Joseph M Scandura
- Department of Medicine; Divisions of Hematology-Oncology and Regenerative Medicine; Laboratory of Molecular Hematopoiesis; Weill Cornell Medical College; New York, NY; Weill Cornell Medical College; Regenerative Medicine, Laboratory of Molecular Hematopoiesis; New York, NY USA
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