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1
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Zhou H, Xu H, Pang S, An L, Shi G, Wang C, Zhang P, Fan X, Yang J, Tang S, Lu Y, Yu L, Chen F, Ma R. Comparison of functional characterization of cancer stem cells in different tumor tissues of pseudomyxoma peritonei. J Transl Med 2024; 22:1022. [PMID: 39543711 PMCID: PMC11566827 DOI: 10.1186/s12967-024-05730-6] [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: 03/17/2024] [Accepted: 10/06/2024] [Indexed: 11/17/2024] Open
Abstract
BACKGROUND Pseudomyxoma peritonei (PMP) is a rare malignant peritoneal tumor that readily recurs and metastasizes. Studies have shown that cancer stem cells (CSCs) play an important role in tumor recurrence, metastasis, and prognosis. OBJECTIVE In this study, our aim was to isolate CSCs from various tissues of PMP patients and compare their proliferation, migration, and anti-inflammatory abilities. METHODS We identified CSCs subsets with markers CD133+, CD166+, and CD133+/CD166+ at the gene level using single-cell mRNA sequencing (scRNA-seq). Appendiceal CSCs (AC), peritoneal CSCs (PC), and mucous CSCs (MC) were obtained using MACSQuant Tyto sorting technology and FlowSight imaging flow cytometry. The cells were cultured and markers were identified. Finally, the functional phenotypes of the three cell types were compared. RESULTS CSCs content was highest in the appendiceal tumor tissue and lowest in the mucous tissue. The cell viability rate of the sorted CSCs was above 98%, and the positive rate of CD133+ and CD166+ was 70-80%, and CD133+/CD166+ was about 30%. Among the three types of CSCs, MC had the highest proliferation ability, and TNF-α has the greatest inhibitory effect on AC migration. CONCLUSION AC in patients was more inert and anti-inflammatory, whereas abdominal cavity MC and PC were more active. This study revealed the biological characteristics of CSCs in different tumor tissues of patients with PMP, providing a reference for future targeted CSCs therapy.
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Affiliation(s)
- Haipeng Zhou
- Department of Myxoma, Aerospace Center Hospital, Beijing, 100049, China
| | - Hongbin Xu
- Department of Myxoma, Aerospace Center Hospital, Beijing, 100049, China
| | - Shaojun Pang
- Department of Myxoma, Aerospace Center Hospital, Beijing, 100049, China
| | - Lubiao An
- Department of Myxoma, Aerospace Center Hospital, Beijing, 100049, China
| | - Guanjun Shi
- Department of Myxoma, Aerospace Center Hospital, Beijing, 100049, China
| | - Chong Wang
- Department of Myxoma, Aerospace Center Hospital, Beijing, 100049, China
| | - Pu Zhang
- Department of Myxoma, Aerospace Center Hospital, Beijing, 100049, China
| | - Xiwen Fan
- Department of Myxoma, Aerospace Center Hospital, Beijing, 100049, China
| | - Jing Yang
- Space Medical Center, Aerospace Center Hospital, Beijing, 100049, China
| | - Shiyi Tang
- Space Medical Center, Aerospace Center Hospital, Beijing, 100049, China
| | - Yiyan Lu
- Department of Pathology, Aerospace Center Hospital, Beijing, 100049, China
| | - Lifei Yu
- Department of Myxoma, Aerospace Center Hospital, Beijing, 100049, China
| | - Feng Chen
- Department of Myxoma, Aerospace Center Hospital, Beijing, 100049, China
| | - Ruiqing Ma
- Department of Myxoma, Aerospace Center Hospital, Beijing, 100049, China.
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2
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Soundararajan L, Warrier S, Dharmarajan A, Bhaskaran N. Predominant factors influencing reactive oxygen species in cancer stem cells. J Cell Biochem 2024; 125:3-21. [PMID: 37997702 DOI: 10.1002/jcb.30506] [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: 08/19/2023] [Revised: 10/17/2023] [Accepted: 11/09/2023] [Indexed: 11/25/2023]
Abstract
Reactive oxygen species (ROS) and its related signaling pathways and regulating molecules play a major role in the growth and development of cancer stem cells. The concept of ROS and cancer stem cells (CSCs) has been gaining much attention since the past decade and the evidence show that these CSCs possess robust self-renewal and tumorigenic potential and are resistant to conventional chemo- and radiotherapy and believed to be responsible for tumor progression, metastasis, and recurrence. It seems reasonable to say that cancer can be cured only if the CSCs are eradicated. ROS are Janus-faced molecules that can regulate cellular physiology as well as induce cytotoxicity, depending on the magnitude, duration, and site of generation. Unlike normal cancer cells, CSCs expel ROS efficiently by upregulating ROS scavengers. This unique redox regulation in CSCs protects them from ROS-mediated cell death and nullifies the effect of radiation, leading to chemoresistance and radioresistance. However, how these CSCs control ROS production by scavenging free radicals and how they maintain low levels of ROS is a challenging to understand and these attributes make CSCs as prime therapeutic targets. Here, we summarize the mechanisms of redox regulation in CSCs, with a focus on therapy resistance, its various pathways and microRNAs regulation, and the potential therapeutic implications of manipulating the ROS levels to eradicate CSCs. A better understanding of these molecules, their interactions in the CSCs may help us to adopt proper control and treatment measures.
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Affiliation(s)
- Loshini Soundararajan
- Manipal Institute of Regenerative Medicine, Manipal Academy of Higher Education (MAHE), Bangalore, Karnataka, India
| | - Sudha Warrier
- Manipal Institute of Regenerative Medicine, Manipal Academy of Higher Education (MAHE), Bangalore, Karnataka, India
- Division of Cancer Stem Cells and Cardiovascular Regeneration, Manipal Institute of Regenerative Medicine, Manipal Academy of Higher Education, Bangalore, Karnataka, India
- Cuor Stem Cellutions Pvt Ltd., Manipal Institute of Regenerative Medicine, Manipal Academy of Higher Education, Bangalore, Karnataka, India
- Department of Biotechnology, Sri Ramachandra Institute of Higher Education and Research, Faculty of Biomedical Sciences and Technology, Chennai, Tamil Nādu, India
| | - Arun Dharmarajan
- Department of Biomedical Sciences, Sri Ramachandra Institute of Higher Education and Research (SRIHER), Faculty of Biomedical Sciences and Technology, Chennai, Tamil Nādu, India
- Stem Cell and Cancer Biology laboratory, Curtin University, Perth, Western Australia, Australia
- School of Pharmacy and Biomedical Sciences, Curtin University, Perth, Western Australia, Australia
- Curtin Health and Innovation Research Institute, Curtin University, Perth, Western Australia, Australia
- School of Human Sciences, University of Western Australia, Perth, Western Australia, Australia
| | - Natarajan Bhaskaran
- Department of Biomedical Sciences, Sri Ramachandra Institute of Higher Education and Research (SRIHER), Faculty of Biomedical Sciences and Technology, Chennai, Tamil Nādu, India
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3
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Xu J, Zhou L, Du X, Qi Z, Chen S, Zhang J, Cao X, Xia J. Transcriptome and Lipidomic Analysis Suggests Lipid Metabolism Reprogramming and Upregulating SPHK1 Promotes Stemness in Pancreatic Ductal Adenocarcinoma Stem-like Cells. Metabolites 2023; 13:1132. [PMID: 37999228 PMCID: PMC10673379 DOI: 10.3390/metabo13111132] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Revised: 10/27/2023] [Accepted: 11/02/2023] [Indexed: 11/25/2023] Open
Abstract
Cancer stem cells (CSCs) are considered to play a key role in the development and progression of pancreatic ductal adenocarcinoma (PDAC). However, little is known about lipid metabolism reprogramming in PDAC CSCs. Here, we assigned stemness indices, which were used to describe and quantify CSCs, to every patient from the Cancer Genome Atlas (TCGA-PAAD) database and observed differences in lipid metabolism between patients with high and low stemness indices. Then, tumor-repopulating cells (TRCs) cultured in soft 3D (three-dimensional) fibrin gels were demonstrated to be an available PDAC cancer stem-like cell (CSLCs) model. Comprehensive transcriptome and lipidomic analysis results suggested that fatty acid metabolism, glycerophospholipid metabolism, and, especially, the sphingolipid metabolism pathway were mostly associated with CSLCs properties. SPHK1 (sphingosine kinases 1), one of the genes involved in sphingolipid metabolism and encoding the key enzyme to catalyze sphingosine to generate S1P (sphingosine-1-phosphate), was identified to be the key gene in promoting the stemness of PDAC. In summary, we explored the characteristics of lipid metabolism both in patients with high stemness indices and in novel CSLCs models, and unraveled a molecular mechanism via which sphingolipid metabolism maintained tumor stemness. These findings may contribute to the development of a strategy for targeting lipid metabolism to inhibit CSCs in PDAC treatment.
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Affiliation(s)
- Jinzhi Xu
- National Medical Center and National Clinical Research Center for Interventional Medicine, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, China
| | - Lina Zhou
- CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China
| | - Xiaojing Du
- Endoscopy Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
| | - Zhuoran Qi
- National Medical Center and National Clinical Research Center for Interventional Medicine, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, China
| | - Sinuo Chen
- National Medical Center and National Clinical Research Center for Interventional Medicine, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, China
| | - Jian Zhang
- National Medical Center and National Clinical Research Center for Interventional Medicine, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, China
| | - Xin Cao
- National Medical Center and National Clinical Research Center for Interventional Medicine, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, China
- Institute of Clinical Science, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Jinglin Xia
- National Medical Center and National Clinical Research Center for Interventional Medicine, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, China
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
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4
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Ogunleye AO, Nimmakayala RK, Batra SK, Ponnusamy MP. Metabolic Rewiring and Stemness: A Critical Attribute of Pancreatic Cancer Progression. Stem Cells 2023; 41:417-430. [PMID: 36869789 PMCID: PMC10183971 DOI: 10.1093/stmcls/sxad017] [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: 11/11/2022] [Accepted: 01/30/2023] [Indexed: 03/05/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive diseases with a poor 5-year survival rate. PDAC cells rely on various metabolic pathways to fuel their unlimited proliferation and metastasis. Reprogramming glucose, fatty acid, amino acid, and nucleic acid metabolisms contributes to PDAC cell growth. Cancer stem cells are the primary cell types that play a critical role in the progression and aggressiveness of PDAC. Emerging studies indicate that the cancer stem cells in PDAC tumors are heterogeneous and show specific metabolic dependencies. In addition, understanding specific metabolic signatures and factors that regulate these metabolic alterations in the cancer stem cells of PDAC paves the way for developing novel therapeutic strategies targeting CSCs. In this review, we discuss the current understanding of PDAC metabolism by specifically exploring the metabolic dependencies of cancer stem cells. We also review the current knowledge of targeting these metabolic factors that regulate CSC maintenance and PDAC progression.
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Affiliation(s)
- Ayoola O Ogunleye
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Rama Krishna Nimmakayala
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Surinder K Batra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
- Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA
| | - Moorthy P Ponnusamy
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
- Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA
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5
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Kuo YC, Kou HW, Hsu CP, Lo CH, Hwang TL. Identification and Clinical Significance of Pancreatic Cancer Stem Cells and Their Chemotherapeutic Drug Resistance. Int J Mol Sci 2023; 24:ijms24087331. [PMID: 37108495 PMCID: PMC10138402 DOI: 10.3390/ijms24087331] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Revised: 04/07/2023] [Accepted: 04/12/2023] [Indexed: 04/29/2023] Open
Abstract
Pancreatic cancer ranks in the 10th-11th position among cancers affecting men in Taiwan, besides being a rather difficult-to-treat disease. The overall 5-year survival rate of pancreatic cancer is only 5-10%, while that of resectable pancreatic cancer is still approximately 15-20%. Cancer stem cells possess intrinsic detoxifying mechanisms that allow them to survive against conventional therapy by developing multidrug resistance. This study was conducted to investigate how to overcome chemoresistance and its mechanisms in pancreatic cancer stem cells (CSCs) using gemcitabine-resistant pancreatic cancer cell lines. Pancreatic CSCs were identified from human pancreatic cancer lines. To determine whether CSCs possess a chemoresistant phenotype, the sensitivity of unselected tumor cells, sorted CSCs, and tumor spheroid cells to fluorouracil (5-FU), gemcitabine (GEM), and cisplatin was analyzed under stem cell conditions or differentiating conditions. Although the mechanisms underlying multidrug resistance in CSCs are poorly understood, ABC transporters such as ABCG2, ABCB1, and ABCC1 are believed to be responsible. Therefore, we measured the mRNA expression levels of ABCG2, ABCB1, and ABCC1 by real-time RT-PCR. Our results showed that no significant differences were found in the effects of different concentrations of gemcitabine on CSCs CD44+/EpCAM+ of various PDAC cell line cultures (BxPC-3, Capan-1, and PANC-1). There was also no difference between CSCs and non-CSCs. Gemcitabine-resistant cells exhibited distinct morphological changes, including a spindle-shaped morphology, the appearance of pseudopodia, and reduced adhesion characteristics of transformed fibroblasts. These cells were found to be more invasive and migratory, and showed increased vimentin expression and decreased E-cadherin expression. Immunofluorescence and immunoblotting experiments demonstrated increased nuclear localization of total β-catenin. These alterations are hallmarks of epithelial-to-mesenchymal transition (EMT). Resistant cells showed activation of the receptor protein tyrosine kinase c-Met and increased expression of the stem cell marker cluster of differentiation (CD) 24, CD44, and epithelial specific antigen (ESA). We concluded that the expression of the ABCG2 transporter protein was significantly higher in CD44+ and EpCAM+ CSCs of PDAC cell lines. Cancer stem-like cells exhibited chemoresistance. Gemcitabine-resistant pancreatic tumor cells were associated with EMT, a more aggressive and invasive phenotype of numerous solid tumors. Increased phosphorylation of c-Met may also be related to chemoresistance, and EMT and could be used as an attractive adjunctive chemotherapeutic target in pancreatic cancer.
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Affiliation(s)
- Yu-Chi Kuo
- Department of Surgery, Chang Gung Memorial Hospital, Chang Gung University, Lin-Kou, Taoyuan 333, Taiwan
| | - Hao-Wei Kou
- Department of Surgery, Chang Gung Memorial Hospital, Chang Gung University, Lin-Kou, Taoyuan 333, Taiwan
| | - Chih-Po Hsu
- Department of Surgery, Chang Gung Memorial Hospital, Chang Gung University, Lin-Kou, Taoyuan 333, Taiwan
| | - Chih-Hong Lo
- Department of Surgery, Chang Gung Memorial Hospital, Chang Gung University, Lin-Kou, Taoyuan 333, Taiwan
| | - Tsann-Long Hwang
- Department of Surgery, Chang Gung Memorial Hospital, Chang Gung University, Lin-Kou, Taoyuan 333, Taiwan
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6
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Kaur K, Jewett A. Supercharged NK Cell-Based Immuotherapy in Humanized Bone Marrow Liver and Thymus (Hu-BLT) Mice Model of Oral, Pancreatic, Glioblastoma, Hepatic, Melanoma and Ovarian Cancers. Crit Rev Immunol 2023; 43:13-25. [PMID: 37938193 DOI: 10.1615/critrevimmunol.2023050618] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2023]
Abstract
In this paper, we review a number of in vitro and in vivo studies regarding the efficacy of supercharged NK (sNK) cell therapy in elimination or treatment of cancer. We have performed studies using six different types of cancer models of oral, pancreatic, glioblastoma, melanoma, hepatic and ovarian cancers using hu-BLT mice. Our in vitro studies demonstrated that primary NK cells preferentially target cancer stem-like cells (CSCs)/poorly differentiated tumors whereas sNK cells target both CSCs/poorly-differentiated and well-differentiated tumors significantly higher than primary activated NK cells. Our in vivo studies in humanized-BLT mice showed that sNK cells alone or in combination with other cancer therapeutics prevented tumor growth and metastasis. In addition, sNK cells were able to increase IFN-γ secretion and cytotoxic function by the immune cells in bone marrow, spleen, gingiva, pancreas and peripheral blood. Furthermore, sNK cells were able to increase the expansion and function of CD8+ T cells both in in vitro and in vivo studies. Overall, our studies demonstrated that sNK cells alone or in combination with other cancer therapeutics were not only effective against eliminating aggressive cancers, but were also able to increase the expansion and function of CD8+ T cells to further target cancer cells, providing a successful approach to eradicate and cure cancer.
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Affiliation(s)
- Kawaljit Kaur
- Division of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, University of California School of Dentistry, 10833 Le Conte Ave, 90095 Los Angeles, CA, USA
| | - Anahid Jewett
- Division of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, University of California School of Dentistry, 10833 Le Conte Ave, 90095 Los Angeles, CA, USA; The Jonsson Comprehensive Cancer Center, UCLA School of Dentistry and Medicine, Los Angeles, CA, USA
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7
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Moreira-Barbosa C, Matos A, Fernandes R, Mendes-Ferreira M, Rodrigues R, Cruz T, Costa ÂM, Cardoso AP, Ghilardi C, Oliveira MJ, Ribeiro R. The role of fatty acids metabolism on cancer progression and therapeutics development. BIOACTIVE LIPIDS 2023:101-132. [DOI: 10.1016/b978-0-12-824043-4.00007-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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8
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Jang G, Oh J, Jun E, Lee J, Kwon JY, Kim J, Lee SH, Kim SC, Cho SY, Lee C. Direct cell-to-cell transfer in stressed tumor microenvironment aggravates tumorigenic or metastatic potential in pancreatic cancer. NPJ Genom Med 2022; 7:63. [PMID: 36302783 PMCID: PMC9613679 DOI: 10.1038/s41525-022-00333-w] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Accepted: 10/11/2022] [Indexed: 11/09/2022] Open
Abstract
Pancreatic cancer exhibits a characteristic tumor microenvironment (TME) due to enhanced fibrosis and hypoxia and is particularly resistant to conventional chemotherapy. However, the molecular mechanisms underlying TME-associated treatment resistance in pancreatic cancer are not fully understood. Here, we developed an in vitro TME mimic system comprising pancreatic cancer cells, fibroblasts and immune cells, and a stress condition, including hypoxia and gemcitabine. Cells with high viability under stress showed evidence of increased direct cell-to-cell transfer of biomolecules. The resulting derivative cells (CD44high/SLC16A1high) were similar to cancer stem cell-like-cells (CSCs) with enhanced anchorage-independent growth or invasiveness and acquired metabolic reprogramming. Furthermore, CD24 was a determinant for transition between the tumorsphere formation or invasive properties. Pancreatic cancer patients with CD44low/SLC16A1low expression exhibited better prognoses compared to other groups. Our results suggest that crosstalk via direct cell-to-cell transfer of cellular components foster chemotherapy-induced tumor evolution and that targeting of CD44 and MCT1(encoded by SLC16A1) may be useful strategy to prevent recurrence of gemcitabine-exposed pancreatic cancers.
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Affiliation(s)
- Giyong Jang
- Department of Life Science, Ewha Womans University, Seoul, 03760, Republic of Korea.,Ewha-JAX Cancer Immunotherapy Research Center, Ewha Womans University, Seoul, 03760, Republic of Korea.,Medical Research Center, Genomic Medicine Institute, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea
| | - Jaeik Oh
- Department of Translational Medicine, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea.,Department of Internal Medicine, Seoul National University Hospital, Seoul, 03080, Republic of Korea
| | - Eunsung Jun
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea.,Asan Medical Institute of Convergence Science and Technology (AMIST), Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea.,Department of Convergence Medicine, Asan Institute for Life Sciences, University of Ulsan College of Medicine and Asan Medical Center, Seoul, 05505, Republic of Korea
| | - Jieun Lee
- Department of Life Science, Ewha Womans University, Seoul, 03760, Republic of Korea.,Ewha-JAX Cancer Immunotherapy Research Center, Ewha Womans University, Seoul, 03760, Republic of Korea.,Department of Surgery, Seoul National University Bundang Hospital, Gyeonggi-do, 13620, Republic of Korea
| | - Jee Young Kwon
- Department of Life Science, Ewha Womans University, Seoul, 03760, Republic of Korea.,Ewha-JAX Cancer Immunotherapy Research Center, Ewha Womans University, Seoul, 03760, Republic of Korea.,The Jackson Laboratory for Genomic Medicine, Farmington, CT, 06032, USA
| | - Jaesang Kim
- Department of Life Science, Ewha Womans University, Seoul, 03760, Republic of Korea.,Ewha-JAX Cancer Immunotherapy Research Center, Ewha Womans University, Seoul, 03760, Republic of Korea
| | - Sang-Hyuk Lee
- Department of Life Science, Ewha Womans University, Seoul, 03760, Republic of Korea.,Ewha-JAX Cancer Immunotherapy Research Center, Ewha Womans University, Seoul, 03760, Republic of Korea.,Department of Bio-Information Science, Ewha Womans University, Seoul, 03760, Republic of Korea
| | - Song Cheol Kim
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea.,Asan Medical Institute of Convergence Science and Technology (AMIST), Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea.,Department of Convergence Medicine, Asan Institute for Life Sciences, University of Ulsan College of Medicine and Asan Medical Center, Seoul, 05505, Republic of Korea
| | - Sung-Yup Cho
- Medical Research Center, Genomic Medicine Institute, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea. .,Department of Translational Medicine, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea. .,Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea. .,Cancer Research Institute, Seoul National University, Seoul, 03080, Republic of Korea.
| | - Charles Lee
- Department of Life Science, Ewha Womans University, Seoul, 03760, Republic of Korea. .,Ewha-JAX Cancer Immunotherapy Research Center, Ewha Womans University, Seoul, 03760, Republic of Korea. .,The Jackson Laboratory for Genomic Medicine, Farmington, CT, 06032, USA.
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9
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Xiao C, Wu G, Chen P, Gao L, Chen G, Zhang H. Phase separation in epigenetics and cancer stem cells. Front Oncol 2022; 12:922604. [PMID: 36081552 PMCID: PMC9445202 DOI: 10.3389/fonc.2022.922604] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Accepted: 07/25/2022] [Indexed: 12/12/2022] Open
Abstract
Accumulating evidence indicates that liquid–liquid phase separation (LLPS) is the basis of the formation of membrane-less compartments in cells. This biomolecular condensate represented by phase separation may influence epigenetics in cancer stem cells (CSCs), a small subpopulation of cancer cells responding to the initiation, maintenance, metastasis, and therapy resistance of cancer. Understanding the underlying biophysical principles and the specific characteristics of biocondensates would provide insights into the precise blocking of potential tumor targets, thereby fundamentally curbing tumor occurrence, recurrence and metastasis. In this review, we summarized the key phenomenon and experimental detection of phase separation and the possibility of regulating the stemness of CSCs through phase separation. We believe that the mechanism of phase separation in CSCs will open up new avenues for the mystery of tumor formation, and modulating phase separation will be a great strategy for CSC-targeted tumor therapy.
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Affiliation(s)
- Chanchan Xiao
- Department of Microbiology and Immunology, School of Medicine, Jinan University, Guangzhou, China
- Institute of Geriatric Immunology, School of Medicine, Jinan University, Guangzhou, China
- Guangdong-Hongkong-Macao Great Bay Area Geroscience Joint Laboratory (GBGJL), School of Medicine, Jinan University, Guangzhou, China
| | - Guangjie Wu
- Department of Microbiology and Immunology, School of Medicine, Jinan University, Guangzhou, China
- Institute of Geriatric Immunology, School of Medicine, Jinan University, Guangzhou, China
- Guangdong-Hongkong-Macao Great Bay Area Geroscience Joint Laboratory (GBGJL), School of Medicine, Jinan University, Guangzhou, China
| | - Pengfei Chen
- Department of Microbiology and Immunology, School of Medicine, Jinan University, Guangzhou, China
- Institute of Geriatric Immunology, School of Medicine, Jinan University, Guangzhou, China
- Guangdong-Hongkong-Macao Great Bay Area Geroscience Joint Laboratory (GBGJL), School of Medicine, Jinan University, Guangzhou, China
| | - Lijuan Gao
- Department of Microbiology and Immunology, School of Medicine, Jinan University, Guangzhou, China
- Institute of Geriatric Immunology, School of Medicine, Jinan University, Guangzhou, China
- Guangdong-Hongkong-Macao Great Bay Area Geroscience Joint Laboratory (GBGJL), School of Medicine, Jinan University, Guangzhou, China
- *Correspondence: Lijuan Gao, ; Guobing Chen, ; Hongyi Zhang,
| | - Guobing Chen
- Department of Microbiology and Immunology, School of Medicine, Jinan University, Guangzhou, China
- Institute of Geriatric Immunology, School of Medicine, Jinan University, Guangzhou, China
- Guangdong-Hongkong-Macao Great Bay Area Geroscience Joint Laboratory (GBGJL), School of Medicine, Jinan University, Guangzhou, China
- *Correspondence: Lijuan Gao, ; Guobing Chen, ; Hongyi Zhang,
| | - Hongyi Zhang
- Department of Microbiology and Immunology, School of Medicine, Jinan University, Guangzhou, China
- Institute of Geriatric Immunology, School of Medicine, Jinan University, Guangzhou, China
- Guangdong-Hongkong-Macao Great Bay Area Geroscience Joint Laboratory (GBGJL), School of Medicine, Jinan University, Guangzhou, China
- *Correspondence: Lijuan Gao, ; Guobing Chen, ; Hongyi Zhang,
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10
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Daley D. The Role of the Microbiome in Pancreatic Oncogenesis. Int Immunol 2022; 34:447-454. [PMID: 35863313 DOI: 10.1093/intimm/dxac036] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Accepted: 07/20/2022] [Indexed: 11/12/2022] Open
Abstract
Bacterial dysbiosis is evolving as an advocate for carcinogenesis and has been associated with pancreatic cancer progression and survival outcomes. The gut and pancreas of cancer patients harbor a unique microbiome that differs significantly from that of healthy individuals. We believe that the pancreatic cancer microbiome regulates tumorigenesis by altering host cell function and modulating immune cells, skewing them towards an immunosuppressive phenotype. Moreover, altering this pathogenic microbiome may enhance the efficacy of current therapies in pancreatic cancer and improve survival outcomes. This review highlights the findings on microbial modulation across various pre-clinical and clinical studies and provides insight into the potential of targeting the microbiome for pancreatic cancer therapy.
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Affiliation(s)
- Donnele Daley
- Department of Surgery, University of Michigan, 1500 E Medical Center Drive, Ann Arbor, MI, USA
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11
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Kaur K, Ko MW, Chen F, Jewett A. Defective NK cell expansion, cytotoxicity, and lack of ability to differentiate tumors from a pancreatic cancer patient in a long term follow-up: implication in the progression of cancer. Cancer Immunol Immunother 2022; 71:1033-1047. [PMID: 34559307 DOI: 10.1007/s00262-021-03044-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Accepted: 08/23/2021] [Indexed: 11/25/2022]
Abstract
The majority of the previous reports on NK cells use cross-sectional studies to establish the status of patient NK cell function, however such studies fail to evaluate the immune status of the patients on a continuous basis from the disease-free stage to progression of cancer. In this study, we performed a prospective study of the immune function by continuously monitoring the NK numbers, expansion and function of a pancreatic cancer patient from 1/6/2016 to 2/14/2019. The results indicated that at initial stages of the disease where no overt disease was identified, the patient had consistently higher percentages of NK and B cells and lower percentages of CD3 + T cells in the peripheral blood. The percentages of CD14 + monocytes were similar at the initial stages of the disease, and at the later stages of the disease, it increased and remained higher in the patient when compared to those from healthy donors. The numbers of expanded NK cells and the cytotoxic function, as well as secretion of IFN-γ from primary and osteoclast expanded patient NK cells remained consistently low throughout the years of follow up. Similarly, the majority of cytokines in patient's serum remained lower with the exception of IL-6 which was higher. The IFN-γ secreted from the patients' NK cells had much lower ability to differentiate the poorly differentiated oral tumors as assessed by their lack of ability to upregulate differentiation antigens. Overall, before any evidence of overt disease, patient NK cells exhibited significant dysfunction. Intervention at the stage of no disease or minimal disease may be important for the prevention of pancreatic cancer progression.
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Affiliation(s)
- Kawaljit Kaur
- Division of Oral Biology and Oral Medicine, School of Dentistry and Medicine, Los Angeles, CA, USA
| | - Meng-Wei Ko
- Division of Oral Biology and Oral Medicine, School of Dentistry and Medicine, Los Angeles, CA, USA
| | - Franklin Chen
- Division of Oral Biology and Oral Medicine, School of Dentistry and Medicine, Los Angeles, CA, USA
| | - Anahid Jewett
- Division of Oral Biology and Oral Medicine, School of Dentistry and Medicine, Los Angeles, CA, USA.
- The Jonsson Comprehensive Cancer Center, UCLA School of Dentistry and Medicine, 10833 Le Conte Ave., Los Angeles, CA, 90095, USA.
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12
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Tian B, Li Q. Single-Cell Sequencing and Its Applications in Liver Cancer. Front Oncol 2022; 12:857037. [PMID: 35574365 PMCID: PMC9097917 DOI: 10.3389/fonc.2022.857037] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Accepted: 03/24/2022] [Indexed: 02/06/2023] Open
Abstract
As one of the most lethal cancers, primary liver cancer (PLC) has high tumor heterogeneity, including the heterogeneity between cancer cells. Traditional methods which have been used to identify tumor heterogeneity for a long time are based on large mixed cell samples, and the research results usually show average level of the cell population, ignoring the heterogeneity between cancer cells. In recent years, single-cell sequencing has been increasingly applied to the studies of PLCs. It can detect the heterogeneity between cancer cells, distinguish each cell subgroup in the tumor microenvironment (TME), and also reveal the clonal characteristics of cancer cells, contributing to understand the evolution of tumor. Here, we introduce the process of single-cell sequencing, review the applications of single-cell sequencing in the heterogeneity of cancer cells, TMEs, oncogenesis, and metastatic mechanisms of liver cancer, and discuss some of the current challenges in the field.
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13
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Xia P, Liu DH. Cancer stem cell markers for liver cancer and pancreatic cancer. Stem Cell Res 2022; 60:102701. [PMID: 35149457 DOI: 10.1016/j.scr.2022.102701] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Revised: 01/31/2022] [Accepted: 02/01/2022] [Indexed: 12/18/2022] Open
Abstract
Cancer stem cells (CSC) theory has ushered in a new era of cancer research. Tumor recurrence, metastasis and chemotherapy resistance are all related to the existence of cancer stem cells. Further understanding of tumor heterogeneity will contribute to targeted treatment. Liver cancer and pancreatic cancer are common digestive gland tumors with high lethality. This article reviews the identification and isolation of CSC markers in hepatocellular carcinoma and pancreatic cancer. The markers related signal pathways are involved in the occurrence and development of tumors, and have a significant impact on the proliferation, metastasis and invasion of cancer cells, which can be used as potential molecular therapeutic targets. This study will be helpful to understand cancer stem cell like cells.
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Affiliation(s)
- Pu Xia
- Biological Anthropology Institute, College of Basic Medical Science, Liaoning Medical University, China.
| | - Da-Hua Liu
- Biological Anthropology Institute, College of Basic Medical Science, Liaoning Medical University, China
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14
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Ponomarev A, Gilazieva Z, Solovyeva V, Allegrucci C, Rizvanov A. Intrinsic and Extrinsic Factors Impacting Cancer Stemness and Tumor Progression. Cancers (Basel) 2022; 14:970. [PMID: 35205716 PMCID: PMC8869813 DOI: 10.3390/cancers14040970] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Revised: 02/03/2022] [Accepted: 02/08/2022] [Indexed: 02/06/2023] Open
Abstract
Tumor heterogeneity represents an important limitation to the development of effective cancer therapies. The presence of cancer stem cells (CSCs) and their differentiation hierarchies contribute to cancer complexity and confer tumors the ability to grow, resist treatment, survive unfavorable conditions, and invade neighboring and distant tissues. A large body of research is currently focusing on understanding the properties of CSCs, including their cellular and molecular origin, as well as their biological behavior in different tumor types. In turn, this knowledge informs strategies for targeting these tumor initiating cells and related cancer stemness. Cancer stemness is modulated by the tumor microenvironment, which influences CSC function and survival. Several advanced in vitro models are currently being developed to study cancer stemness in order to advance new knowledge of the key molecular pathways involved in CSC self-renewal and dormancy, as well as to mimic the complexity of patients' tumors in pre-clinical drug testing. In this review, we discuss CSCs and the modulation of cancer stemness by the tumor microenvironment, stemness factors and signaling pathways. In addition, we introduce current models that allow the study of CSCs for the development of new targeted therapies.
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Affiliation(s)
- Alexey Ponomarev
- Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia; (A.P.); (Z.G.); (V.S.)
| | - Zarema Gilazieva
- Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia; (A.P.); (Z.G.); (V.S.)
| | - Valeriya Solovyeva
- Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia; (A.P.); (Z.G.); (V.S.)
| | - Cinzia Allegrucci
- School of Veterinary Medicine and Science (SVMS) and Biodiscovery Institute, University of Nottingham, Nottingham NG7 2RD, UK;
| | - Albert Rizvanov
- Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia; (A.P.); (Z.G.); (V.S.)
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15
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microRNA-21 Regulates Stemness in Pancreatic Ductal Adenocarcinoma Cells. Int J Mol Sci 2022; 23:ijms23031275. [PMID: 35163198 PMCID: PMC8835847 DOI: 10.3390/ijms23031275] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Revised: 01/13/2022] [Accepted: 01/21/2022] [Indexed: 02/06/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the most common and aggressive type of pancreatic cancer (PCa) with a low survival rate. microRNAs (miRs) are endogenous, non-coding RNAs that moderate numerous biological processes. miRs have been associated with the chemoresistance and metastasis of PDAC and the presence of a subpopulation of highly plastic "stem"-like cells within the tumor, known as cancer stem cells (CSCs). In this study, we investigated the role of miR-21, which is highly expressed in Panc-1 and MiaPaCa-2 PDAC cells in association with CSCs. Following miR-21 knockouts (KO) from both MiaPaCa-2 and Panc-1 cell lines, reversed expressions of epithelial-mesenchymal transition (EMT) and CSCs markers were observed. The expression patterns of key CSC markers, including CD44, CD133, CX-C chemokine receptor type 4 (CXCR4), and aldehyde dehydrogenase-1 (ALDH1), were changed depending on miR-21 status. miR-21 (KO) suppressed cellular invasion of Panc-1 and MiaPaCa-2 cells, as well as the cellular proliferation of MiaPaCa-2 cells. Our data suggest that miR-21 is involved in the stemness of PDAC cells, may play roles in mesenchymal transition, and that miR-21 poses as a novel, functional biomarker for PDAC aggressiveness.
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16
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Jiang P, Li F, Liu Z, Hao S, Gao J, Li S. BTB and CNC homology 1 (Bach1) induces lung cancer stem cell phenotypes by stimulating CD44 expression. Respir Res 2021; 22:320. [PMID: 34949193 PMCID: PMC8697453 DOI: 10.1186/s12931-021-01918-2] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Accepted: 12/17/2021] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Growing evidence suggests that cancer stem cells (CSCs) are responsible for cancer initiation in tumors. Bach1 has been identified to contribute to several tumor progression, including lung cancer. The role of Bach1 in CSCs remains poorly known. Therefore, the function of Bach1 on lung CSCs was focused currently. METHODS The expression of Bach1, CD133, CD44, Sox2, Nanog and Oct4 mRNA was assessed using Real-Time Quantitative Reverse Transcription PCR (RT-qPCR). Protein expression of Bach1, CD133, CD44, Sox2, Nanog, Oct4, p53, BCL2, BAX, p-p38, p-AKT1, c-Fos and c-Jun protein was analyzed by western blotting. 5-ethynyl-29-deoxyuridine (EdU), colony formation, Flow cytometry analysis and transwell invasion assay were carried out to analyze lung cancer cell proliferation, apoptosis and invasion respectively. Tumor sphere formation assay was utilized to evaluate spheroid capacity. Flow cytometry analysis was carried out to isolate CD133 or CD44 positive lung cancer cells. The relationship between Bach1 and CD44 was verified using ChIP-qPCR and dual-luciferase reporter assay. Xenograft tumor tissues were collected for hematoxylin and eosin (HE) staining and IHC analysis to evaluate histology and Ki-67. RESULTS The ratio of CD44 + CSCs from A549 and SPC-A1 cells were significantly enriched. Tumor growth of CD44 + CSCs was obviously suppressed in vivo compared to CD44- CSCs. Bach1 expression was obviously increased in CD44 + CSCs. Then, via using the in vitro experiment, it was observed that CSCs proliferation and invasion were greatly reduced by the down-regulation of Bach1 while cell apoptosis was triggered by knockdown of Bach1. Loss of Bach1 was able to repress tumor-sphere formation and tumor-initiating CSC markers. A repression of CSCs growth and metastasis of shRNA-Bach1 was confirmed using xenograft models and caudal vein injection. The direct interaction between Bach1 and CD44 was confirmed by ChIP-qPCR and dual-luciferase reporter assay. Furthermore, mitogen-activated protein kinases (MAPK) signaling pathway was selected and we proved the effects of Bach1 on lung CSCs were associated with the activation of the MAPK pathway. As manifested, loss of Bach1 was able to repress p-p38, p-AKT1, c-Fos, c-Jun protein levels in lung CSCs. Inhibition of MAPK signaling remarkably restrained lung CSCs growth and CSCs properties induced by Bach1 overexpression. CONCLUSION In summary, we imply that Bach1 demonstrates great potential for the treatment of lung cancer metastasis and recurrence via activating CD44 and MPAK signaling.
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Affiliation(s)
- Pan Jiang
- Department of Nutrition, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, China
| | - Fan Li
- Department of Nutrition, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, China
| | - Zilong Liu
- Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, China
| | - Shengyu Hao
- Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, China.
| | - Jian Gao
- Department of Nutrition, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, China.
| | - Shanqun Li
- Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, China.
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17
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Li B, Qin Y, Yu X, Xu X, Yu W. Lipid raft involvement in signal transduction in cancer cell survival, cell death and metastasis. Cell Prolif 2021; 55:e13167. [PMID: 34939255 PMCID: PMC8780926 DOI: 10.1111/cpr.13167] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Revised: 11/08/2021] [Accepted: 11/30/2021] [Indexed: 12/19/2022] Open
Abstract
Lipid rafts are cholesterol‐ and sphingolipid‐enriched specialized membrane domains within the plasma membrane. Lipid rafts regulate the density and activity of signal receptors by compartmentalizing them, promoting signalling cascades that play important roles in the survival, death and metastasis of cancer cells. In this review, we emphasize the current concept initially postulated by F. Mollinedo and C. Gajate on the importance of lipid rafts in cancer survival, death and metastasis by describing representative signalling pathways, including the IGF system and the PI3K/AKT, Fas/CD95, VEGF/VEGFR2 and CD44 signalling pathways, and we also discuss the concept of CASMER (cluster of apoptotic signalling molecule‐enriched rafts), coined, originally introduced and further advanced by F. Mollinedo and C. Gajate in the period 2005–2010. Then, we summarize relevant research progress and suggest that lipid rafts play important roles in the survival, death and metastasis of cancer cells, making them promising targets for cancer therapy.
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Affiliation(s)
- Borui Li
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.,Shanghai Pancreatic Cancer Institute, Shanghai, China.,Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Yi Qin
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.,Shanghai Pancreatic Cancer Institute, Shanghai, China.,Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Xianjun Yu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.,Shanghai Pancreatic Cancer Institute, Shanghai, China.,Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Xiaowu Xu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.,Shanghai Pancreatic Cancer Institute, Shanghai, China.,Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Wenyan Yu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.,Shanghai Pancreatic Cancer Institute, Shanghai, China.,Pancreatic Cancer Institute, Fudan University, Shanghai, China
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18
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Gajate C, Gayet O, Fraunhoffer NA, Iovanna J, Dusetti N, Mollinedo F. Induction of Apoptosis in Human Pancreatic Cancer Stem Cells by the Endoplasmic Reticulum-Targeted Alkylphospholipid Analog Edelfosine and Potentiation by Autophagy Inhibition. Cancers (Basel) 2021; 13:cancers13236124. [PMID: 34885233 PMCID: PMC8656492 DOI: 10.3390/cancers13236124] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2021] [Revised: 11/29/2021] [Accepted: 11/30/2021] [Indexed: 12/12/2022] Open
Abstract
Pancreatic cancer is one of the most lethal malignancies with a poor and gloomy prognosis and the highest mortality-to-incidence ratio. Pancreatic cancer remains an incurable malignancy, and current therapies are ineffective. We isolated cancer stem cells (CSCs) from the human PANC-1 pancreatic cancer cell line as CD44+CD24+EpCAM+ cells. These CSCs form pancreatic cancer spheres or spheroids and develop tumors in SCID mice after subcutaneous injection of as few as 100 cells per mouse. Here, we found that the alkylphospholipid analog edelfosine inhibited CSC pancreatic cancer spheroid formation and induced cell death, as assessed by an increase in the percentage of cells in the sub-G0/G1 region by means of flow cytometry, indicative of DNA breakdown and apoptosis. This correlated with an increase in caspase-3 activity and PARP breakdown, as a major substrate of caspase-3, following PANC-1 CSC treatment with edelfosine. The antitumor ether lipid edelfosine colocalized with the endoplasmic reticulum in both PANC-1 cells as well as PANC-1 CSCs by using a fluorescent edelfosine analog, and induced an endoplasmic reticulum stress response in both PANC-1 cells and PANC-1 CSCs, with a potent CHOP/GADD153 upregulation. Edelfosine elicited a strong autophagy response in both PANC-1 cells and PANC-1 CSCs, and preincubation of CSCs with autophagy inhibitors, chloroquine or bafilomycin A1, enhanced edelfosine-induced apoptosis. Primary cultures from pancreatic cancer patients were sensitive to edelfosine, as well as their respective isolated CSCs. Nontumorigenic pancreatic human cell line HPNE and normal human fibroblasts were largely spared. These data suggest that pancreatic CSCs isolated from established cell lines and pancreatic cancer patients are sensitive to edelfosine through its accumulation in the endoplasmic reticulum and induction of endoplasmic reticulum stress.
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Affiliation(s)
- Consuelo Gajate
- Laboratory of Cell Death and Cancer Therapy, Department of Molecular Biomedicine, Centro de Investigaciones Biológicas Margarita Salas, Consejo Superior de Investigaciones Científicas (CSIC), Ramiro de Maeztu 9, E-28040 Madrid, Spain;
- Centro de Investigación del Cáncer, Instituto de Biología Molecular y Celular del Cáncer, Campus Miguel de Unamuno, Consejo Superior de Investigaciones Científicas (CSIC)-Universidad de Salamanca, E-37007 Salamanca, Spain
| | - Odile Gayet
- Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Institut Paoli-Calmettes, Aix-Marseille Université, Parc Scientifique et Technologique de Luminy, CEDEX 09, 13288 Marseille, France; (O.G.); (N.A.F.); (J.I.); (N.D.)
| | - Nicolas A. Fraunhoffer
- Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Institut Paoli-Calmettes, Aix-Marseille Université, Parc Scientifique et Technologique de Luminy, CEDEX 09, 13288 Marseille, France; (O.G.); (N.A.F.); (J.I.); (N.D.)
| | - Juan Iovanna
- Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Institut Paoli-Calmettes, Aix-Marseille Université, Parc Scientifique et Technologique de Luminy, CEDEX 09, 13288 Marseille, France; (O.G.); (N.A.F.); (J.I.); (N.D.)
| | - Nelson Dusetti
- Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Institut Paoli-Calmettes, Aix-Marseille Université, Parc Scientifique et Technologique de Luminy, CEDEX 09, 13288 Marseille, France; (O.G.); (N.A.F.); (J.I.); (N.D.)
| | - Faustino Mollinedo
- Laboratory of Cell Death and Cancer Therapy, Department of Molecular Biomedicine, Centro de Investigaciones Biológicas Margarita Salas, Consejo Superior de Investigaciones Científicas (CSIC), Ramiro de Maeztu 9, E-28040 Madrid, Spain;
- Centro de Investigación del Cáncer, Instituto de Biología Molecular y Celular del Cáncer, Campus Miguel de Unamuno, Consejo Superior de Investigaciones Científicas (CSIC)-Universidad de Salamanca, E-37007 Salamanca, Spain
- Correspondence:
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19
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Miyazaki T, Khan T, Tachihara Y, Itoh M, Miyazawa T, Suganami T, Miyahara Y, Cabral H, Matsumoto A. Boronic Acid Ligands Can Target Multiple Subpopulations of Pancreatic Cancer Stem Cells via pH-Dependent Glycan-Terminal Sialic Acid Recognition. ACS APPLIED BIO MATERIALS 2021; 4:6647-6651. [PMID: 35006967 DOI: 10.1021/acsabm.1c00383] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Eradication of cancer stem cells (CSCs) is an ultimate goal in cancer chemotherapy. Although a ligand-assisted targeting approach seems rational, the existence of subpopulations of CSCs and their discrimination from those present on healthy sites makes it a severe challenge. Some boronic acid (BA) derivatives are known for the ability to bind with glycan-terminal sialic acid (SA), in a manner dependent on the acidification found in hypoxic tumoral microenvironment. Taking advantage of this feature, here we show that the BA-ligand fluorescence conjugate can effectively target multiple CSC subpopulations in parallel, which otherwise must be independently aimed when using antibody--ligands.
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Affiliation(s)
- Takuya Miyazaki
- Kanagawa Institute of Industrial Science and Technology (KISTEC), Kanagawa 243-0435, Japan.,Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Tokyo 101-0062, Japan.,Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, Tokyo 113-8656, Japan
| | - Thahomina Khan
- Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Tokyo 101-0062, Japan
| | - Yoshihiro Tachihara
- Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, Tokyo 113-8656, Japan
| | - Michiko Itoh
- Kanagawa Institute of Industrial Science and Technology (KISTEC), Kanagawa 243-0435, Japan.,Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Tokyo 101-0062, Japan.,Department of Molecular Medicine and Metabolism, Research Institute of Environmental Medicine, Nagoya University, Nagoya 464-8601, Japan
| | - Taiki Miyazawa
- New Industry Creation Hatchery Center, Tohoku University, Sendai 980-8579, Japan
| | - Takayoshi Suganami
- Department of Molecular Medicine and Metabolism, Research Institute of Environmental Medicine, Nagoya University, Nagoya 464-8601, Japan
| | - Yuji Miyahara
- Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Tokyo 101-0062, Japan
| | - Horacio Cabral
- Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, Tokyo 113-8656, Japan
| | - Akira Matsumoto
- Kanagawa Institute of Industrial Science and Technology (KISTEC), Kanagawa 243-0435, Japan.,Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Tokyo 101-0062, Japan
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20
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Ramaiah MJ, Tangutur AD, Manyam RR. Epigenetic modulation and understanding of HDAC inhibitors in cancer therapy. Life Sci 2021; 277:119504. [PMID: 33872660 DOI: 10.1016/j.lfs.2021.119504] [Citation(s) in RCA: 149] [Impact Index Per Article: 37.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2021] [Revised: 03/20/2021] [Accepted: 04/09/2021] [Indexed: 12/15/2022]
Abstract
The role of genetic and epigenetic factors in tumor initiation and progression is well documented. Histone deacetylases (HDACs), histone methyl transferases (HMTs), and DNA methyl transferases. (DNMTs) are the main proteins that are involved in regulating the chromatin conformation. Among these, histone deacetylases (HDAC) deacetylate the histone and induce gene repression thereby leading to cancer. In contrast, histone acetyl transferases (HATs) that include GCN5, p300/CBP, PCAF, Tip 60 acetylate the histones. HDAC inhibitors are potent drug molecules that can induce acetylation of histones at lysine residues and induce open chromatin conformation at tumor suppressor gene loci and thus resulting in tumor suppression. The key processes regulated by HDAC inhibitors include cell-cycle arrest, chemo-sensitization, apoptosis induction, upregulation of tumor suppressors. Even though FDA approved drugs are confined mainly to haematological malignancies, the research on HDAC inhibitors in glioblastoma multiforme and triple negative breast cancer (TNBC) are providing positive results. Thus, several combinations of HDAC inhibitors along with DNA methyl transferase inhibitors and histone methyl transferase inhibitors are in clinical trials. This review focuses on how HDAC inhibitors regulate the expression of coding and non-coding genes with specific emphasis on their anti-cancer potential.
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Affiliation(s)
- M Janaki Ramaiah
- Laboratory of Functional genomics and Disease Biology, School of Chemical and Biotechnology, SASTRA Deemed University, Thanjavur 613401, Tamil Nadu, India.
| | - Anjana Devi Tangutur
- Department of Applied Biology, CSIR-Indian Institute of Chemical Technology (CSIR-IICT), Hyderabad 500 007, Telangana, India
| | - Rajasekhar Reddy Manyam
- Department of Computer Science and Engineering, Koneru Lakshmaiah Education Foundation, Vaddeswaram, Andhra Pradesh, India
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21
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Nimmakayala RK, Leon F, Rachagani S, Rauth S, Nallasamy P, Marimuthu S, Shailendra GK, Chhonker YS, Chugh S, Chirravuri R, Gupta R, Mallya K, Prajapati DR, Lele SM, C Caffrey T, L Grem J, Grandgenett PM, Hollingsworth MA, Murry DJ, Batra SK, Ponnusamy MP. Metabolic programming of distinct cancer stem cells promotes metastasis of pancreatic ductal adenocarcinoma. Oncogene 2021; 40:215-231. [PMID: 33110235 PMCID: PMC10041665 DOI: 10.1038/s41388-020-01518-2] [Citation(s) in RCA: 71] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 10/02/2020] [Accepted: 10/09/2020] [Indexed: 02/06/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) metastasizes to distant organs, which is the primary cause of mortality; however, specific features mediating organ-specific metastasis remain unexplored. Emerging evidence demonstrates that cancer stem cells (CSCs) and cellular metabolism play a pivotal role in metastasis. Here we investigated the role of distinct subtypes of pancreatic CSCs and their metabolomic signatures in organ-specific metastatic colonization. We found that PDAC consists of ALDH+/CD133+ and drug-resistant (MDR1+) subtypes of CSCs with specific metabolic and stemness signatures. Human PDAC tissues with gemcitabine treatment, autochthonous mouse tumors from KrasG12D; Pdx1-Cre (KC) and KrasG12D; Trp53R172H; Pdx-1 Cre (KPC) mice, and KPC- Liver/Lung metastatic cells were used to evaluate the CSC, EMT (epithelial-to-mesenchymal transition), and metabolic profiles. A strong association was observed between distinct CSC subtypes and organ-specific colonization. The liver metastasis showed drug-resistant CSC- and EMT-like phenotype with aerobic glycolysis and fatty acid β-oxidation-mediated oxidative (glyco-oxidative) metabolism. On the contrary, lung metastasis displayed ALDH+/CD133+ and MET-like phenotype with oxidative metabolism. These results were obtained by evaluating FACS-based side population (SP), autofluorescence (AF+) and Alde-red assays for CSCs, and Seahorse-based oxygen consumption rate (OCR), extracellular acidification rate (ECAR), and fatty acid β-oxidation (FAO)-mediated OCR assays for metabolic features along with specific gene signatures. Further, we developed in vitro human liver and lung PDAC metastasis models by using a combination of liver or lung decellularized scaffolds, a co-culture, and a sphere culture methods. PDAC cells grown in the liver-mimicking model showed the enrichment of MDR1+ and CPT1A+ populations, whereas the PDAC cells grown in the lung-mimicking environment showed the enrichment of ALDH+/CD133+ populations. In addition, we observed significantly elevated expression of ALDH1 in lung metastasis and MDR1/LDH-A expression in liver metastasis compared to human primary PDAC tumors. Our studies elucidate that distinct CSCs adapt unique metabolic signatures for organotropic metastasis, which will pave the way for the development of targeted therapy for PDAC metastasis.
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Affiliation(s)
- Rama Krishna Nimmakayala
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA
| | - Frank Leon
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA
| | - Satyanarayana Rachagani
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA
| | - Sanchita Rauth
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA
| | - Palanisamy Nallasamy
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA
| | - Saravanakumar Marimuthu
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA
| | - Gautam K Shailendra
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA
| | - Yashpal S Chhonker
- Department of Pharmacy Practice and Science, College of Pharmacy, University of Nebraska Medical Center, 986145 Nebraska Medical Center, Omaha, NE, 68198-6145, USA
| | - Seema Chugh
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA
| | - Ramakanth Chirravuri
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA
| | - Rohitesh Gupta
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA
| | - Kavita Mallya
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA
| | - Dipakkumar R Prajapati
- Department of Pathology and Microbiology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, USA
| | - Subodh M Lele
- Department of Pathology and Microbiology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, USA
| | - Thomas C Caffrey
- Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA
| | - Jean L Grem
- Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA
| | - Paul M Grandgenett
- Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA
| | - Michael A Hollingsworth
- Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA
| | - Daryl J Murry
- Department of Pharmacy Practice and Science, College of Pharmacy, University of Nebraska Medical Center, 986145 Nebraska Medical Center, Omaha, NE, 68198-6145, USA
| | - Surinder K Batra
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA. .,Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA.
| | - Moorthy P Ponnusamy
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA. .,Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA.
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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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23
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Prostate cancer-derived holoclones: a novel and effective model for evaluating cancer stemness. Sci Rep 2020; 10:11329. [PMID: 32647229 PMCID: PMC7347552 DOI: 10.1038/s41598-020-68187-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2020] [Accepted: 06/19/2020] [Indexed: 12/19/2022] Open
Abstract
Prostate cancer accounts for approximately 13.5% of all newly diagnosed male cancer cases. Significant clinical burdens remain in terms of ineffective prognostication, with overtreatment of insignificant disease. Additionally, the pathobiology underlying disease heterogeneity remains poorly understood. As the role of cancer stem cells in the perpetuation of aggressive carcinoma is being substantiated by experimental evidence, it is crucially important to understand the molecular mechanisms, which regulate key features of cancer stem cells. We investigated two methods for in vitro cultivation of putative prostate cancer stem cells based on ‘high-salt agar’ and ‘monoclonal cultivation’. Data demonstrated ‘monoclonal cultivation’ as the superior method. We demonstrated that ‘holoclones’ expressed canonical stem markers, retained the exclusive ability to generate poorly differentiated tumours in NOD/SCID mice and possessed a unique mRNA-miRNA gene signature. miRNA:Target interactions analysis visualised potentially critical regulatory networks, which are dysregulated in prostate cancer holoclones. The characterisation of this tumorigenic population lays the groundwork for this model to be used in the identification of proteomic or small non-coding RNA therapeutic targets for the eradication of this critical cellular population. This is significant, as it provides a potential route to limit development of aggressive disease and thus improve survival rates.
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24
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Malinowski B, Musiała N, Wiciński M. Metformin's Modulatory Effects on miRNAs Function in Cancer Stem Cells-A Systematic Review. Cells 2020; 9:cells9061401. [PMID: 32512882 PMCID: PMC7348732 DOI: 10.3390/cells9061401] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Revised: 05/27/2020] [Accepted: 06/02/2020] [Indexed: 02/07/2023] Open
Abstract
Cancer stem cells (CSCs) have been reported in various hematopoietic and solid tumors, therefore, are considered to promote cancer progression, metastasis, recurrence and drug resistance. However, regulation of CSCs at the molecular level is not fully understood. microRNAs (miRNAs) have been identified as key regulators of CSCs by modulating their major functions: self-renewal capacity, invasion, migration and proliferation. Various studies suggest that metformin, an anti-diabetic drug, has an anti-tumor activity but its precise mechanism of action has not been understood. The present article was written in accordance to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. We systematically reviewed evidence for metformin’s ability to eradicate CSCs through modulating the expression of miRNAs in various solid tumors. PubMed and MEDLINE were searched from January 1990 to January 2020 for in vitro studies. Two authors independently selected and reviewed articles according to predefined eligibility criteria and assessed risk of bias of included studies. Four papers met the inclusion criteria and presented low risk bias. All of the included studies reported a suppression of CSCs’ major function after metformin dosage. Moreover, it was showed that metformin anti-tumor mechanism of action is based on regulation of miRNAs expression. Metformin inhibited cell survival, clonogenicity, wound-healing capacity, sphere formation and promotes chemosensitivity of tumor cells. Due to the small number of publications, aforementioned evidences are limited but may be consider as background for clinical studies.
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25
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Mollinedo F, Gajate C. Lipid rafts as signaling hubs in cancer cell survival/death and invasion: implications in tumor progression and therapy: Thematic Review Series: Biology of Lipid Rafts. J Lipid Res 2020; 61:611-635. [PMID: 33715811 PMCID: PMC7193951 DOI: 10.1194/jlr.tr119000439] [Citation(s) in RCA: 171] [Impact Index Per Article: 34.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2019] [Revised: 01/17/2020] [Indexed: 12/13/2022] Open
Abstract
Cholesterol/sphingolipid-rich membrane domains, known as lipid rafts or membrane rafts, play a critical role in the compartmentalization of signaling pathways. Physical segregation of proteins in lipid rafts may modulate the accessibility of proteins to regulatory or effector molecules. Thus, lipid rafts serve as sorting platforms and hubs for signal transduction proteins. Cancer cells contain higher levels of intracellular cholesterol and lipid rafts than their normal non-tumorigenic counterparts. Many signal transduction processes involved in cancer development (insulin-like growth factor system and phosphatidylinositol 3-kinase-AKT) and metastasis [cluster of differentiation (CD)44] are dependent on or modulated by lipid rafts. Additional proteins playing an important role in several malignant cancers (e.g., transmembrane glycoprotein mucin 1) are also being detected in association with lipid rafts, suggesting a major role of lipid rafts in tumor progression. Conversely, lipid rafts also serve as scaffolds for the recruitment and clustering of Fas/CD95 death receptors and downstream signaling molecules leading to cell death-promoting raft platforms. The partition of death receptors and downstream signaling molecules in aggregated lipid rafts has led to the formation of the so-called cluster of apoptotic signaling molecule-enriched rafts, or CASMER, which leads to apoptosis amplification and can be pharmacologically modulated. These death-promoting rafts can be viewed as a linchpin from which apoptotic signals are launched. In this review, we discuss the involvement of lipid rafts in major signaling processes in cancer cells, including cell survival, cell death, and metastasis, and we consider the potential of lipid raft modulation as a promising target in cancer therapy.
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Affiliation(s)
- Faustino Mollinedo
- Laboratory of Cell Death and Cancer Therapy, Department of Molecular Biomedicine, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Cientificas (CSIC), E-28040 Madrid, Spain. mailto:
| | - Consuelo Gajate
- Laboratory of Cell Death and Cancer Therapy, Department of Molecular Biomedicine, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Cientificas (CSIC), E-28040 Madrid, Spain
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26
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Dai PL, Du XS, Hou Y, Li L, Xia YX, Wang L, Chen HX, Chang L, Li WH. Different Proteins Regulated Apoptosis, Proliferation and Metastasis of Lung Adenocarcinoma After Radiotherapy at Different Time. Cancer Manag Res 2020; 12:2437-2447. [PMID: 32308480 PMCID: PMC7135201 DOI: 10.2147/cmar.s219967] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2019] [Accepted: 03/15/2020] [Indexed: 12/25/2022] Open
Abstract
Introduction The biological changes after irradiation in lung cancer cells are important to reduce recurrence and metastasis of lung cancer. To optimize radiotherapy of lung adenocarcinoma, our study systematically explored the mechanisms of biological behaviors in residual A549 and XWLC-05 cells after irradiation. Methods Colony formation assay, cell proliferation assay, cell migration assay, flow cytometry, BALB/C-nu mice xenograft models and Western blot of pan-AKT, p-Akt380, p-Akt473, PCNA, DNA-PKCS, KU70, KU80, CD133, CD144, MMP2 and P53 were used in our study to assess biological changes after irradiation with 0, 4 and 8 Gy at 0–336 hr after irradiation in vitro and 20 Gy at transplantation group, irradiated transplantation group, residual tumor 0, 7, 14, 21, and 28 days groups in vivo. Results The ability of cell proliferation and radiosensitivity of residual XWLC-05 cells was better than A549 cells after radiation in vivo and in vitro. MMP-2 has statistical differences in vitro and in vivo and increased with the migratory ability of cells in vitro. PCNA and P53 have statistical differences in XWLC-05 and A549 cells and the changes of them are similar to the proliferation of residual cells within first 336 hr after irradiation in vitro. Pan-AKT increased after irradiation, and residual tumor 21-day group (1.5722) has statistic differences between transplantation group (0.9763, p=0.018) and irradiated transplantation group (0.8455, p=0.006) in vivo. Pan-AKT rose to highest when 21-day after residual tumor reach to 0.5 mm2. MMP2 has statistical differences between transplantation group (0.4619) and residual tumor 14-day group (0.8729, p=0.043). P53 has statistical differences between residual tumor 7-day group (0.6184) and residual tumor 28 days group (1.0394, p=0.007). DNA-PKCS has statistical differences between residual tumor 28 days group (1.1769) and transplantation group (0.2483, p=0.010), irradiated transplantation group (0.1983, p=0.002) and residual tumor 21 days group (0.2017, p=0.003), residual tumor 0 days group (0.5992) and irradiated transplantation group (0.1983, p=0.027) and residual tumor 21 days group (0.2017, p=0.002). KU80 and KU70 have no statistical differences at any time point. Conclusion Different proteins regulated apoptosis, proliferation and metastasis of lung adenocarcinoma after radiotherapy at different times. MMP-2 might regulate metastasis ability of XWLC-05 and A549 cells in vitro and in vivo. PCNA and P53 may play important roles in proliferation of vitro XWLC-05 and A549 cells within first 336 hr after irradiation in vitro. After that, P53 may through PI3K/AKT pathway regulate cell proliferation after irradiation in vitro. DNA-PKCS may play a more important role in DNA damage repair than KU70 and KU80 after 336 hr in vitro because it rapidly rose than KU70 and KU80 after irradiation. Different cells have different time rhythm in apoptosis, proliferation and metastasis after radiotherapy. Time rhythm of cells after irradiation should be delivered and more attention should be paid to resist cancer cell proliferation and metastasis.
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Affiliation(s)
- P L Dai
- Radiotherapy Department, The Third Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650100, People's Republic of China.,Kunming Medical University, Kunming, Yunnan 650100, People's Republic of China
| | - X S Du
- Oncology Department, The Fifth People's Hospital of Huaian, Jiangsu 223001, People's Republic of China
| | - Y Hou
- Radiotherapy Department, The Third Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650100, People's Republic of China
| | - L Li
- Radiotherapy Department, The Third Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650100, People's Republic of China
| | - Y X Xia
- Radiotherapy Department, The Third Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650100, People's Republic of China
| | - L Wang
- Radiotherapy Department, The Third Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650100, People's Republic of China
| | - H X Chen
- Radiotherapy Department, The Third Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650100, People's Republic of China
| | - L Chang
- Radiotherapy Department, The Third Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650100, People's Republic of China
| | - W H Li
- Radiotherapy Department, The Third Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650100, People's Republic of China
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27
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Quan Q, Wang X, Lu C, Ma W, Wang Y, Xia G, Wang C, Yang G. Cancer stem-like cells with hybrid epithelial/mesenchymal phenotype leading the collective invasion. Cancer Sci 2020; 111:467-476. [PMID: 31845453 PMCID: PMC7004545 DOI: 10.1111/cas.14285] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2019] [Revised: 12/02/2019] [Accepted: 12/08/2019] [Indexed: 02/06/2023] Open
Abstract
Collective invasion of cancer cells is the key process of circulating tumor cell (CTC) cluster formation, and greatly contributes to metastasis. Cancer stem-like cells (CSC) have a distinct advantage of motility for metastatic dissemination. To verify the role of CSC in the collective invasion, we performed 3D assays to investigate the collective invasion from cancer cell spheroids. The results demonstrated that CSC can significantly promote both collective and single-cell invasion. Further study showed that CSC prefer to move outside and lead the collective invasion. More interestingly, approximately 60% of the leader CSC in collective invasion co-expressed both epithelial and mesenchymal genes, while only 4% co-expressed in single invasive CSC, indicating that CSC with hybrid epithelial/mesenchymal phenotype play a key role in cancer cell collective invasion.
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Affiliation(s)
- Qianghua Quan
- State Key Laboratory of AgrobiotechnologyCollege of Biological SciencesChina Agricultural UniversityBeijingChina
- State Key Laboratory of Nuclear Physics and TechnologySchool of PhysicsPeking UniversityBeijingChina
| | - Xudong Wang
- State Key Laboratory of Nuclear Physics and TechnologySchool of PhysicsPeking UniversityBeijingChina
| | - Chunyang Lu
- State Key Laboratory of Nuclear Physics and TechnologySchool of PhysicsPeking UniversityBeijingChina
| | - Wenzong Ma
- State Key Laboratory of Nuclear Physics and TechnologySchool of PhysicsPeking UniversityBeijingChina
| | - Yugang Wang
- State Key Laboratory of Nuclear Physics and TechnologySchool of PhysicsPeking UniversityBeijingChina
| | - Guoliang Xia
- State Key Laboratory of AgrobiotechnologyCollege of Biological SciencesChina Agricultural UniversityBeijingChina
| | - Chao Wang
- State Key Laboratory of AgrobiotechnologyCollege of Biological SciencesChina Agricultural UniversityBeijingChina
| | - Gen Yang
- State Key Laboratory of Nuclear Physics and TechnologySchool of PhysicsPeking UniversityBeijingChina
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28
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Jiang J, Yu C, Guo X, Zhang H, Tian S, Cai K, He Z, Sun C. G Protein-Coupled Receptor GPR87 Promotes the Expansion of PDA Stem Cells through Activating JAK2/STAT3. MOLECULAR THERAPY-ONCOLYTICS 2020; 17:384-393. [PMID: 32405536 PMCID: PMC7210383 DOI: 10.1016/j.omto.2020.01.006] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/27/2019] [Accepted: 01/13/2020] [Indexed: 12/12/2022]
Abstract
Cancer stem cells are the main reason for drug resistance and tumor relapse, and screening the targets for cancer stem cells is essential for tumor therapy. Here, we studied the role and regulatory mechanism of a G protein-coupled receptor named as G protein-coupled receptor 87 (GPR87) in the expansion of pancreatic ductal adenocarcinoma (PDA) stem cells. We found that GPR87 was an independent prognostic factor for PDA patients: patients with high GPR87 had a poor outcome. GPR87 significantly promoted the sphere formation ability, increased side population (SP) cell number, increased the expression of PDA stem cell markers, and increased the tumor initiation ability, suggesting that GPR87 promotes the expansion of PDA stem cells. Mechanism analysis suggested that signal transducer and activator of transcription 3 (STAT3) directly bound to the promoter of GPR87 to increase GPR87 expression; inversely, GPR87 also activated STAT3. Further analysis suggested that GPR87 activated Janus kinase 2 (JAK2), which can activate STAT3, inhibiting JAK2 activation in GPR87-overexpressing PDA cells, which significantly inhibited the expansion of PDA stem cells; these findings suggested that GPR87, JAK2, and STAT3 formed a positive feedback loop increasing PDA stem cell population. In PDA specimens, GPR87 expression is positively correlated with the phosphorylation level of STAT3 and JAK2, confirming GPR87 promoted PDA stem cell expansion through activating JAK2/STAT3. In summary, we found that GPR87, together with JAK2 and STAT3, formed a positive feedback loop to promote the expansion of PDA stem cells.
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Affiliation(s)
- Jianxin Jiang
- Department of Hepatic-Biliary Surgery, Renmin Hospital of Wuhan University, 99 Ziyang Road, Wuhan, Hubei 430030, People's Republic of China
| | - Chao Yu
- Department of Hepatic-Biliary-Pancreatic Surgery, The Affiliated Hospital of Guizhou Medical University, 28 Guiyi Road, Guiyang, Guizhou 550000, People's Republic of China
| | - Xingjun Guo
- Department of Biliary-Pancreatic Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave., Wuhan, Hubei 430030, People's Republic of China
| | - Hao Zhang
- Department of Hepatic-Biliary-Pancreatic Surgery, The Affiliated Hospital of Guizhou Medical University, 28 Guiyi Road, Guiyang, Guizhou 550000, People's Republic of China
| | - She Tian
- Department of Hepatic-Biliary-Pancreatic Surgery, The Affiliated Hospital of Guizhou Medical University, 28 Guiyi Road, Guiyang, Guizhou 550000, People's Republic of China
| | - Kun Cai
- Department of Hepatic-Biliary-Pancreatic Surgery, The Affiliated Hospital of Guizhou Medical University, 28 Guiyi Road, Guiyang, Guizhou 550000, People's Republic of China
| | - Zhiwei He
- Department of Hepatic-Biliary-Pancreatic Surgery, The Affiliated Hospital of Guizhou Medical University, 28 Guiyi Road, Guiyang, Guizhou 550000, People's Republic of China
| | - Chengyi Sun
- Department of Hepatic-Biliary-Pancreatic Surgery, The Affiliated Hospital of Guizhou Medical University, 28 Guiyi Road, Guiyang, Guizhou 550000, People's Republic of China
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29
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Kaur K, Kozlowska AK, Topchyan P, Ko MW, Ohanian N, Chiang J, Cook J, Maung PO, Park SH, Cacalano N, Fang C, Jewett A. Probiotic-Treated Super-Charged NK Cells Efficiently Clear Poorly Differentiated Pancreatic Tumors in Hu-BLT Mice. Cancers (Basel) 2019; 12:cancers12010063. [PMID: 31878338 PMCID: PMC7017229 DOI: 10.3390/cancers12010063] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2019] [Revised: 12/18/2019] [Accepted: 12/19/2019] [Indexed: 01/01/2023] Open
Abstract
Abstract: Background and Aims: We have previously demonstrated that the stage of differentiation of tumors has profound effect on the function of NK cells, and that stem-like/poorly differentiated tumors were preferentially targeted by the NK cells. Therefore, in this study we determined the role of super-charged NK cells in immune mobilization, lysis, and differentiation of stem-like/undifferentiated tumors implanted in the pancreas of humanized-BLT (hu-BLT) mice fed with or without AJ2 probiotics. The phenotype, growth rate and metastatic potential of pancreatic tumors differentiated by the NK cells (NK-differentiated) or patient derived differentiated or stem-like/undifferentiated pancreatic tumors were investigated. Methods: Pancreatic tumor implantation was performed in NSG and hu-BLT mice. Stage of differentiation of tumors was determined using our published criteria for well-differentiated tumors exhibiting higher surface expression of MHC- class I, CD54, and PD-L1 (B7H1) and lower expression of CD44 receptors. The inverse was seen for poorly-differentiated tumors. Results: Stem-like/undifferentiated pancreatic tumors grew rapidly and formed large tumors and exhibited lower expression of above-mentioned differentiation antigens in the pancreas of NSG and hu-BLT mice. Unlike stem-like/undifferentiated tumors, NK-differentiated MP2 (MiaPaCa-2) tumors or patient-derived differentiated tumors were not able to grow or grew smaller tumors, and were unable to metastasize in NSG or hu-BLT mice, and they were susceptible to chemotherapeutic drugs. Stem-like/undifferentiated pancreatic tumors implanted in the pancreas of hu-BLT mice and injected with super-charged NK cells formed much smaller tumors, proliferated less, and exhibited differentiated phenotype. When differentiation of stem-like tumors by the NK cells was prevented by the addition of antibodies to IFN-γ and TNF-α, tumors grew rapidly and metastasized, and they remained resistant to chemotherapeutic drugs. Greater numbers of immune cells infiltrated the tumors of NK-injected and AJ2-probiotic bacteria-fed mice. Moreover, increased IFN-γ secretion in the presence of decreased IL-6 was seen in tumors resected and cultured from NK-injected and AJ2 fed mice. Tumor-induced decreases in NK cytotoxicity and IFN-γ secretion were restored/increased within PBMCs, spleen, and bone marrow when mice received NK cells and were fed with AJ2. Conclusion: NK cells prevent growth of pancreatic tumors through lysis and differentiation, thereby curtailing the growth and metastatic potential of stem-like/undifferentiated-tumors.
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Affiliation(s)
- Kawaljit Kaur
- Division of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, Department of Dentistry, University of California Los Angeles (UCLA), Los Angeles, CA 90095, USA; (K.K.); (A.K.K.); (P.T.); (M.-W.K.); (N.O.); (J.C.); (J.C.); (P.O.M.); (S.-H.P.)
| | - Anna Karolina Kozlowska
- Division of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, Department of Dentistry, University of California Los Angeles (UCLA), Los Angeles, CA 90095, USA; (K.K.); (A.K.K.); (P.T.); (M.-W.K.); (N.O.); (J.C.); (J.C.); (P.O.M.); (S.-H.P.)
- Department of Tumor Immunology, Chair of Medical Biotechnology, Poznan University of Medical Sciences, 61-701 Poznan, Poland
| | - Paytsar Topchyan
- Division of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, Department of Dentistry, University of California Los Angeles (UCLA), Los Angeles, CA 90095, USA; (K.K.); (A.K.K.); (P.T.); (M.-W.K.); (N.O.); (J.C.); (J.C.); (P.O.M.); (S.-H.P.)
| | - Meng-Wei Ko
- Division of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, Department of Dentistry, University of California Los Angeles (UCLA), Los Angeles, CA 90095, USA; (K.K.); (A.K.K.); (P.T.); (M.-W.K.); (N.O.); (J.C.); (J.C.); (P.O.M.); (S.-H.P.)
| | - Nick Ohanian
- Division of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, Department of Dentistry, University of California Los Angeles (UCLA), Los Angeles, CA 90095, USA; (K.K.); (A.K.K.); (P.T.); (M.-W.K.); (N.O.); (J.C.); (J.C.); (P.O.M.); (S.-H.P.)
| | - Jessica Chiang
- Division of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, Department of Dentistry, University of California Los Angeles (UCLA), Los Angeles, CA 90095, USA; (K.K.); (A.K.K.); (P.T.); (M.-W.K.); (N.O.); (J.C.); (J.C.); (P.O.M.); (S.-H.P.)
| | - Jessica Cook
- Division of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, Department of Dentistry, University of California Los Angeles (UCLA), Los Angeles, CA 90095, USA; (K.K.); (A.K.K.); (P.T.); (M.-W.K.); (N.O.); (J.C.); (J.C.); (P.O.M.); (S.-H.P.)
| | - Phyu Ou Maung
- Division of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, Department of Dentistry, University of California Los Angeles (UCLA), Los Angeles, CA 90095, USA; (K.K.); (A.K.K.); (P.T.); (M.-W.K.); (N.O.); (J.C.); (J.C.); (P.O.M.); (S.-H.P.)
| | - So-Hyun Park
- Division of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, Department of Dentistry, University of California Los Angeles (UCLA), Los Angeles, CA 90095, USA; (K.K.); (A.K.K.); (P.T.); (M.-W.K.); (N.O.); (J.C.); (J.C.); (P.O.M.); (S.-H.P.)
| | - Nicholas Cacalano
- The Jonsson Comprehensive Cancer Center, Los Angeles, CA 90095, USA;
- Department of Radiation Oncology, Division of Molecular and Cellular Oncology, UCLA School of Dentistry and Medicine, Los Angeles, CA 90095, USA
| | - Changge Fang
- BioPro Diagnostics, LLC, 4919 Brook Hills Drive, Annandale, VA 22003, USA;
| | - Anahid Jewett
- Division of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, Department of Dentistry, University of California Los Angeles (UCLA), Los Angeles, CA 90095, USA; (K.K.); (A.K.K.); (P.T.); (M.-W.K.); (N.O.); (J.C.); (J.C.); (P.O.M.); (S.-H.P.)
- The Jonsson Comprehensive Cancer Center, Los Angeles, CA 90095, USA;
- Correspondence: ; Tel.: +1-310-968-4994; Fax: +1-310-794-7109
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Alvarado-Ortiz E, Sarabia-Sánchez MÁ, García-Carrancá A. Molecular Mechanisms Underlying the Functions of Cellular Markers Associated with the Phenotype of Cancer Stem Cells. Curr Stem Cell Res Ther 2019; 14:405-420. [PMID: 30147013 DOI: 10.2174/1574888x13666180821154752] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2018] [Revised: 07/18/2018] [Accepted: 08/13/2018] [Indexed: 12/19/2022]
Abstract
Cancer Stem Cells (CSC) generally constitute a minor cellular population within tumors that exhibits some capacities of normal Stem Cells (SC). The existence of CSC, able to self-renew and differentiate, influences central aspects of tumor biology, in part because they can continue tumor growth, give rise to metastasis, and acquire drug and radioresistance, which open new avenues for therapeutics. It is well known that SC constantly interacts with their niche, which includes mesenchymal cells, extracellular ligands, and the Extra Cellular Matrix (ECM). These interactions regularly lead to homeostasis and maintenance of SC characteristics. However, the exact participation of each of these components for CSC maintenance is not clear, as they appear to be context- or cell-specific. In the recent past, surface cellular markers have been fundamental molecular tools for identifying CSC and distinguishing them from other tumor cells. Importantly, some of these cellular markers have been shown to possess functional roles that affect central aspects of CSC. Likewise, some of these markers can participate in regulating the interaction of CSC with their niche, particularly the ECM. We focused this review on the molecular mechanisms of surface cellular markers commonly employed to identify CSC, highlighting the signaling pathways and mechanisms involved in CSC-ECM interactions, through each of the cellular markers commonly used in the study of CSC, such as CD44, CD133, CD49f, CD24, CXCR4, and LGR5. Their presence does not necessarily implicate them in CSC biology.
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Affiliation(s)
- Eduardo Alvarado-Ortiz
- Programa de Maestría y Doctorado en Ciencias Biológicas, Facultad de Ciencias, Universidad Nacional Autónoma de México, México City, México.,Laboratory of Virus and Cancer, Unidad de Investigacion Biomedica en Cáncer, Instituto de Investigaciones Biomedicas, Universidad Nacional Autonoma de Mexico & Subdireccion de Investigacion Basica, Instituto Nacional de Cancerologia, Secretaria de Salud, Ciudad de Mexico, Mexico
| | - Miguel Á Sarabia-Sánchez
- Laboratory of Virus and Cancer, Unidad de Investigacion Biomedica en Cáncer, Instituto de Investigaciones Biomedicas, Universidad Nacional Autonoma de Mexico & Subdireccion de Investigacion Basica, Instituto Nacional de Cancerologia, Secretaria de Salud, Ciudad de Mexico, Mexico.,Programa de Maestría y Doctorado en Ciencias Bioquímicas, Facultad de Química, Universidad Nacional Autónoma de México, , México City, México
| | - Alejandro García-Carrancá
- Laboratory of Virus and Cancer, Unidad de Investigacion Biomedica en Cáncer, Instituto de Investigaciones Biomedicas, Universidad Nacional Autonoma de Mexico & Subdireccion de Investigacion Basica, Instituto Nacional de Cancerologia, Secretaria de Salud, Ciudad de Mexico, Mexico
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31
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Ayres Pereira M, Chio IIC. Metastasis in Pancreatic Ductal Adenocarcinoma: Current Standing and Methodologies. Genes (Basel) 2019; 11:E6. [PMID: 31861620 PMCID: PMC7016631 DOI: 10.3390/genes11010006] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Revised: 12/11/2019] [Accepted: 12/17/2019] [Indexed: 01/18/2023] Open
Abstract
Pancreatic ductal adenocarcinoma is an extremely aggressive disease with a high metastatic potential. Most patients are diagnosed with metastatic disease, at which the five-year survival rate is only 3%. A better understanding of the mechanisms that drive metastasis is imperative for the development of better therapeutic interventions. Here, we take the reader through our current knowledge of the parameters that support metastatic progression in pancreatic ductal adenocarcinoma, and the experimental models that are at our disposal to study this process. We also describe the advantages and limitations of these models to study the different aspects of metastatic dissemination.
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Affiliation(s)
| | - Iok In Christine Chio
- Institute for Cancer Genetics, Department of Genetics and Development, Columbia University Medical Center, New York, NY 10032, USA;
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32
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Sharma NS, Gnamlin P, Durden B, Gupta VK, Kesh K, Garrido VT, Dudeja V, Saluja A, Banerjee S. Long non-coding RNA GAS5 acts as proliferation "brakes" in CD133+ cells responsible for tumor recurrence. Oncogenesis 2019; 8:68. [PMID: 31740660 PMCID: PMC6861230 DOI: 10.1038/s41389-019-0177-4] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2019] [Revised: 10/23/2019] [Accepted: 10/28/2019] [Indexed: 12/11/2022] Open
Abstract
Presence of quiescent, therapy evasive population often described as cancer stem cells (CSC) or tumor initiating cells (TIC) is often attributed to extreme metastasis and tumor recurrence. This population is typically enriched in a tumor as a result of microenvironment or chemotherapy induced stress. The TIC population adapts to this stress by turning on cell cycle arrest programs that is a “fail-safe” mechanism to prevent expansion of malignant cells to prevent further injury. Upon removal of the “stress” conditions, these cells restart their cell cycle and regain their proliferative nature thereby resulting in tumor relapse. Growth Arrest Specific 5 (GAS5) is a long-non-coding RNA that plays a vital role in this process. In pancreatic cancer, CD133+ population is a typical representation of the TIC population that is responsible for tumor relapse. In this study, we show for the first time that emergence of CD133+ population coincides with upregulation of GAS5, that reprograms the cell cycle to slow proliferation by inhibiting GR mediated cell cycle control. The CD133+ population further routed metabolites like glucose to shunt pathways like pentose phosphate pathway, that were predominantly biosynthetic in spite of being quiescent in nature but did not use it immediately for nucleic acid synthesis. Upon inhibiting GAS5, these cells were released from their growth arrest and restarted the nucleic acid synthesis and proliferation. Our study thus showed that GAS5 acts as a molecular switch for regulating quiescence and growth arrest in CD133+ population, that is responsible for aggressive biology of pancreatic tumors.
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Affiliation(s)
- Nikita S Sharma
- Department of Surgery, Miller school of Medicine, University of Miami, Miami, FL, USA
| | - Prisca Gnamlin
- Department of Surgery, Miller school of Medicine, University of Miami, Miami, FL, USA
| | - Brittany Durden
- Department of Surgery, Miller school of Medicine, University of Miami, Miami, FL, USA
| | - Vineet K Gupta
- Department of Surgery, Miller school of Medicine, University of Miami, Miami, FL, USA
| | - Kousik Kesh
- Department of Surgery, Miller school of Medicine, University of Miami, Miami, FL, USA
| | - Vanessa T Garrido
- Department of Surgery, Miller school of Medicine, University of Miami, Miami, FL, USA
| | - Vikas Dudeja
- Department of Surgery, Miller school of Medicine, University of Miami, Miami, FL, USA.,Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA
| | - Ashok Saluja
- Department of Surgery, Miller school of Medicine, University of Miami, Miami, FL, USA.,Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA
| | - Sulagna Banerjee
- Department of Surgery, Miller school of Medicine, University of Miami, Miami, FL, USA. .,Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA.
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Sun HR, Wang S, Yan SC, Zhang Y, Nelson PJ, Jia HL, Qin LX, Dong QZ. Therapeutic Strategies Targeting Cancer Stem Cells and Their Microenvironment. Front Oncol 2019; 9:1104. [PMID: 31709180 PMCID: PMC6821685 DOI: 10.3389/fonc.2019.01104] [Citation(s) in RCA: 67] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2019] [Accepted: 10/07/2019] [Indexed: 12/12/2022] Open
Abstract
Cancer stem cells (CSCs) have been demonstrated in a variety of tumors and are thought to act as a clonogenic core for the genesis of new tumor growth. This small subpopulation of cancer cells has been proposed to help drive tumorigenesis, metastasis, recurrence and conventional therapy resistance. CSCs show self-renewal and flexible clonogenic properties and help define specific tumor microenvironments (TME). The interaction between CSCs and TME is thought to function as a dynamic support system that fosters the generation and maintenance of CSCs. Investigation of the interaction between CSCs and the TME is shedding light on the biologic mechanisms underlying the process of tumor malignancy, metastasis, and therapy resistance. We summarize recent advances in CSC biology and their environment, and discuss the challenges and future strategies for targeting this biology as a new therapeutic approach.
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Affiliation(s)
- Hao-Ran Sun
- Department of General Surgery, Cancer Metastasis Institute, Institutes of Biomedical Sciences, Huashan Hospital, Fudan University, Shanghai, China
| | - Shun Wang
- Department of General Surgery, Cancer Metastasis Institute, Institutes of Biomedical Sciences, Huashan Hospital, Fudan University, Shanghai, China
| | - Shi-Can Yan
- Department of General Surgery, Cancer Metastasis Institute, Institutes of Biomedical Sciences, Huashan Hospital, Fudan University, Shanghai, China
| | - Yu Zhang
- Department of General Surgery, Cancer Metastasis Institute, Institutes of Biomedical Sciences, Huashan Hospital, Fudan University, Shanghai, China
| | - Peter J Nelson
- Medizinische Klinik und Poliklinik IV, Ludwig-Maximilian-University (LMU), Munich, Germany
| | - Hu-Liang Jia
- Department of General Surgery, Cancer Metastasis Institute, Institutes of Biomedical Sciences, Huashan Hospital, Fudan University, Shanghai, China
| | - Lun-Xiu Qin
- Department of General Surgery, Cancer Metastasis Institute, Institutes of Biomedical Sciences, Huashan Hospital, Fudan University, Shanghai, China
| | - Qiong-Zhu Dong
- Department of General Surgery, Cancer Metastasis Institute, Institutes of Biomedical Sciences, Huashan Hospital, Fudan University, Shanghai, China
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Xu Y, Yang X, Mei S, Sun Y, Li J. Acquisition of temozolomide resistance by the rat C6 glioma cell line increases cell migration and side population phenotype. Oncol Rep 2019; 42:2355-2362. [PMID: 31578583 PMCID: PMC6826311 DOI: 10.3892/or.2019.7350] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2019] [Accepted: 09/11/2019] [Indexed: 12/18/2022] Open
Abstract
Cancer stem cells are reportedly associated with drug resistance in glioma, but there are conflicting findings on the effects of cancer stem cells on drug resistance. The aim of the present study was to identify the underlying mechanisms of drug resistance in rat C6 glioma cells, through the use of Transwell invasion assays, flow cytometric and western blot analyses as well as immunohistochemical staining. The results revealed that acquisition of drug resistance by C6 cells enhanced migration ability in vivo and in vitro. Notably, drug resistance did not depend on the cancer stem cells of C6 cells, but on the increase of a side population phenotype. Blockade of the ABC transporter could increase sensitivity to temozolomide and temozolomide‑induced apoptosis in C6 cells. Collectively, these data indicated that drug resistance of C6 cells was mediated by the side population phenotype rather than by cancer stem cells.
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Affiliation(s)
- Ya Xu
- Department of Clinical Laboratory, The Affiliated Hospital of KMUST, Medical Faculty, Kunming University of Science and Technology, Kunming, Yunnan 650032, P.R. China
| | - Xiangcai Yang
- Department of Clinical Laboratory, The Affiliated Hospital of KMUST, Medical Faculty, Kunming University of Science and Technology, Kunming, Yunnan 650032, P.R. China
| | - Shuting Mei
- Department of Clinical Laboratory, The Affiliated Hospital of KMUST, Medical Faculty, Kunming University of Science and Technology, Kunming, Yunnan 650032, P.R. China
| | - Yi Sun
- Department of Clinical Laboratory, The Affiliated Hospital of KMUST, Medical Faculty, Kunming University of Science and Technology, Kunming, Yunnan 650032, P.R. China
| | - Jiejing Li
- Department of Clinical Laboratory, The Affiliated Hospital of KMUST, Medical Faculty, Kunming University of Science and Technology, Kunming, Yunnan 650032, P.R. China
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35
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Hocevar BA. Loss of Disabled-2 Expression in Pancreatic Cancer Progression. Sci Rep 2019; 9:7532. [PMID: 31101868 PMCID: PMC6525241 DOI: 10.1038/s41598-019-43992-z] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2016] [Accepted: 12/12/2018] [Indexed: 02/07/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer type characterized by rapid metastasis and resistance to chemotherapy, properties that are shared by cancer stem cells (CSCs). In pancreatic cancer, tumor cells which possess the properties of CSCs also phenotypically resemble cells that have undergone epithelial-to-mesenchymal transition or EMT. Disabled-2 (Dab2) is a multifunctional scaffold protein frequently downregulated in cancer that has been linked to the process of EMT. However, the role of Dab2 in pancreatic cancer development and progression remains unclear. Downregulation of Dab2 expression in pancreatic cancer cell lines was found to trigger induction of genes characteristic of EMT and the CSC phenotype, while overexpression of Dab2 in the Panc1 cell line blocked the process of TGFβ-stimulated EMT. In addition, selective inhibition of the TGFβRI/RII receptors was found to reverse genes altered by Dab2 downregulation. Dab2 mRNA expression was found to be decreased in PDAC tumor samples, as compared to levels observed in normal pancreatic tissue. Methylation of the Dab2 gene promoter was demonstrated in Stage I PDAC tumors and in the MiaPaCa2 cell line, suggesting that promoter methylation may silence Dab2 expression early in pancreatic cancer progression. These results suggest that Dab2 may function as a tumor suppressor in pancreatic cancer by modulation of the TGFβ-stimulated EMT and CSC phenotype.
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Affiliation(s)
- Barbara A Hocevar
- Department of Environmental and Occupational Health, School of Public Health, Indiana University, Bloomington, IN, USA.
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36
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唐 娜, 周 略, 成 志, 邓 永, 丁 彦. [Culture and identification of tumor stem cells from surgically resected colorectal cancer tissues]. NAN FANG YI KE DA XUE XUE BAO = JOURNAL OF SOUTHERN MEDICAL UNIVERSITY 2019; 39:415-421. [PMID: 31068284 PMCID: PMC6743995 DOI: 10.12122/j.issn.1673-4254.2019.04.06] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 12/27/2018] [Indexed: 11/24/2022]
Abstract
OBJECTIVE To obtain cancer stem cells (CSCs) from surgically resected colorectal cancer specimens and identify their stem cell characteristics. METHODS Colorectal cancer tissue specimen obtained from a patient undergoing radical resection of colorectal cancer were implanted in nude mice, and the xenograft was harvested 1 month later to obtain purified tumor cells by enzyme digestion and adherent culture. The CSCs were screened by limiting dilution method and serum-free culture to identify their phenotypes. Soft agar colony assay was used to assess the proliferative ability of the CSCs and human colorectal cancer cell line SW480. The tumorigenic ability of the isolated CSCs and SW480 cells was evaluated by observing their subcutaneous tumor formation in nude mice. Western blotting and immunofluorescence assay were used to detect the immunophenotype of the CSCs and SW480 cells. RESULTS The primary cultured CSCs from clinical specimens of colorectal cancer underwent differentiation in the presence of serum in the culture. Soft agar colony formation assay showed that the CSCs had a colony formation rate above 50%, significantly higher than the rate of colorectal cancer SW480 cells (4.41%; P < 0.01). In nude mice, subcutaneous injection of 500 CSCs was sufficient to result in subcutaneous tumor formation, while the injection of 500 SW480 cells failed to form any subcutaneous tumors. The CSCs expressed CD133 and CD44 but not CK7, while SW480 cells expressed CK7 but not CD133 or CD44. CONCLUSIONS CSCs can be derived by primary culture of cancer cells obtained from surgically resected colorectal cancer tissue followed by serum-free culture, and the CSCs obtained have self-renewal and differentiation abilities.
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Affiliation(s)
- 娜 唐
- 南方科技大学第一附属医院//深圳市人民医院 病理科，广东 深圳 518020Department of Pathology, Shenzhen People's Hospital/ First Affiliated Hospital of Southern University of Science and Technology, Shenzhen 518020, China
- 暨南大学第二临床医学院//深圳市人民医院病理科，广东 深圳 518020Department of Pathology, Shenzhen People's Hospital/Second Clinical College of Jinan University, Shenzhen 518020, China
| | - 略 周
- 南方科技大学第一附属医院//深圳市人民医院 放疗科，广东 深圳 518020Department of Radiation Oncology, Shenzhen People's Hospital/First Affiliated Hospital of Southern University of Science and Technology, Shenzhen 518020, China
| | - 志强 成
- 南方科技大学第一附属医院//深圳市人民医院 病理科，广东 深圳 518020Department of Pathology, Shenzhen People's Hospital/ First Affiliated Hospital of Southern University of Science and Technology, Shenzhen 518020, China
| | - 永键 邓
- 南方医科大学 南方医院病理科，广东 广州 510515Department of Pathology, Nanfang Hospital, Department of Pathology, Southern Medical University, Guangzhou 510515, China
- 南方医科大学 基础医学院病理学系，广东 广州 510515Department of Pathology, Nanfang Hospital, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
| | - 彦青 丁
- 南方医科大学 南方医院病理科，广东 广州 510515Department of Pathology, Nanfang Hospital, Department of Pathology, Southern Medical University, Guangzhou 510515, China
- 南方医科大学 基础医学院病理学系，广东 广州 510515Department of Pathology, Nanfang Hospital, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
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37
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Lee IC. Cancer-on-a-chip for Drug Screening. Curr Pharm Des 2019; 24:5407-5418. [DOI: 10.2174/1381612825666190206235233] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2018] [Accepted: 02/02/2019] [Indexed: 12/24/2022]
Abstract
:
The oncology pharmaceutical research spent a shocking amount of money on target validation and
drug optimization in preclinical models because many oncology drugs fail during clinical trial phase III. One of
the most important reasons for oncology drug failures in clinical trials may due to the poor predictive tool of
existing preclinical models. Therefore, in cancer research and personalized medicine field, it is critical to improve
the effectiveness of preclinical predictions of the drug response of patients to therapies and to reduce costly failures
in clinical trials. Three dimensional (3D) tumor models combine micro-manufacturing technologies mimic
critical physiologic parameters present in vivo, including complex multicellular architecture with multicellular
arrangement and extracellular matrix deposition, packed 3D structures with cell–cell interactions, such as tight
junctions, barriers to mass transport of drugs, nutrients and other factors, which are similar to in vivo tumor tissues.
These systems provide a solution to mimic the physiological environment for improving predictive accuracy
in oncology drug discovery.
:
his review gives an overview of the innovations, development and limitations of different types of tumor-like
construction techniques such as self-assemble spheroid formation, spheroids formation by micro-manufacturing
technologies, micro-dissected tumor tissues and tumor organoid. Combination of 3D tumor-like construction and
microfluidic techniques to achieve tumor on a chip for in vitro tumor environment modeling and drug screening
were all included. Eventually, developmental directions and technical challenges in the research field are also
discussed. We believe tumor on chip models have provided better sufficient clinical predictive power and will
bridge the gap between proof-of-concept studies and a wider implementation within the oncology drug development
for pathophysiological applications.
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Affiliation(s)
- I-Chi Lee
- Graduate Institute of Biomedical Engineering, Chang Gung University, Taoyuan, Taiwan
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38
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Xing L, Sun F, Wang Z, Li Y, Yang Z, Wang F, Zhai G, Tan H. Characterization and bioactivity of self-assembled anti-angiogenic chondroitin sulfate-ES2-AF nanoparticle conjugate. Int J Nanomedicine 2019; 14:2573-2589. [PMID: 31040673 PMCID: PMC6462165 DOI: 10.2147/ijn.s195934] [Citation(s) in RCA: 12] [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] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND In the past few years, significant progress has been made in inhibiting neovascularization at the tumor site, cutting off the nutrient supply of the tumor, and inhibiting tumor growth and metastasis. However, many proteins/peptides have the disadvantage of poor stability, short half-life, and uncertain targeting ability. Chemical modification can be used to overcome these disadvantages; many polyethylene glycol-modified proteins/peptides have been approved by US FDA. The purpose of this study was to obtain a novel anti-angiogenic chondroitin sulfate (CS)-peptide nanoparticle conjugate with efficient anti-neovascularization and tumor targeting ability and an acceptable half-life. MATERIALS AND METHODS The CS-ES2-AF nanoparticle conjugate was synthesized and characterized using 1H-nuclear magnetic resonance spectroscopy, transmission electron microscopy, and particle size and zeta potential analyzer. The anti-angiogenic ability was studied using MTT, migration, tube formation, and chick chorioallantoic membrane assays. The targeting ability of CS-ES2-AF was studied by ELISA, surface plasmon resonance, and bioimaging. The pharmacokinetics was also studied. RESULTS The CS-ES2-AF could self-assemble into stable nanoparticles in aqueous solution, which significantly enhances its anti-neovascularization activity, tumor targeting more explicit, and prolongs its half-life. CONCLUSION CS is an effective protein/peptide modifier, and CS-ES2-AF displayed good potential in tumor targeting therapy.
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Affiliation(s)
- Liang Xing
- National Glycoengineering Research Center, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, Shandong, People's Republic of China,
- Shandong Provincial Key Laboratory of Carbohydrate Chemistry and Glycobiology, Shandong University, Jinan 250012, Shandong, People's Republic of China,
| | - Feng Sun
- National Glycoengineering Research Center, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, Shandong, People's Republic of China,
- Shandong Provincial Key Laboratory of Carbohydrate Chemistry and Glycobiology, Shandong University, Jinan 250012, Shandong, People's Republic of China,
| | - Zhendong Wang
- National Glycoengineering Research Center, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, Shandong, People's Republic of China,
- Shandong Provincial Key Laboratory of Carbohydrate Chemistry and Glycobiology, Shandong University, Jinan 250012, Shandong, People's Republic of China,
| | - Yan Li
- National Glycoengineering Research Center, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, Shandong, People's Republic of China,
- Shandong Provincial Key Laboratory of Carbohydrate Chemistry and Glycobiology, Shandong University, Jinan 250012, Shandong, People's Republic of China,
| | - Zhifang Yang
- National Glycoengineering Research Center, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, Shandong, People's Republic of China,
- Shandong Provincial Key Laboratory of Carbohydrate Chemistry and Glycobiology, Shandong University, Jinan 250012, Shandong, People's Republic of China,
| | - Fengshan Wang
- National Glycoengineering Research Center, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, Shandong, People's Republic of China,
- School of Pharmaceutical Sciences, Shandong University, Jinan 250012, Shandong, People's Republic of China,
| | - Guangxi Zhai
- School of Pharmaceutical Sciences, Shandong University, Jinan 250012, Shandong, People's Republic of China,
| | - Haining Tan
- National Glycoengineering Research Center, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, Shandong, People's Republic of China,
- Shandong Provincial Key Laboratory of Carbohydrate Chemistry and Glycobiology, Shandong University, Jinan 250012, Shandong, People's Republic of China,
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Liu J, Zhang Y, Sun S, Zhang G, Jiang K, Sun P, Zhang Y, Yao B, Sui R, Chen Y, Guo X, Tang T, Shi J, Liang H, Piao H. Bufalin Induces Apoptosis and Improves the Sensitivity of Human Glioma Stem-Like Cells to Temozolamide. Oncol Res 2019; 27:475-486. [PMID: 29793559 PMCID: PMC7848418 DOI: 10.3727/096504018x15270916676926] [Citation(s) in RCA: 12] [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] [Indexed: 01/04/2023] Open
Abstract
Glioma is the most common malignant tumor of the central nervous system, and it is characterized by high relapse and fatality rates and poor prognosis. Bufalin is one of the main ingredients of Chan-su, a traditional Chinese medicine (TCM) extracted from toad venom. Previous studies revealed that bufalin exerted inhibitory effects on a variety of tumor cells. To demonstrate the inhibitory effect of bufalin on glioma cells and glioma stem-like cells (GSCs) and discuss the underlying mechanism, the proliferation of glioma cells was detected by MTT and colony formation assays following treatment with bufalin. In addition, we investigated whether bufalin inhibits or kills GSCs using flow cytometry, Western blotting, and reverse transcription polymerase chain reaction analysis (RT-PCR). Finally, we investigated whether bufalin could improve the therapeutic effect of temozolomide (TMZ) and discussed the underlying mechanism. Taken together, our data demonstrated that bufalin inhibits glioma cell growth and proliferation, inhibits GSC proliferation, and kills GSCs. Bufalin was found to induce the apoptosis of GSCs by upregulating the expression of the apoptotic proteins cleaved caspase 3 and poly(ADP-ribose) polymerase (PARP) and by downregulating the expression of human telomerase reverse transcriptase, which is a marker of telomerase activity. Bufalin also improved the inhibitory effect of TMZ on GSCs by activating the mitochondrial apoptotic pathway. These results suggest that bufalin damages GSCs, induces apoptosis, and enhances the sensitivity of GSCs to TMZ.
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Affiliation(s)
- Jia Liu
- *Department of Neurosurgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, Liaoning Province, P.R. China
| | - Ying Zhang
- †Liaoning University of Traditional Chinese Medicine, Shenyang, Liaoning Province, P.R. China
| | - Shulan Sun
- ‡Central Laboratory, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, Liaoning Province, P.R. China
| | - Guirong Zhang
- ‡Central Laboratory, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, Liaoning Province, P.R. China
| | - Ke Jiang
- §Institute of Cancer Stem Cell, Dalian Medical University, Dalian, Liaoning Province, P.R. China
| | - Peixin Sun
- *Department of Neurosurgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, Liaoning Province, P.R. China
| | - Ye Zhang
- *Department of Neurosurgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, Liaoning Province, P.R. China
| | - Bing Yao
- *Department of Neurosurgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, Liaoning Province, P.R. China
| | - Rui Sui
- *Department of Neurosurgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, Liaoning Province, P.R. China
| | - Yi Chen
- *Department of Neurosurgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, Liaoning Province, P.R. China
| | - Xu Guo
- *Department of Neurosurgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, Liaoning Province, P.R. China
| | - Tao Tang
- *Department of Neurosurgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, Liaoning Province, P.R. China
| | - Ji Shi
- *Department of Neurosurgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, Liaoning Province, P.R. China
| | - Haiyang Liang
- *Department of Neurosurgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, Liaoning Province, P.R. China
| | - Haozhe Piao
- *Department of Neurosurgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, Liaoning Province, P.R. China
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Khelwatty SA, Essapen S, Bagwan I, Green M, Seddon AM, Modjtahedi H. Co-expression and prognostic significance of putative CSC markers CD44, CD133, wild-type EGFR and EGFRvIII in metastatic colorectal cancer. Oncotarget 2019; 10:1704-1715. [PMID: 30899442 PMCID: PMC6422200 DOI: 10.18632/oncotarget.26722] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2019] [Accepted: 02/15/2019] [Indexed: 12/24/2022] Open
Abstract
The presence of colorectal cancer stem cells (CSCs) have been associated with tumour initiation and resistance to therapy. This study investigated the co-expression and prognostic significance of the CSCs biomarkers CD44 and CD133 with wild-type EGFR (wtEGFR) and EGFRvIII in colorectal cancer (CRC). The expression of these biomarkers were determined in tumours from 70 patients with metastatic CRC by immunohistochemistry, and in a panel of human CRC cell lines, and their variants with acquired-resistance to EGFR inhibitors, by flow cytometry. The expression of CD44, CD133, wtEGFR and EGFRvIII were present in 17%, 23%, 26% and 13% of cases and the co-expression of CD44/CD133 with wtEGFR and EGFRvIII were present in 9% and 3% of the cases respectively. Only co-expression of CSCs/EGFRvIII (P = 0.037), and amphiregulin (P = 0.017) were associated with worse overall survival. Interestingly, disease-free survival was improved in BTC expressing patients (P = 0.025). In vitro CD133 expression and its co-expression with CD44 were associated with primary-resistance to irinotecan and acquired-resistance to anti-EGFR inhibitors respectively. Our results suggest co-expression of CSCs and EGFRvIII could be potential biomarkers of worse overall survival and resistance to therapy in patients with mCRC and warrants further validation in a larger cohort.
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Affiliation(s)
| | - Sharadah Essapen
- School of Life Sciences, Pharmacy and Chemistry, Kingston University London, Kingston, UK.,St. Luke's Cancer Centre, Royal Surrey County Hospital, Guildford, Surrey, UK
| | - Izhar Bagwan
- Department of Histopathology, Royal Surrey County Hospital, Guildford, Surrey, UK
| | - Margaret Green
- Department of Histopathology, Royal Surrey County Hospital, Guildford, Surrey, UK
| | - Alan M Seddon
- School of Life Sciences, Pharmacy and Chemistry, Kingston University London, Kingston, UK
| | - Helmout Modjtahedi
- School of Life Sciences, Pharmacy and Chemistry, Kingston University London, Kingston, UK
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Dang SC, Qian XB, Jin W, Cui L, Chen JX, Gu M. G-protein-signaling modulator 2 expression and role in a CD133 + pancreatic cancer stem cell subset. Onco Targets Ther 2019; 12:785-794. [PMID: 30774366 PMCID: PMC6352860 DOI: 10.2147/ott.s187670] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND To investigate the expression and role of G-protein-signaling modulator 2 (GPSM2) in a CD133+ pancreatic stem cell subset. MATERIALS AND METHODS Pancreatic cancer stem cells (PCSCs) from the cell line PANC-1 were sorted into CD133+ and CD133- subsets by flow cytometry. The tumorigenic potential of the subsets was assessed by subcutaneous tumor formation experiments in nude mice. Differential expression of GPSM2 was examined by real-time quantitative-PCR (qPCR) and Western blotting. To silence GPSM2 expression, a shRNA lentiviral vector targeting GPSM2 was constructed and stably transfected into CD133+ PCSCs. The inhibitory efficiency of the GPSM2 gene was verified by qPCR and Western blotting. The proliferation, colony formation, and migration abilities of the transfected CD133+ pancreatic cancer cells were assessed by MTT, soft agar colony formation, and Transwell assays. RESULTS CD133+ and CD133- cell subsets were successfully isolated from PANC-1 cells. The CD133+ subset subcutaneously formed tumors in nude mice that were significantly bigger (343.05±57.59 mm3 vs 176.86±32.58 mm3, P<0.01) and denser (4.13±0.37 g vs 1.07±0.21 g, P<0.01) than those of the CD133- group. The GPSM2 mRNA and protein expression was significantly higher in CD133+ cells than in CD133- cells. Stable downregulation of GPSM2 expression reduced the proliferation, colony formation, and migration abilities of CD133+ PANC-1 cells (P<0.05). CONCLUSION The CD133+PANC-1 cells have obvious stem cell characteristics and increased GPSM2 expression. Downregulation of GPSM2 significantly reduces the proliferation and migration ability of the cells. Therefore, GPSM2 may provide an important target for regulating PCSCs.
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Affiliation(s)
- Sheng-Chun Dang
- Department of General Surgery, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu 212001, People's Republic of China
| | - Xiao-Bao Qian
- Department of General Surgery, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu 212001, People's Republic of China
| | - Wei Jin
- Department of Obstetrics and Gynecology, ChangShu No. 2 People's Hospital, Changshu, Jiangsu 215500, People's Republic of China
| | - Lei Cui
- Department of General Surgery, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu 212001, People's Republic of China
| | - Ji-Xiang Chen
- Department of General Surgery, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu 212001, People's Republic of China
| | - Min Gu
- Department of Oncology, Zhenjiang Hospital of Traditional Chinese and Western Medicine, Zhenjiang, Jiangsu 212001, People's Republic of China,
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van Schaijik B, Wickremesekera AC, Mantamadiotis T, Kaye AH, Tan ST, Stylli SS, Itinteang T. Circulating tumor stem cells and glioblastoma: A review. J Clin Neurosci 2019; 61:5-9. [PMID: 30622004 DOI: 10.1016/j.jocn.2018.12.019] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2018] [Accepted: 12/22/2018] [Indexed: 12/26/2022]
Abstract
Glioblastoma (GB) is the most aggressive primary brain tumor in adults. The aggressive nature of GB has been attributed to the presence of cancer stem cells (CSCs) which drive tumorigenesis and are thought to be the root cause of the disease. Circulating tumor stem cells (CTSCs), which can be derived from CSCs, have been identified in numerous types of cancer including GB, have been proposed to contribute to local and distant recurrence. There are many technical difficulties in studying CTSCs, therefore there is a significant gap in the literature pertaining to how they arise and function, and how the understanding of the biology of CTSCs could elucidate the underlying cause of local recurrence and metastasis. An initial epithelial-to-mesenchymal transition (EMT) followed by mesenchymal-to-epithelial transition involving these primitive cells appear to be the critical processes underpinning metastasis. This review focuses on the association between CSCs undergoing EMT to become CTSCs, and how this could arise from the CSC subpopulation in GB, and contribute to the understanding of the pathogenesis and treatment.
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Affiliation(s)
| | - Agadha C Wickremesekera
- Gillies McIndoe Research Institute, Wellington, New Zealand; Department of Neurosurgery, Wellington Regional Hospital, Wellington, New Zealand
| | - Theo Mantamadiotis
- Department of Microbiology & Immunology, School of Biomedical Sciences, The University of Melbourne, Melbourne, Victoria 3000, Australia; Department of Surgery, The University of Melbourne, The Royal Melbourne Hospital, Parkville, Victoria 3050, Australia
| | - Andrew H Kaye
- Department of Surgery, The University of Melbourne, The Royal Melbourne Hospital, Parkville, Victoria 3050, Australia; Department of Neurosurgery, The Royal Melbourne Hospital, Parkville, Victoria 3050, Australia
| | - Swee T Tan
- Gillies McIndoe Research Institute, Wellington, New Zealand; Wellington Regional Plastic, Maxillofacial & Burns Unit, Hutt Hospital, Wellington, New Zealand.
| | - Stanley S Stylli
- Department of Surgery, The University of Melbourne, The Royal Melbourne Hospital, Parkville, Victoria 3050, Australia; Department of Neurosurgery, The Royal Melbourne Hospital, Parkville, Victoria 3050, Australia
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Asadzadeh Z, Mansoori B, Mohammadi A, Aghajani M, Haji‐Asgarzadeh K, Safarzadeh E, Mokhtarzadeh A, Duijf PHG, Baradaran B. microRNAs in cancer stem cells: Biology, pathways, and therapeutic opportunities. J Cell Physiol 2018; 234:10002-10017. [DOI: 10.1002/jcp.27885] [Citation(s) in RCA: 66] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2018] [Accepted: 11/13/2018] [Indexed: 12/18/2022]
Affiliation(s)
- Zahra Asadzadeh
- Immunology Research Center, Tabriz University of Medical Sciences Tabriz Iran
| | - Behzad Mansoori
- Immunology Research Center, Tabriz University of Medical Sciences Tabriz Iran
- Student Research Committee, Tabriz University of Medical Sciences Tabriz Iran
| | - Ali Mohammadi
- Immunology Research Center, Tabriz University of Medical Sciences Tabriz Iran
| | - Marjan Aghajani
- Immunology Research Center, Tabriz University of Medical Sciences Tabriz Iran
| | | | - Elham Safarzadeh
- Immunology Research Center, Tabriz University of Medical Sciences Tabriz Iran
- Department of Microbiology & Immunology Faculty of Medicine, Ardabil University of Medical Sciences Ardabil Iran
| | - Ahad Mokhtarzadeh
- Immunology Research Center, Tabriz University of Medical Sciences Tabriz Iran
| | - Pascal H. G. Duijf
- Translational Research Institute, University of Queensland Diamantina Institute, The University of Queensland Brisbane Queensland Australia
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences Tabriz Iran
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Steinbichler TB, Dudás J, Skvortsov S, Ganswindt U, Riechelmann H, Skvortsova II. Therapy resistance mediated by cancer stem cells. Semin Cancer Biol 2018; 53:156-167. [PMID: 30471331 DOI: 10.1016/j.semcancer.2018.11.006] [Citation(s) in RCA: 200] [Impact Index Per Article: 28.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2018] [Revised: 11/19/2018] [Accepted: 11/19/2018] [Indexed: 12/13/2022]
Abstract
Cancer stem cells (CSC) possess abilities generally associated with embryonic or adult stem cells, especially self-renewal and differentiation. The CSC model assumes that this subpopulation of cells sustains malignant growth, which suggests a hierarchical organization of tumors in which CSCs are on top and responsible for the generation of intratumoral heterogeneity. Effective tumor therapy requires the eradication of CSC as they can support regrowth of the tumor resulting in recurrence. However, eradication of CSC is difficult because they frequently are therapy resistant. Therapy resistance is mediated by the acquisition of dormancy, increased DNA repair and drug efflux capacity, decreased apoptosis as well as the interaction between CSC and their supporting microenvironment, the CSC niche. This review highlights the role of CSC in chemo- and radiotherapy resistance as well as possible ways to overcome CSC mediated therapy resistance.
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Affiliation(s)
| | - József Dudás
- Department of Otorhinolaryngology, Head and Neck Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Sergej Skvortsov
- Department of Therapeutic Radiology and Oncology, Medical University of Innsbruck, Innsbruck, Austria; EXTRO-Lab, Tyrolean Cancer Research Institute, Innsbruck, Austria
| | - Ute Ganswindt
- Department of Therapeutic Radiology and Oncology, Medical University of Innsbruck, Innsbruck, Austria
| | - Herbert Riechelmann
- Department of Otorhinolaryngology, Head and Neck Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Ira-Ida Skvortsova
- Department of Therapeutic Radiology and Oncology, Medical University of Innsbruck, Innsbruck, Austria; EXTRO-Lab, Tyrolean Cancer Research Institute, Innsbruck, Austria.
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Ortiz-Montero P, Liu-Bordes WY, Londoño-Vallejo A, Vernot JP. CD24 expression and stem-associated features define tumor cell heterogeneity and tumorigenic capacities in a model of carcinogenesis. Cancer Manag Res 2018; 10:5767-5784. [PMID: 30510447 PMCID: PMC6248383 DOI: 10.2147/cmar.s176654] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Background Most carcinomas are composed of heterogeneous populations of tumor cells with distinct and apparently stable phenotypic characteristics. Methods Using an in vitro model of carcinogenesis we aimed at experimentally elucidating the significance of heterogeneity in the expression of CD24, a marker frequently overexpressed in various cancers and correlated with poor prognosis. Results We show that CD24Neg and CD24Pos cells issued from the same tumorigenic cell line display striking differences in stem-related properties, expression of epithelial-mesenchymal transition/mesenchymal-epithelial transition markers, and tumorigenic capacity. Indeed, while CD24Neg cells were as tumorigenic as the parental cell line, CD24Pos cells, although unable to form tumors, were unexpectedly more mesenchymal, displayed enhanced stemness-related properties, and expressed a proinflammatory signature. Conclusion Our findings support the view that acquisition of stem-like cell, CD24-associated, attributes like migration, invasion, and plasticity by a tumor subpopulation is not necessarily related to local tumor growth but may be required for escaping the niche and colonizing distant sites.
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Affiliation(s)
- Paola Ortiz-Montero
- Cellular and Molecular Physiology Group, Faculty of Medicine, Department of Physiological Sciences, National University of Colombia, Bogotá, Colombia,
| | - Win-Yan Liu-Bordes
- Institut Curie, PSL Research University, Sorbonne University, CNRS UMR3244 Telomere and Cancer Lab, Paris, France
| | - Arturo Londoño-Vallejo
- Institut Curie, PSL Research University, Sorbonne University, CNRS UMR3244 Telomere and Cancer Lab, Paris, France
| | - Jean-Paul Vernot
- Cellular and Molecular Physiology Group, Faculty of Medicine, Department of Physiological Sciences, National University of Colombia, Bogotá, Colombia, .,Biomedical Research Institute, Faculty of Medicine, National University of Colombia, Bogotá, Colombia,
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Cao J, Ma J, Sun L, Li J, Qin T, Zhou C, Cheng L, Chen K, Qian W, Duan W, Wang F, Wu E, Wang Z, Ma Q, Han L. Targeting glypican-4 overcomes 5-FU resistance and attenuates stem cell-like properties via suppression of Wnt/β-catenin pathway in pancreatic cancer cells. J Cell Biochem 2018; 119:9498-9512. [PMID: 30010221 DOI: 10.1002/jcb.27266] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2018] [Revised: 06/12/2018] [Accepted: 06/22/2018] [Indexed: 12/12/2022]
Abstract
The existences of cancer stem cells in patients with pancreatic cancer are considered as pivotal factors contributing to chemoresistance and disease relapse. Glypican-4 (GPC4) is one of the members of the glypicans family, which underlies human congenital malformations and multiple diseases. However, its potential biological function in pancreatic cancer still remains elusive. In this study, we are the first to demonstrate that GPC4 was involved in 5-fluorouracil (5-FU) resistance and pancreatic cancer stemness through comprehensive bioinformatical analysis. Functional experiments showed that knockdown of GPC4 sensitized pancreatic cancer cells to 5-FU and attenuated stem cell-like properties. In terms of mechanism research, knockdown of GPC4 suppressed the activation of Wnt/β-catenin pathway and its downstream targets. Furthermore, the expression of GPC4 was significantly upregulated in pancreatic cancer tissues compared with normal tissues and remarkably correlated with patients' overall survival according to the data derived from the Cancer Genome Atlas database. Taken together, our results suggest that GPC4 is a key regulator in chemoresistance and pancreatic cancer stemness. Thus, targeting GPC4 may serve as a promising strategy for pancreatic cancer therapy.
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Affiliation(s)
- Junyu Cao
- Department of Hepatobiliary Surgery, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China
| | - Jiguang Ma
- Department of Anesthesiology, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China
| | - Liankang Sun
- Department of Hepatobiliary Surgery, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China
| | - Jie Li
- Department of Hepatobiliary Surgery, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China
| | - Tao Qin
- Department of Hepatobiliary Surgery, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China
| | - Cancan Zhou
- Department of Hepatobiliary Surgery, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China
| | - Liang Cheng
- Department of Hepatobiliary Surgery, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China
| | - Ke Chen
- Department of Hepatobiliary Surgery, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China
| | - Weikun Qian
- Department of Hepatobiliary Surgery, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China
| | - Wanxing Duan
- Department of Hepatobiliary Surgery, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China
| | - Fengfei Wang
- Department of Neurosurgery, Baylor Scott & White Health, Temple, Texas
- Neuroscience Institute, Baylor Scott & White Health, Temple, Texas
- Department of Surgery, Texas A & M University College of Medicine, College Station, Texas
- Department of Neurology, Baylor Scott & White Health, Temple, Texas
| | - Erxi Wu
- Department of Neurosurgery, Baylor Scott & White Health, Temple, Texas
- Neuroscience Institute, Baylor Scott & White Health, Temple, Texas
- Department of Surgery, Texas A & M University College of Medicine, College Station, Texas
- Department of Pharmaceutical Sciences, Texas A & M University College of Pharmacy, College Station, Texas
| | - Zheng Wang
- Department of Hepatobiliary Surgery, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China
| | - Qingyong Ma
- Department of Hepatobiliary Surgery, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China
| | - Liang Han
- Department of Hepatobiliary Surgery, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China
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Enrichment of cancer stem cells by agarose multi-well dishes and 3D spheroid culture. Cell Tissue Res 2018; 375:397-408. [PMID: 30244317 DOI: 10.1007/s00441-018-2920-0] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2017] [Accepted: 09/05/2018] [Indexed: 01/03/2023]
Abstract
As the theory of cancer stem cells (CSCs) is maturing, CSC-targeted therapy is emerging as an important therapeutic strategy and seeking the ideal method for rapid enrichment and purification of CSCs has become crucial. So far, based on the known CSC phenotypes and biological characteristics, the methods for enrichment CSCs mainly include low adhesion culture, low oxygen culture, chemotherapy drug stimulation and side population (SP) sorting but these methods cannot realize quick enrichment of the desired CSCs. Herein, we adopt a novel method that efficiently enriches a certain amount of CSCs through agarose multi-well dishes using rubber micro-molds to make cancer cells into cell spheroids (3D). These 3D cancer cell spheroids in the proportions of expression of CSC biomarkers (single stain of CD44, CD44v6 and CD133 or double stain of both CD44 and CD133) were significantly higher than those of the conventional adherent culture (2D) using flow cytometry analysis. In addition, the expression levels of stemness transcription factors such as OCT4, NANOG and SOX2 in 3D were also significantly higher than that in 2D through Western blot (WB) and quantitative polymerase chain reaction (qPCR) assays. In addition, the CSCs in 3D could form colonies with different sizes in soft agar. In conclusion, we developed a new method to enrich some kinds of CSCs, which might be a benefit for future CSC-targeted therapy studies and anti-CSC drug screening applications.
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48
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Dong R, Chen P, Chen Q. Inhibition of pancreatic cancer stem cells by Rauwolfia vomitoria extract. Oncol Rep 2018; 40:3144-3154. [PMID: 30272287 PMCID: PMC6196640 DOI: 10.3892/or.2018.6713] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2017] [Accepted: 05/25/2018] [Indexed: 01/05/2023] Open
Abstract
The poor treatment outcomes of pancreatic cancer are linked to an enrichment of cancer stem cells (CSCs) in these tumors, which are resistant to chemotherapy and promote metastasis and tumor recurrence. The present study investigated an extract from the root of the medicinal plant Rauwolfia vomitoria (Rau) for its activity against pancreatic CSCs. In vitro tumor spheroid formation and CSC markers were tested, and in vivo tumorigenicity was evaluated in nude mice. Rau inhibited the overall proliferation of human pancreatic cancer cell lines with a 50% inhibitory concentration (IC50) ranging between 125 and 325 µg/ml, and showed limited cytotoxicity towards normal epithelial cells. The pancreatic CSC population, identified using cell surface markers or a tumor spheroid formation assay, was significantly reduced, with an IC50 value of ~100 µg/ml treatment for 48 h and ~27 µg/ml for long-term tumor spheroid formation. The levels of CSC-related gene Nanog and nuclear β-catenin were decreased, suggesting suppression of the Wnt/β-catenin signaling pathway. In vivo, 20 mg/kg of Rau administered five times per week by oral gavage significantly reduced the tumorigenicity of PANC-1 cells in immunocompromised mice. Taken together, these data showed that Rau preferentially inhibited pancreatic cancer stem cells. Further investigation is warranted to examine the potential of Rau as a novel treatment for pancreatic cancer.
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Affiliation(s)
- Ruochen Dong
- Department of Pharmacology, Toxicology and Therapeutics, KU Integrative Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Ping Chen
- Department of Pharmacology, Toxicology and Therapeutics, KU Integrative Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Qi Chen
- Department of Pharmacology, Toxicology and Therapeutics, KU Integrative Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA
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Adamska A, Falasca M. ATP-binding cassette transporters in progression and clinical outcome of pancreatic cancer: What is the way forward? World J Gastroenterol 2018; 24:3222-3238. [PMID: 30090003 PMCID: PMC6079284 DOI: 10.3748/wjg.v24.i29.3222] [Citation(s) in RCA: 78] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2018] [Revised: 05/31/2018] [Accepted: 06/27/2018] [Indexed: 02/06/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive diseases and is characterized by high chemoresistance, leading to the lack of effective therapeutic approaches and grim prognosis. Despite increasing understanding of the mechanisms of chemoresistance in cancer and the role of ATP-binding cassette (ABC) transporters in this resistance, the therapeutic potential of their pharmacological inhibition has not been successfully exploited yet. In spite of the discovery of potent pharmacological modulators of ABC transporters, the results obtained in clinical trials have been so far disappointing, with high toxicity levels impairing their successful administration to the patients. Critically, although ABC transporters have been mostly studied for their involvement in development of multidrug resistance (MDR), in recent years the contribution of ABC transporters to cancer initiation and progression has emerged as an important area of research, the understanding of which could significantly influence the development of more specific and efficient therapies. In this review, we explore the role of ABC transporters in the development and progression of malignancies, with focus on PDAC. Their established involvement in development of MDR will be also presented. Moreover, an emerging role for ABC transporters as prognostic tools for patients' survival will be discussed, demonstrating the therapeutic potential of ABC transporters in cancer therapy.
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Affiliation(s)
- Aleksandra Adamska
- Metabolic Signalling Group, School of Pharmacy and Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth 6102, WA, Australia
| | - Marco Falasca
- Metabolic Signalling Group, School of Pharmacy and Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth 6102, WA, Australia
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50
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Subramaniam D, Kaushik G, Dandawate P, Anant S. Targeting Cancer Stem Cells for Chemoprevention of Pancreatic Cancer. Curr Med Chem 2018; 25:2585-2594. [PMID: 28137215 DOI: 10.2174/0929867324666170127095832] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2016] [Revised: 12/17/2016] [Accepted: 12/17/2016] [Indexed: 02/06/2023]
Abstract
Pancreatic ductal adenocarcinoma is one of the deadliest cancers worldwide and the fourth leading cause of cancer-related deaths in United States. Regardless of the advances in molecular pathogenesis and consequential efforts to suppress the disease, this cancer remains a major health problem in United States. By 2030, the projection is that pancreatic cancer will be climb up to be the second leading cause of cancer-related deaths in the United States. Pancreatic cancer is a rapidly invasive and highly metastatic cancer, and does not respond to standard therapies. Emerging evidence supports that the presence of a unique population of cells called cancer stem cells (CSCs) as potential cancer inducing cells and efforts are underway to develop therapeutic strategies targeting these cells. CSCs are rare quiescent cells, and with the capacity to self-renew through asymmetric/symmetric cell division, as well as differentiate into various lineages of cells in the cancer. Studies have been shown that CSCs are highly resistant to standard therapy and also responsible for drug resistance, cancer recurrence and metastasis. To overcome this problem, we need novel preventive agents that target these CSCs. Natural compounds or phytochemicals have ability to target these CSCs and their signaling pathways. Therefore, in the present review article, we summarize our current understanding of pancreatic CSCs and their signaling pathways, and the phytochemicals that target these cells including curcumin, resveratrol, tea polyphenol EGCG (epigallocatechin- 3-gallate), crocetinic acid, sulforaphane, genistein, indole-3-carbinol, vitamin E δ- tocotrienol, Plumbagin, quercetin, triptolide, Licofelene and Quinomycin. These natural compounds or phytochemicals, which inhibit cancer stem cells may prove to be promising agents for the prevention and treatment of pancreatic cancers.
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Affiliation(s)
- Dharmalingam Subramaniam
- Department of Surgery, the University of Kansas Medical Center, Kansas City, KS 66160, United States.,The University of Kansas Cancer Center, The University of Kansas Medical Center, Kansas City, KS 66160, United States
| | - Gaurav Kaushik
- Department of Surgery, the University of Kansas Medical Center, Kansas City, KS 66160, United States
| | - Prasad Dandawate
- Department of Surgery, the University of Kansas Medical Center, Kansas City, KS 66160, United States
| | - Shrikant Anant
- Department of Surgery, the University of Kansas Medical Center, Kansas City, KS 66160, United States.,The University of Kansas Cancer Center, The University of Kansas Medical Center, Kansas City, KS 66160, United States
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