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Sun Z, Zhao W, Fei X, He B, Shi L, Zhang Z, Cai S. Static magnetic field inhibits epithelial mesenchymal transition and metastasis of glioma. Sci Rep 2025; 15:12430. [PMID: 40216876 PMCID: PMC11992211 DOI: 10.1038/s41598-025-96047-x] [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: 11/02/2024] [Accepted: 03/25/2025] [Indexed: 04/14/2025] Open
Abstract
Gliomas exhibit suboptimal responses to conventional treatments, with tumor cell migration remaining a significant challenge in therapy. Epithelial-mesenchymal transition (EMT) is crucial for glioma cell invasion, and transforming growth factor β1(TGF-β1) is a key factor promoting proliferation, migration, and EMT in glioblastoma (GBM). Although magnetic fields are widely used in the diagnosis and treatment of various diseases, their effects on EMT in glioma cells remain unclear. In this study, we investigated whether a static magnetic field (SMF) could inhibit EMT and metastasis in glioma cells. Cellular functional assays using the U251 and U87 glioma cell lines were performed to investigate their functional and phenotypic changes. Results showed that TGF-β1 treatment increased the invasion and migration capabilities of glioma cells, while simultaneously reducing apoptosis. However, when SMF was combined with TGF-β1 treatment, a significant reduction in cell migration and invasion was observed, along with an increase in apoptosis. Additionally, this combination treatment significantly decreased the protein expression of mesenchymal markers N-cadherin and β-catenin, as well as reduced the levels of the matrix metalloproteinase (MMP)-2. Collectively, these findings suggest that SMFs may attenuate glioma cell metastasis by inhibiting EMT. Therefore, SMFs could represent a promising therapeutic strategy for diminishing glioma metastasis.
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Affiliation(s)
- Ziyu Sun
- Department of Neurosurgery, Gusu School, Nanjing Medical University, The First People's Hospital of Kunshan, Suzhou, People's Republic of China
| | - Wenxuan Zhao
- Department of Neurosurgery, Gusu School, Nanjing Medical University, The First People's Hospital of Kunshan, Suzhou, People's Republic of China
| | - Xifeng Fei
- Department of Neurosurgery, Suzhou Kowloon Hospital, Shanghai Jiaotong University School of Medicine, Suzhou, People's Republic of China
| | - Bao He
- Department of Neurosurgery, Gusu School, Nanjing Medical University, The First People's Hospital of Kunshan, Suzhou, People's Republic of China
| | - Lei Shi
- Department of Neurosurgery, Gusu School, Nanjing Medical University, The First People's Hospital of Kunshan, Suzhou, People's Republic of China.
| | - Zhen Zhang
- Department of Radiology, Affiliated Kunshan Hospital of Jiangsu University, China Medical University, Gusu School Nanjing Medical University, Suzhou, People's Republic of China.
| | - Shizhong Cai
- Department of Child and Adolescent Healthcare, Children's Hospital of Soochow University, Suzhou, Jiangsu, People's Republic of China.
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Wu M, Xiao Y, Wang Y, Deng L, Wang X, An T. Establishment of a clinical model based on vessels encapsulating tumour clusters that could efficiently predict recurrence of patients with hepatocellular carcinoma after curative hepatectomy. Pathology 2025; 57:320-327. [PMID: 39668071 DOI: 10.1016/j.pathol.2024.08.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Revised: 07/20/2024] [Accepted: 08/25/2024] [Indexed: 12/14/2024]
Abstract
According to previous studies, vessels encapsulating tumour clusters (VETC) could promote metastasis of hepatocellular carcinoma (HCC) in a manner independent from epithelial-mesenchymal transition (EMT). However, the prognostic significance of VETC among patients undergoing curative hepatectomy has not been fully explored. This study was performed to assess the prognostic significance of VETC among patients with HCC undergoing curative hepatectomy. A total of 81 patients were included in this study. A predictive model based on VETC was established, then this model was compared with the American Joint Committee on Cancer, Tumor Node Metastasis (AJCC TNM) stage and Barcelona Clinic Liver Cancer (BCLC) system. It was revealed by multivariate Cox regression analysis that a high neutrophil-to-lymphocyte ratio (NLR) [p=0.013, hazard ratio (HR)=6.175, 95% confidence interval (CI) 1.468-25.977], number of tumours (p<0.001, HR=4.119, 95% CI 1.886-8.995) and VETC positivity (p=0.010, HR=2.440, 95% CI 1.235-4.821) were independent predictive factors for disease-free survival (DFS). Additionally, by Kaplan-Meier analysis, we revealed that VETC positivity was associated with worse DFS (p=0.018). The clinical predictive model combining the NLR, number of tumours, and VETC was compared with AJCC TNM stage and BCLC classification system by performing time-dependent receiver operating curve (td-ROC) analysis, revealing that the clinical predictive model was superior to AJCC TNM stage and BCLC system at different timepoints. Additionally, we demonstrated that the clinical model could well predict DFS by plotting calibration curves. VETC could be utilised as an efficient prognostic factor for HCC and the clinical predictive model combining the NLR, number of tumours, and VETC was superior to AJCC TNM stage and BCLC system in predicting cancer recurrence.
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Affiliation(s)
- Meilong Wu
- Division of Hepatobiliary and Pancreatic Surgery, Department of General Surgery, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University), Shenzhen, Guangdong, China; The First Affiliated Hospital, Southern University of Science and Technology, Shenzhen, Guangdong, China
| | - Ying Xiao
- Department of Pathology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China
| | - Yan Wang
- The First Affiliated Hospital, Southern University of Science and Technology, Shenzhen, Guangdong, China; Department of Radiology, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University), Shenzhen, Guangdong, China
| | - Lingna Deng
- Department of Pathology, Qingyuan People's Hospital, Qingyuan, Guangdong, China
| | - Xiaojuan Wang
- Hepatopancreatobiliary Center, Beijing Tsinghua Changgung Hospital, Key Laboratory of Digital Intelligence Hepatology (Chinese Ministry of Education), School of Clinical Medicine, Tsinghua University, Beijing, China; Institute for Organ Transplantation and Bionics, Institute for Precision Medicine of School of Clinical Medicine, Tsinghua University, Beijing, China.
| | - Tailai An
- Division of Hepatobiliary and Pancreatic Surgery, Department of General Surgery, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University), Shenzhen, Guangdong, China; The First Affiliated Hospital, Southern University of Science and Technology, Shenzhen, Guangdong, China.
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3
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Nakamura ET, Park A, Pereira MA, Kikawa D, Tustumi F. Prognosis value of heat-shock proteins in esophageal and esophagogastric cancer: A systematic review and meta-analysis. World J Gastrointest Oncol 2024; 16:1578-1595. [PMID: 38660660 PMCID: PMC11037039 DOI: 10.4251/wjgo.v16.i4.1578] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2023] [Revised: 12/24/2023] [Accepted: 01/23/2024] [Indexed: 04/10/2024] Open
Abstract
BACKGROUND Heat shock proteins (HSPs) are molecular chaperones that play an important role in cellular protection against stress events and have been reported to be overexpressed in many cancers. The prognostic significance of HSPs and their regulatory factors, such as heat shock factor 1 (HSF1) and CHIP, are poorly understood. AIM To investigate the relationship between HSP expression and prognosis in esophageal and esophagogastric cancer. METHODS A systematic review was conducted in accordance with PRISMA recommendations (PROSPERO: CRD42022370653), on Embase, PubMed, Cochrane, and LILACS. Cohort, case-control, and cross-sectional studies of patients with esophagus or esophagogastric cancer were included. HSP-positive patients were compared with HSP-negative, and the endpoints analyzed were lymph node metastasis, tumor depth, distant metastasis, and overall survival (OS). HSPs were stratified according to the HSP family, and the summary risk difference (RD) was calculated using a random-effect model. RESULTS The final selection comprised 27 studies, including esophageal squamous cell carcinoma (21), esophagogastric adenocarcinoma (5), and mixed neoplasms (1). The pooled sample size was 3465 patients. HSP40 and 60 were associated with a higher 3-year OS [HSP40: RD = 0.22; 95% confidence interval (CI): 0.09-0.35; HSP60: RD = 0.33; 95%CI: 0.17-0.50], while HSF1 was associated with a poor 3-year OS (RD = -0.22; 95%CI: -0.32 to -0.12). The other HSP families were not associated with long-term survival. HSF1 was associated with a higher probability of lymph node metastasis (RD = -0.16; 95%CI: -0.29 to -0.04). HSP40 was associated with a lower probability of lymph node dissemination (RD = 0.18; 95%CI: 0.03-0.33). The expression of other HSP families was not significantly related to tumor depth and lymph node or distant metastasis. CONCLUSION The expression levels of certain families of HSP, such as HSP40 and 60 and HSF1, are associated with long-term survival and lymph node dissemination in patients with esophageal and esophagogastric cancer.
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Affiliation(s)
- Eric Toshiyuki Nakamura
- Department of Gastroenterology, Instituto do Câncer, Hospital das Clínicas da Universidade de São Paulo, Faculdade de Medicina, Universidade de São Paulo, São Paulo 01246000, Brazil
- Department of Scientific Initiation, Universidade Mogi das Cruzes, São Paulo 08780911, Brazil
| | - Amanda Park
- Department of Evidence-Based Medicine, Centro Universitário Lusíada, Centre for Evidence-Based Medicine, Centro Universitário Lusíada (UNILUS), Santos, Brazil
| | - Marina Alessandra Pereira
- Department of Gastroenterology, Instituto do Câncer, Hospital das Clínicas da Universidade de São Paulo, Faculdade de Medicina, Universidade de São Paulo, São Paulo 01246000, Brazil
| | - Daniel Kikawa
- Department of Scientific Initiation, Universidade Mogi das Cruzes, São Paulo 08780911, Brazil
| | - Francisco Tustumi
- Department of Gastroenterology, Instituto do Câncer, Hospital das Clínicas da Universidade de São Paulo, Faculdade de Medicina, Universidade de São Paulo, São Paulo 01246000, Brazil
- Department of Surgery, Hospital Israelita Albert Einstein, São Paulo 05652900, Brazil
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Murai T, Matsuda S. Fatty Acid Metabolites and the Tumor Microenvironment as Potent Regulators of Cancer Stem Cell Signaling. Metabolites 2023; 13:709. [PMID: 37367867 DOI: 10.3390/metabo13060709] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 05/22/2023] [Accepted: 05/29/2023] [Indexed: 06/28/2023] Open
Abstract
Individual cancer cells are not equal but are organized into a cellular hierarchy in which only a rare few leukemia cells can self-renew in a manner reminiscent of the characteristic stem cell properties. The PI3K/AKT pathway functions in a variety of cancers and plays a critical role in the survival and proliferation of healthy cells under physiologic conditions. In addition, cancer stem cells might exhibit a variety of metabolic reprogramming phenotypes that cannot be completely attributed to the intrinsic heterogeneity of cancer. Given the heterogeneity of cancer stem cells, new strategies with single-cell resolution will become a powerful tool to eradicate the aggressive cell population harboring cancer stem cell phenotypes. Here, this article will provide an overview of the most important signaling pathways of cancer stem cells regarding their relevance to the tumor microenvironment and fatty acid metabolism, suggesting valuable strategies among cancer immunotherapies to inhibit the recurrence of tumors.
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Affiliation(s)
- Toshiyuki Murai
- Graduate School of Medicine, Osaka University, 2-2 Yamada-oka, Suita 565-0871, Japan
| | - Satoru Matsuda
- Department of Food Science and Nutrition, Nara Women's University, Kita-Uoya Nishimachi, Nara 630-8506, Japan
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Jiang K, Dong C, Yin Z, Li R, Mao J, Wang C, Zhang J, Gao Z, Liang R, Wang Q, Wang L. Exosome-derived ENO1 regulates integrin α6β4 expression and promotes hepatocellular carcinoma growth and metastasis. Cell Death Dis 2020; 11:972. [PMID: 33184263 PMCID: PMC7661725 DOI: 10.1038/s41419-020-03179-1] [Citation(s) in RCA: 65] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Revised: 10/27/2020] [Accepted: 10/27/2020] [Indexed: 02/07/2023]
Abstract
Alpha-enolase (ENO1) has been found to be dysregulated in several human malignancies, including hepatocellular carcinoma (HCC). Although the role of ENO1 as a glycolytic enzyme in HCC cells has been well characterized, little is known about the other roles of ENO1, especially exosome-derived ENO1, in regulating HCC progression. Here, we demonstrated that ENO1 is frequently upregulated in HCC cells or tissues, with even higher expression in highly metastatic HCC cells or metastatic tissues as well as in exosomes derived from highly metastatic sources. Moreover, ENO1 expression is associated with the tumor-node-metastasis (TNM) stage, differentiation grade and poor prognosis in HCC patients. Surprisingly, ENO1 can be transferred between HCC cells via exosome-mediated crosstalk, exhibiting an effect similar to that of ENO1 overexpression in HCC cells, which promoted the growth and metastasis of HCC cells with low ENO1 expression by upregulating integrin α6β4 expression and activating the FAK/Src-p38MAPK pathway. In summary, our data suggest that exosome-derived ENO1 is essential to promoting HCC growth, metastasis, and further patient deterioration. The findings from this study implicate a novel biomarker for the clinical evaluation of HCC progression, especially the prediction of HCC metastatic risk.
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Affiliation(s)
- Keqiu Jiang
- Engineering Research Center for New Materials and Precision Treatment Technology of Malignant Tumors Therapy, Dalian Medical University, NO. 467 Zhongshan Road, Dalian, Liaoning, 116027, China
- Engineering Technology Research Center for Translational Medicine, Dalian Medical University, NO. 467 Zhongshan Road, Dalian, Liaoning, 116027, China
- Division of Hepatobiliary and Pancreatic Surgery, Department of General Surgery, The Second Affiliated Hospital of Dalian Medical University, NO. 467 Zhongshan Road, Dalian, Liaoning, 116027, China
| | - Chengyong Dong
- Division of Hepatobiliary and Pancreatic Surgery, Department of General Surgery, The Second Affiliated Hospital of Dalian Medical University, NO. 467 Zhongshan Road, Dalian, Liaoning, 116027, China
| | - Zeli Yin
- Engineering Research Center for New Materials and Precision Treatment Technology of Malignant Tumors Therapy, Dalian Medical University, NO. 467 Zhongshan Road, Dalian, Liaoning, 116027, China
- Engineering Technology Research Center for Translational Medicine, Dalian Medical University, NO. 467 Zhongshan Road, Dalian, Liaoning, 116027, China
- Division of Hepatobiliary and Pancreatic Surgery, Department of General Surgery, The Second Affiliated Hospital of Dalian Medical University, NO. 467 Zhongshan Road, Dalian, Liaoning, 116027, China
| | - Rui Li
- Engineering Research Center for New Materials and Precision Treatment Technology of Malignant Tumors Therapy, Dalian Medical University, NO. 467 Zhongshan Road, Dalian, Liaoning, 116027, China
- Engineering Technology Research Center for Translational Medicine, Dalian Medical University, NO. 467 Zhongshan Road, Dalian, Liaoning, 116027, China
- Division of Hepatobiliary and Pancreatic Surgery, Department of General Surgery, The Second Affiliated Hospital of Dalian Medical University, NO. 467 Zhongshan Road, Dalian, Liaoning, 116027, China
| | - Jiakai Mao
- Engineering Research Center for New Materials and Precision Treatment Technology of Malignant Tumors Therapy, Dalian Medical University, NO. 467 Zhongshan Road, Dalian, Liaoning, 116027, China
- Engineering Technology Research Center for Translational Medicine, Dalian Medical University, NO. 467 Zhongshan Road, Dalian, Liaoning, 116027, China
- Division of Hepatobiliary and Pancreatic Surgery, Department of General Surgery, The Second Affiliated Hospital of Dalian Medical University, NO. 467 Zhongshan Road, Dalian, Liaoning, 116027, China
| | - Chengye Wang
- Engineering Research Center for New Materials and Precision Treatment Technology of Malignant Tumors Therapy, Dalian Medical University, NO. 467 Zhongshan Road, Dalian, Liaoning, 116027, China
- Engineering Technology Research Center for Translational Medicine, Dalian Medical University, NO. 467 Zhongshan Road, Dalian, Liaoning, 116027, China
| | - Junlin Zhang
- Engineering Research Center for New Materials and Precision Treatment Technology of Malignant Tumors Therapy, Dalian Medical University, NO. 467 Zhongshan Road, Dalian, Liaoning, 116027, China
- Engineering Technology Research Center for Translational Medicine, Dalian Medical University, NO. 467 Zhongshan Road, Dalian, Liaoning, 116027, China
- Division of Hepatobiliary and Pancreatic Surgery, Department of General Surgery, The Second Affiliated Hospital of Dalian Medical University, NO. 467 Zhongshan Road, Dalian, Liaoning, 116027, China
| | - Zhenming Gao
- Division of Hepatobiliary and Pancreatic Surgery, Department of General Surgery, The Second Affiliated Hospital of Dalian Medical University, NO. 467 Zhongshan Road, Dalian, Liaoning, 116027, China
| | - Rui Liang
- Division of Hepatobiliary and Pancreatic Surgery, Department of General Surgery, The Second Affiliated Hospital of Dalian Medical University, NO. 467 Zhongshan Road, Dalian, Liaoning, 116027, China
| | - Qi Wang
- Department of Respiratory Medicine, The Second Affiliated Hospital of Dalian Medical University, NO. 467 Zhongshan Road, Dalian, Liaoning, 116027, China.
| | - Liming Wang
- Engineering Research Center for New Materials and Precision Treatment Technology of Malignant Tumors Therapy, Dalian Medical University, NO. 467 Zhongshan Road, Dalian, Liaoning, 116027, China.
- Engineering Technology Research Center for Translational Medicine, Dalian Medical University, NO. 467 Zhongshan Road, Dalian, Liaoning, 116027, China.
- Division of Hepatobiliary and Pancreatic Surgery, Department of General Surgery, The Second Affiliated Hospital of Dalian Medical University, NO. 467 Zhongshan Road, Dalian, Liaoning, 116027, China.
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Zhang Q, Rong Y, Yi K, Huang L, Chen M, Wang F. Circulating tumor cells in hepatocellular carcinoma: single-cell based analysis, preclinical models, and clinical applications. Theranostics 2020; 10:12060-12071. [PMID: 33204329 PMCID: PMC7667686 DOI: 10.7150/thno.48918] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2020] [Accepted: 09/23/2020] [Indexed: 02/07/2023] Open
Abstract
Circulating tumor cells (CTCs) are shed into the bloodstream from primary tumors and metastatic lesions and provide significant information about tumor progression and metastasis. CTCs contribute to tumor metastasis through the epithelial-to-mesenchymal transition (EMT). CTC clusters and stem-like phenotypes lead to a more aggressive and metastatic potential. CTCs retain the heterogeneity and imitate the nature of corresponding primary tumors. Therefore, it is important to use single-cell based analysis to obtain information on tumor heterogeneity and biology. CTCs are also good candidates for building preclinical models (especially 3D organoid cultures) for drug screening, disease modeling, genome editing, tumor immunity research, and organ-like biobank establishment. In this article, we summarize the current CTC capture technology, dissect the phenotypes associated with CTC metastasis, and review the progress in single-cell based analysis and preclinical modeling of the pattern and kinetics of CTCs. In particular, we discuss the use of CTCs to assess the progression of hepatocellular carcinoma (HCC).
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Affiliation(s)
| | | | | | | | | | - Fubing Wang
- Department of Laboratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan 430071, P. R. China
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Qin S, Jiang J, Lu Y, Nice EC, Huang C, Zhang J, He W. Emerging role of tumor cell plasticity in modifying therapeutic response. Signal Transduct Target Ther 2020; 5:228. [PMID: 33028808 PMCID: PMC7541492 DOI: 10.1038/s41392-020-00313-5] [Citation(s) in RCA: 144] [Impact Index Per Article: 28.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Revised: 08/25/2020] [Accepted: 08/30/2020] [Indexed: 02/07/2023] Open
Abstract
Resistance to cancer therapy is a major barrier to cancer management. Conventional views have proposed that acquisition of resistance may result from genetic mutations. However, accumulating evidence implicates a key role of non-mutational resistance mechanisms underlying drug tolerance, the latter of which is the focus that will be discussed here. Such non-mutational processes are largely driven by tumor cell plasticity, which renders tumor cells insusceptible to the drug-targeted pathway, thereby facilitating the tumor cell survival and growth. The concept of tumor cell plasticity highlights the significance of re-activation of developmental programs that are closely correlated with epithelial-mesenchymal transition, acquisition properties of cancer stem cells, and trans-differentiation potential during drug exposure. From observations in various cancers, this concept provides an opportunity for investigating the nature of anticancer drug resistance. Over the years, our understanding of the emerging role of phenotype switching in modifying therapeutic response has considerably increased. This expanded knowledge of tumor cell plasticity contributes to developing novel therapeutic strategies or combination therapy regimens using available anticancer drugs, which are likely to improve patient outcomes in clinical practice.
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Affiliation(s)
- Siyuan Qin
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, 610041, Chengdu, People's Republic of China
| | - Jingwen Jiang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, 610041, Chengdu, People's Republic of China
| | - Yi Lu
- School of Medicine, Southern University of Science and Technology Shenzhen, Shenzhen, Guangdong, 518055, People's Republic of China
- Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Shenzhen, Guangdong, People's Republic of China
| | - Edouard C Nice
- Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, Australia
| | - Canhua Huang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, 610041, Chengdu, People's Republic of China.
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, 1166 Liutai Road, 611137, Chengdu, People's Republic of China.
| | - Jian Zhang
- School of Medicine, Southern University of Science and Technology Shenzhen, Shenzhen, Guangdong, 518055, People's Republic of China.
- Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Shenzhen, Guangdong, People's Republic of China.
| | - Weifeng He
- State Key Laboratory of Trauma, Burn and Combined Injury, Institute of Burn Research, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, People's Republic of China.
- Chongqing Key Laboratory for Disease Proteomics, Chongqing, People's Republic of China.
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Bakir B, Chiarella AM, Pitarresi JR, Rustgi AK. EMT, MET, Plasticity, and Tumor Metastasis. Trends Cell Biol 2020; 30:764-776. [PMID: 32800658 PMCID: PMC7647095 DOI: 10.1016/j.tcb.2020.07.003] [Citation(s) in RCA: 639] [Impact Index Per Article: 127.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Revised: 07/02/2020] [Accepted: 07/10/2020] [Indexed: 01/06/2023]
Abstract
Cancer cell identity and plasticity are required in transition states, such as epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET), in primary tumor initiation, progression, and metastasis. The functional roles of EMT, MET, and the partial state (referred to as pEMT) may vary based on the type of tumor, the state of dissemination, and the degree of metastatic colonization. Herein, we review EMT, MET, pEMT, and plasticity in the context of tumor metastasis.
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Affiliation(s)
- Basil Bakir
- Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Anna M Chiarella
- Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA
| | - Jason R Pitarresi
- Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Anil K Rustgi
- Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA.
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9
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Zou T, Liu JY, She L, Yin JY, Li X, Li XP, Zhou HH, Chen J, Liu ZQ. The Association Between Heat-Shock Protein Polymorphisms and Prognosis in Lung Cancer Patients Treated With Platinum-Based Chemotherapy. Front Pharmacol 2020; 11:1029. [PMID: 32848724 PMCID: PMC7396685 DOI: 10.3389/fphar.2020.01029] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Accepted: 06/24/2020] [Indexed: 12/14/2022] Open
Abstract
Objective Lung cancer is one of the most prevalent cancers and the leading cause of cancer-related death in the world. Platinum-based chemotherapy plays an important role in lung cancer treatment, but the therapeutic effect varies from person to person. Heat shock proteins (HSPs) have been reported to be associated with the survival time of lung cancer patients, which may be a potential biomarker in lung cancer treatment. The aim of this study was to investigate the association between genetic polymorphisms and the prognosis in lung cancer patients treated with platinum-based chemotherapy. Methods We performed genotyping in 19 single nucleotide polymorphisms (SNPs) of HSP genes and Rho family genes of 346 lung cancer patients by SequenomMassARRAY. We used Cox proportional hazard models, state and plink to analyze the associations between SNPs and the prognosis of lung cancer patients. Results We found that the polymorphisms of HSPB1 rs2070804 and HSPA4 rs3088225 were significantly associated with lung cancer survival (p=0.015, p=0.049*, respectively). We also discovered the statistically significant differences between rs2070804 with age, gender, histology and stage, rs3088225 with gender and stage, which can affect lung cancer prognosis. Conclusion The results of our study suggest that HSPB1 rs2070804 (G>T) and HSPA4 rs3088225 (A>G) may be useful biomarkers for predicting the prognosis of lung cancer patients treated with platinum-based chemotherapy.
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Affiliation(s)
- Ting Zou
- National Institution of Drug Clinical Trial, Xiangya Hospital, Central South University, Changsha, China.,Department of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Xiangya Hospital, Central South University, Changsha, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Jun-Yan Liu
- Department of Orthopaedics, The First Affiliated Hospital of the University of South China, Hengyang, China
| | - Li She
- Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha, China.,Otolaryngology Major Disease Research Key Laboratory of Hunan Province, Xiangya Hospital, Central South University, Changsha, China
| | - Ji-Ye Yin
- Department of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Xiangya Hospital, Central South University, Changsha, China
| | - Xi Li
- Department of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Xiangya Hospital, Central South University, Changsha, China
| | - Xiang-Ping Li
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, China
| | - Hong-Hao Zhou
- Department of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Xiangya Hospital, Central South University, Changsha, China
| | - Juan Chen
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, China
| | - Zhao-Qian Liu
- Department of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Xiangya Hospital, Central South University, Changsha, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
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10
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Buffone A, Weaver VM. Don't sugarcoat it: How glycocalyx composition influences cancer progression. J Cell Biol 2020; 219:133536. [PMID: 31874115 PMCID: PMC7039198 DOI: 10.1083/jcb.201910070] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Revised: 11/19/2019] [Accepted: 12/03/2019] [Indexed: 12/17/2022] Open
Abstract
Buffone and Weaver discuss how the structure of the backbones and glycans of the tumor glycocalyx governs cell–matrix interactions and directs cancer progression. Mechanical interactions between tumors and the extracellular matrix (ECM) of the surrounding tissues have profound effects on a wide variety of cellular functions. An underappreciated mediator of tumor–ECM interactions is the glycocalyx, the sugar-decorated proteins and lipids that act as a buffer between the tumor and the ECM, which in turn mediates all cell-tissue mechanics. Importantly, tumors have an increase in the density of the glycocalyx, which in turn increases the tension of the cell membrane, alters tissue mechanics, and drives a more cancerous phenotype. In this review, we describe the basic components of the glycocalyx and the glycan moieties implicated in cancer. Next, we examine the important role the glycocalyx plays in driving tension-mediated cancer cell signaling through a self-enforcing feedback loop that expands the glycocalyx and furthers cancer progression. Finally, we discuss current tools used to edit the composition of the glycocalyx and the future challenges in leveraging these tools into a novel tractable approach to treat cancer.
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Affiliation(s)
- Alexander Buffone
- Department of Bioengineering, University of Pennsylvania, Philadelphia, PA.,Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California, San Francisco, San Francisco, CA
| | - Valerie M Weaver
- Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California, San Francisco, San Francisco, CA.,Departments of Radiation Oncology and Bioengineering and Therapeutic Sciences, Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, and Helen Diller Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA
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11
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Li Y, Lv Z, Zhang S, Wang Z, He L, Tang M, Pu W, Zhao H, Zhang Z, Shi Q, Cai D, Wu M, Hu G, Lui KO, Feng J, Nieto MA, Zhou B. Genetic Fate Mapping of Transient Cell Fate Reveals N-Cadherin Activity and Function in Tumor Metastasis. Dev Cell 2020; 54:593-607.e5. [PMID: 32668208 DOI: 10.1016/j.devcel.2020.06.021] [Citation(s) in RCA: 67] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Revised: 04/26/2020] [Accepted: 06/16/2020] [Indexed: 01/06/2023]
Abstract
Genetic lineage tracing unravels cell fate and plasticity in development, tissue homeostasis, and diseases. However, it remains technically challenging to trace temporary or transient cell fate, such as epithelial-to-mesenchymal transition (EMT) in tumor metastasis. Here, we generated a genetic fate-mapping system for temporally seamless tracing of transient cell fate. Highlighting its immediate application, we used it to study EMT gene activity from the local primary tumor to a distant metastatic site in vivo. In a spontaneous breast-to-lung metastasis model, we found that primary tumor cells activated vimentin and N-cadherin in situ, but only N-cadherin was activated and functionally required during metastasis. Tumor cells that have ever expressed N-cadherin constituted the majority of metastases in lungs, and functional deletion of N-cad significantly reduced metastasis. The seamless genetic recording system described here provides an alternative way for understanding transient cell fate and plasticity in biological processes.
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Affiliation(s)
- Yan Li
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China
| | - Zan Lv
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China
| | - Shaohua Zhang
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China
| | - Zhuo Wang
- Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, Fudan University, 201100, Shanghai, China
| | - Lingjuan He
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China
| | - Muxue Tang
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China
| | - Wenjuan Pu
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China
| | - Huan Zhao
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China
| | - Zhenqian Zhang
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China
| | - Qihui Shi
- Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, Fudan University, 201100, Shanghai, China
| | - Dongqing Cai
- Key Laboratory of Regenerative Medicine of Ministry of Education, Institute of Aging and Regenerative Medicine, Jinan University, Guangzhou 510632, China
| | - Mingfu Wu
- Center for Cardiovascular Sciences, Albany Medical College, Albany, NY 12208, USA
| | - Guohong Hu
- Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Kathy O Lui
- Department of Chemical Pathology, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR 999077, China
| | - Jing Feng
- Laboratory Medicine, Southern Medical University Affiliated Fengxian Hospital, Shanghai 201400, China
| | - M Angela Nieto
- Institute de Neurociencias CSIC-UMH, Avda. Ramon y Cajal s/n, 03550 San Juan de Alicante, Spain
| | - Bin Zhou
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China; Key Laboratory of Regenerative Medicine of Ministry of Education, Institute of Aging and Regenerative Medicine, Jinan University, Guangzhou 510632, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China.
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12
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Chen F, Zhong Z, Tan HY, Wang N, Feng Y. The Significance of Circulating Tumor Cells in Patients with Hepatocellular Carcinoma: Real-Time Monitoring and Moving Targets for Cancer Therapy. Cancers (Basel) 2020; 12:1734. [PMID: 32610709 PMCID: PMC7408113 DOI: 10.3390/cancers12071734] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Revised: 06/26/2020] [Accepted: 06/27/2020] [Indexed: 02/08/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is ranked as the sixth most common cancer around the world. With the emergence of the state-of-the-art modalities lately, such as liver transplantation, image-guided ablation, and chemoembolization, the death rate is still high due to high metastasis rate after therapy. Observation by biannual ultrasonography allows effective diagnosis at an early stage for candidates with no extrahepatic metastasis, but its effectiveness still remains unsatisfactory. Developing a new test with improved effectiveness and specificity is urgently needed for HCC diagnosis, especially for patients after first line therapy. Circulating tumor cells (CTCs) are a small sub-population of tumor cells in human peripheral blood, they release from the primary tumor and invade into the blood circulatory system, thereby residing into the distal tissues and survive. As CTCs have specific and aggressive properties, they can evade from immune defenses, induce gene alterations, and modulate signal transductions. Ultimately, CTCs can manipulate tumor behaviors and patient reactions to anti-tumor treatment. Given the fact that in HCC blood is present around the immediate vicinity of the tumor, which allows thousands of CTCs to release into the blood circulation daily, so CTCs are considered to be the main cause for HCC occurrence, and are also a pivotal factor for HCC prognosis. In this review, we highlight the characteristics and enrichment strategies of CTCs, and focus on the use of CTCs for tumor evaluation and management in patients with HCC.
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Affiliation(s)
| | | | | | | | - Yibin Feng
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR 852, China; (F.C.); (Z.Z.); (H.-Y.T.); (N.W.)
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13
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Prospects for Comprehensive Analyses of Circulating Tumor Cells in Tumor Biology. Cancers (Basel) 2020; 12:cancers12051135. [PMID: 32369927 PMCID: PMC7281475 DOI: 10.3390/cancers12051135] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2020] [Revised: 04/29/2020] [Accepted: 04/29/2020] [Indexed: 12/24/2022] Open
Abstract
The comprehensive analysis of biological and clinical aspects of circulating tumor cells (CTCs) has attracted interest as a means of enabling non-invasive, real-time monitoring of cancer patients and enhancing our fundamental understanding of tumor metastasis. However, CTC populations are extremely small when compared to other cell populations in the blood, limiting our comprehension of CTC biology and their clinical utility. Recently developed proteomic and genomic techniques that require only a small amount of sample have attracted much interest and expanded the potential utility of CTCs. Cancer heterogeneity, including specific mutations, greatly impacts disease diagnosis and the choice of available therapeutic strategies. The CTC population consists primarily of cancer stem cells, and CTC subpopulations are thought to undergo epithelial-mesenchymal transition during dissemination. To better characterize tumor cell populations, we demonstrated that changes in genomic profiles identified via next-generation sequencing of liquid biopsy samples could be expanded upon to increase sensitivity without decreasing specificity by using a combination of assays with CTCs and circulating tumor DNA. To enhance our understanding of CTC biology, we developed a metabolome analysis method applicable to single CTCs. Here, we review-omics studies related to CTC analysis and discuss various clinical and biological issues related to CTCs.
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14
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Yang J, Antin P, Berx G, Blanpain C, Brabletz T, Bronner M, Campbell K, Cano A, Casanova J, Christofori G, Dedhar S, Derynck R, Ford HL, Fuxe J, García de Herreros A, Goodall GJ, Hadjantonakis AK, Huang RYJ, Kalcheim C, Kalluri R, Kang Y, Khew-Goodall Y, Levine H, Liu J, Longmore GD, Mani SA, Massagué J, Mayor R, McClay D, Mostov KE, Newgreen DF, Nieto MA, Puisieux A, Runyan R, Savagner P, Stanger B, Stemmler MP, Takahashi Y, Takeichi M, Theveneau E, Thiery JP, Thompson EW, Weinberg RA, Williams ED, Xing J, Zhou BP, Sheng G. Guidelines and definitions for research on epithelial-mesenchymal transition. Nat Rev Mol Cell Biol 2020; 21:341-352. [PMID: 32300252 PMCID: PMC7250738 DOI: 10.1038/s41580-020-0237-9] [Citation(s) in RCA: 1329] [Impact Index Per Article: 265.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/11/2020] [Indexed: 02/06/2023]
Abstract
Epithelial–mesenchymal transition (EMT) encompasses dynamic changes in cellular organization from epithelial to mesenchymal phenotypes, which leads to functional changes in cell migration and invasion. EMT occurs in a diverse range of physiological and pathological conditions and is driven by a conserved set of inducing signals, transcriptional regulators and downstream effectors. With over 5,700 publications indexed by Web of Science in 2019 alone, research on EMT is expanding rapidly. This growing interest warrants the need for a consensus among researchers when referring to and undertaking research on EMT. This Consensus Statement, mediated by ‘the EMT International Association’ (TEMTIA), is the outcome of a 2-year-long discussion among EMT researchers and aims to both clarify the nomenclature and provide definitions and guidelines for EMT research in future publications. We trust that these guidelines will help to reduce misunderstanding and misinterpretation of research data generated in various experimental models and to promote cross-disciplinary collaboration to identify and address key open questions in this research field. While recognizing the importance of maintaining diversity in experimental approaches and conceptual frameworks, we emphasize that lasting contributions of EMT research to increasing our understanding of developmental processes and combatting cancer and other diseases depend on the adoption of a unified terminology to describe EMT. In this Consensus Statement, the authors (on behalf of the EMT International Association) propose guidelines to define epithelial–mesenchymal transition, its phenotypic plasticity and the associated multiple intermediate epithelial–mesenchymal cell states. Clarification of nomenclature and definitions will help reduce misinterpretation of research data generated in different experimental model systems and promote cross-disciplinary collaboration.
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Affiliation(s)
- Jing Yang
- Departments of Pharmacology and Pediatrics, Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA.
| | - Parker Antin
- Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ, USA
| | - Geert Berx
- Molecular and Cellular Oncology Lab, Department of Biomedical Molecular Biology, Ghent University, Cancer Research Institute Ghent (CRIG), VIB Center for Inflammation Research, Ghent, Belgium
| | - Cédric Blanpain
- Laboratory of Stem Cells and Cancer, Université Libre de Bruxelles, Bruxelles, Belgium
| | - Thomas Brabletz
- Department of Experimental Medicine 1, Nikolaus-Fiebiger-Center for Molecular Medicine, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany
| | - Marianne Bronner
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA
| | - Kyra Campbell
- Department of Biomedical Science and Bateson Centre, University of Sheffield, Sheffield, UK
| | - Amparo Cano
- Departamento de Bioquímica, Universidad Autónoma de Madrid (UAM), Instituto de Investigaciones Biomédicas 'Alberto Sols' (CSIC-UAM), IdiPAZ & Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
| | - Jordi Casanova
- Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology/Institut de Biologia Molecular de Barcelona (IBMB-CSIC), Barcelona, Spain
| | | | - Shoukat Dedhar
- Department of Biochemistry and Molecular Biology, University of British Columbia and British Columbia Cancer Research Centre, Vancouver, BC, Canada
| | - Rik Derynck
- Departments of Cell and Tissue Biology, and Anatomy, University of California at San Francisco, San Francisco, CA, USA
| | - Heide L Ford
- Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Jonas Fuxe
- Department of Laboratory Medicine (LABMED), Division of Pathology, Karolinska University Hospital and Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden
| | - Antonio García de Herreros
- Programa de Recerca en Càncer, Institut Hospital del Mar d'Investigacions Mèdiques (IMIM) and Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain
| | - Gregory J Goodall
- Centre for Cancer Biology, An alliance of SA Pathology and University of South Australia, Adelaide, SA, Australia
| | - Anna-Katerina Hadjantonakis
- Developmental Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Ruby Y J Huang
- School of Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Chaya Kalcheim
- Department of Medical Neurobiology, Institute for medical Research Israel-Canada and the Safra Center for Neurosciences, Hebrew University of Jerusalem, Hadassah Medical School, Jerusalem, Israel
| | - Raghu Kalluri
- Department of Cancer Biology, Metastasis Research Center, MD Anderson Cancer Center, Houston, TX, USA
| | - Yibin Kang
- Department of Molecular Biology, Princeton University, Princeton, NJ, USA
| | - Yeesim Khew-Goodall
- Centre for Cancer Biology, an Alliance of SA Pathology and the University of South Australia, Adelaide, SA, Australia
| | - Herbert Levine
- Department of Physics, Northeastern University, Boston, MA, USA
| | - Jinsong Liu
- Department of Anatomic Pathology, The Division of Pathology and Laboratory Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Gregory D Longmore
- Department of Medicine (Oncology) and Department of Cell Biology and Physiology, ICCE Institute, Washington University, St. Louis, MO, USA
| | - Sendurai A Mani
- Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Joan Massagué
- Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Roberto Mayor
- Department of Cell and Developmental Biology, University College London, London, UK
| | - David McClay
- Department of Biology, Duke University, Durham, NC, USA
| | - Keith E Mostov
- Departments of Anatomy and Biochemistry/Biophysics, University of California, San Francisco, School of Medicine, San Francisco, CA, USA
| | - Donald F Newgreen
- Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, VIC, Australia
| | - M Angela Nieto
- Instituto de Neurociencias (CSIC-UMH) Avda Ramon y Cajal s/n, Sant Joan d´Alacant, Spain
| | - Alain Puisieux
- Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Cancer Research Center of Lyon, Lyon, France.,Institut Curie, PSL Research University, Paris, France
| | - Raymond Runyan
- Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ, USA
| | - Pierre Savagner
- INSERM UMR 1186, Integrative Tumor Immunology and Genetic Oncology, Gustave Roussy, University Paris-Saclay, Villejuif, France
| | - Ben Stanger
- Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Marc P Stemmler
- Department of Experimental Medicine 1, Nikolaus-Fiebiger-Center for Molecular Medicine, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany
| | - Yoshiko Takahashi
- Department of Zoology, Graduate School of Science, Kyoto University, Kyoto, Japan
| | | | - Eric Theveneau
- Centre de Biologie du Développement (CBD), Centre de Biologie Intégrative (CBI), Université de Toulouse, CNRS, UPS, Toulouse, France
| | - Jean Paul Thiery
- Guangzhou Regenerative Medicine and Health, Guangdong Laboratory, Guangzhou, China
| | - Erik W Thompson
- School of Biomedical Sciences and Institute of Health and Biomedical Innovation, Queensland University of Technology, Translational Research Institute, Woolloongabba, QLD, Australia
| | - Robert A Weinberg
- Whitehead Institute for Biomedical Research, Department of Biology, MIT Ludwig Center for Molecular Oncology, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Elizabeth D Williams
- Australian Prostate Cancer Research Centre-Queensland (APCRC-Q) and Queensland Bladder Cancer Initiative (QBCI), School of Biomedical Sciences and Institute of Health and Biomedical Innovation, Queensland University of Technology, Woolloongabba, QLD, Australia
| | - Jianhua Xing
- Department of Computational and Systems Biology and UPMC-Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA
| | - Binhua P Zhou
- Department of Molecular and Cellular Biochemistry and UK Markey Cancer Center, University of Kentucky College of Medicine, Lexington, KY, USA
| | - Guojun Sheng
- International Research Center for Medical Sciences (IRCMS), Kumamoto University, Kumamoto, Japan.
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15
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Orenstein JM. An ultrastructural pathologist's views on fibroblasts, modified smooth muscle cells, wound healing, stenosing arteriopathies, Kawasaki disease, Dupuytren's contracture, and the stroma of carcinomas. Ultrastruct Pathol 2020; 44:2-14. [PMID: 32154752 DOI: 10.1080/01913123.2019.1704332] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
It wasn't until 1960 that the dense bodies of the peripheral actin arrays of fibroblasts were finally visualized, i.e., stress fibers (SFs). Mistakenly assumed that its SFs turned the fibroblast into a unique cell situated somewhere in a continuum between it and a smooth muscle cell (SMC), it was descriptively named a "myofibroblast" (MF). Automatically, spindle cells with SFs and/or smooth muscle actin by SMA IHC-staining, became MFs, although endothelial cells, pericytes, modified SMCs (mSMC), and myoepithelial cells all contain SFs. An invisible "intermediate" cell was hypothesized to exist somewhere between SMA-negative and positive fibroblasts, and named a "proto-myofibroblast". The sub-epithelial spindle cells of normal and malignant tumors of the GI, GU, and respiratory tracts are all fibroblasts with SFs. The second erroneous myofibroblast came from a 1971 rat wound healing study and its 1974 human counterpart. Updated analysis of the papers' TEMs proved that the cells are mSMCs and not fibroblasts (AKA: MFs). The pathognomonic cells of Dupuytren's contracture are mSMCs and fibroblasts and that of the stenosing arteriopathy of Kawasaki Disease and other similar arteriopathies are mSMCs. TEM remains a powerful tool.
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16
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Yun CW, Kim HJ, Lim JH, Lee SH. Heat Shock Proteins: Agents of Cancer Development and Therapeutic Targets in Anti-Cancer Therapy. Cells 2019; 9:cells9010060. [PMID: 31878360 PMCID: PMC7017199 DOI: 10.3390/cells9010060] [Citation(s) in RCA: 180] [Impact Index Per Article: 30.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2019] [Revised: 12/06/2019] [Accepted: 12/21/2019] [Indexed: 12/24/2022] Open
Abstract
Heat shock proteins (HSPs) constitute a large family of molecular chaperones classified by their molecular weights, and they include HSP27, HSP40, HSP60, HSP70, and HSP90. HSPs function in diverse physiological and protective processes to assist in maintaining cellular homeostasis. In particular, HSPs participate in protein folding and maturation processes under diverse stressors such as heat shock, hypoxia, and degradation. Notably, HSPs also play essential roles across cancers as they are implicated in a variety of cancer-related activities such as cell proliferation, metastasis, and anti-cancer drug resistance. In this review, we comprehensively discuss the functions of HSPs in association with cancer initiation, progression, and metastasis and anti-cancer therapy resistance. Moreover, the potential utilization of HSPs to enhance the effects of chemo-, radio-, and immunotherapy is explored. Taken together, HSPs have multiple clinical usages as biomarkers for cancer diagnosis and prognosis as well as the potential therapeutic targets for anti-cancer treatment.
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Affiliation(s)
- Chul Won Yun
- Medical Science Research Institute, Soonchunhyang University Seoul Hospital, Seoul 04401, Korea; (C.W.Y.); (H.J.K.); (J.H.L.)
| | - Hyung Joo Kim
- Medical Science Research Institute, Soonchunhyang University Seoul Hospital, Seoul 04401, Korea; (C.W.Y.); (H.J.K.); (J.H.L.)
| | - Ji Ho Lim
- Medical Science Research Institute, Soonchunhyang University Seoul Hospital, Seoul 04401, Korea; (C.W.Y.); (H.J.K.); (J.H.L.)
| | - Sang Hun Lee
- Medical Science Research Institute, Soonchunhyang University Seoul Hospital, Seoul 04401, Korea; (C.W.Y.); (H.J.K.); (J.H.L.)
- Department of Biochemistry, Soonchunhyang University College of Medicine, Cheonan 31538, Korea
- Correspondence: ; Tel.: +82-02-709-2029
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17
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Li Y, Duan J, Chai X, Yang M, Wang J, Chen R, Sun Z. Microarray-assisted size-effect study of amorphous silica nanoparticles on human bronchial epithelial cells. NANOSCALE 2019; 11:22907-22923. [PMID: 31763651 DOI: 10.1039/c9nr07350g] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
Amorphous silica nanoparticles (SiNPs) are not only abundant in nature, but also the second largest engineering nanomaterials in terms of annual output. Respiratory exposure is the main route for SiNPs to enter the human body. A large number of studies have focused on the respiratory toxicity of SiNPs and demonstrated that SiNPs could induce pulmonary tissue damage, inflammation, fibrosis, and even the malignant transformation of bronchial epithelial cells, while the size-dependent toxicity of SiNPs and their underlying biological mechanisms remain unclear. In this regard, a transcriptomics study would be conductive to gaining a better understanding of the toxic mechanism. In the present study, microarray analysis was performed to investigate the genome-wide transcriptional alteration induced by different sizes of SiNPs in human primary bronchial epithelial cells (BEAS-2B). To determine the effect of the particle size on the toxicity, nanoparticles of two sizes (41 nm and 61 nm) and submicron particles of one size (206 nm) were introduced. The bioinformatics analysis results indicated that: (1) the number of differentially expressed genes in the three SiNP-treated groups increased with the particle size decreasing; (2) the genes involved in the immune and inflammatory response, gene expression, signal transduction, endoplasmic reticulum stress, oxidative stress, cell metabolism, and cell proliferation were gradually upregulated with the particle size decreasing, while the genes related to the morphological development of the respiratory system were gradually downregulated with the particle size decreasing; (3) the modes of action of the two nanoparticles overlapped with each other to some degree, and there existed many different modes compared to those from the submicron particles; (4) both the silica nanoparticles affected the pathways associated with the cell entry of silica nanoparticles, autophagy and lysosomal dysfunction, endoplasmic reticulum stress, inflammatory response, DNA damage, and gene expression, as well as apoptotic resistance and cancer. To the best of our knowledge, this is the first study that has reported the alteration trend of gene expression profiles with the change in silica particle size. Our study provides a great deal of information on the toxic mechanisms underlying the respiratory toxicity induced by SiNPs, and can also serve as an experimental basis for the toxicity and safety evaluation of silica nanoparticles.
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Affiliation(s)
- Yang Li
- School of Public Health, Beijing, 100069, China and Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing, 100069, China.
| | - Junchao Duan
- School of Public Health, Beijing, 100069, China and Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing, 100069, China.
| | - Xiangyuan Chai
- Xuanwu Hospital, Capital Medical University, Beijing, 100053, China
| | - Man Yang
- School of Public Health, Beijing, 100069, China and Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing, 100069, China.
| | - Ji Wang
- School of Public Health, Beijing, 100069, China and Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing, 100069, China.
| | - Rui Chen
- School of Public Health, Beijing, 100069, China and Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing, 100069, China.
| | - Zhiwei Sun
- School of Public Health, Beijing, 100069, China and Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing, 100069, China.
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18
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Yang C, Xia BR, Jin WL, Lou G. Circulating tumor cells in precision oncology: clinical applications in liquid biopsy and 3D organoid model. Cancer Cell Int 2019; 19:341. [PMID: 31866766 PMCID: PMC6918690 DOI: 10.1186/s12935-019-1067-8] [Citation(s) in RCA: 82] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2019] [Accepted: 12/10/2019] [Indexed: 12/20/2022] Open
Abstract
Circulating tumor cells (CTCs) are a rare subset of cells found in the blood of patients with solid tumors, which function as a seed for metastases. Cancer cells metastasize through the bloodstream either as single migratory CTCs or as multicellular groupings-CTC clusters. The CTCs preserve primary tumor heterogeneity and mimic tumor properties, and may be considered as clinical biomarker, preclinical model, and therapeutic target. The potential clinical application of CTCs is being a component of liquid biopsy. CTCs are also good candidates for generating preclinical models, especially 3D organoid cultures, which could be applied in drug screening, disease modeling, genome editing, tumor immunity, and organoid biobanks. In this review, we summarize current knowledge on the value and promise of evolving CTC technologies and highlight cutting-edge research on CTCs in liquid biopsy, tumor metastasis, and organoid preclinical models. The study of CTCs offers broad pathways to develop new biomarkers for tumor patient diagnosis, prognosis, and response to therapy, as well as translational models accelerating oncologic drug development.
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Affiliation(s)
- Chang Yang
- 1Department of Gynecology Oncology, The Tumor Hospital, Harbin Medical University, Harbin, 150086 People's Republic of China
| | - Bai-Rong Xia
- 1Department of Gynecology Oncology, The Tumor Hospital, Harbin Medical University, Harbin, 150086 People's Republic of China
| | - Wei-Lin Jin
- 2Institute of Nano Biomedicine and Engineering, Shanghai Engineering Center for Intelligent Diagnosis and Treatment Instrument, Department of Instrument Science and Engineering, Key Laboratory for Thin Film and Microfabrication Technology of Ministry of Education, School of Electronic Information and Electronic Engineering, Shanghai Jiao Tong University, Shanghai, 200240 People's Republic of China.,3National Center for Translational Medicine, Collaborative Innovational Center for System Biology, Shanghai Jiao Tong University, Shanghai, 200240 People's Republic of China
| | - Ge Lou
- 1Department of Gynecology Oncology, The Tumor Hospital, Harbin Medical University, Harbin, 150086 People's Republic of China
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19
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Monkman JH, Thompson EW, Nagaraj SH. Targeting Epithelial Mesenchymal Plasticity in Pancreatic Cancer: A Compendium of Preclinical Discovery in a Heterogeneous Disease. Cancers (Basel) 2019; 11:E1745. [PMID: 31703358 PMCID: PMC6896204 DOI: 10.3390/cancers11111745] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2019] [Revised: 10/30/2019] [Accepted: 10/30/2019] [Indexed: 12/13/2022] Open
Abstract
Pancreatic Ductal Adenocarcinoma (PDAC) is a particularly insidious and aggressive disease that causes significant mortality worldwide. The direct correlation between PDAC incidence, disease progression, and mortality highlights the critical need to understand the mechanisms by which PDAC cells rapidly progress to drive metastatic disease in order to identify actionable vulnerabilities. One such proposed vulnerability is epithelial mesenchymal plasticity (EMP), a process whereby neoplastic epithelial cells delaminate from their neighbours, either collectively or individually, allowing for their subsequent invasion into host tissue. This disruption of tissue homeostasis, particularly in PDAC, further promotes cellular transformation by inducing inflammatory interactions with the stromal compartment, which in turn contributes to intratumoural heterogeneity. This review describes the role of EMP in PDAC, and the preclinical target discovery that has been conducted to identify the molecular regulators and effectors of this EMP program. While inhibition of individual targets may provide therapeutic insights, a single 'master-key' remains elusive, making their collective interactions of greater importance in controlling the behaviours' of heterogeneous tumour cell populations. Much work has been undertaken to understand key transcriptional programs that drive EMP in certain contexts, however, a collaborative appreciation for the subtle, context-dependent programs governing EMP regulation is needed in order to design therapeutic strategies to curb PDAC mortality.
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Affiliation(s)
- James H. Monkman
- Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, QLD 4059, Australia;
- School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD 4059, Australia
- Translational Research Institute, Brisbane, QLD 4102, Australia
| | - Erik W. Thompson
- Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, QLD 4059, Australia;
- School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD 4059, Australia
- Translational Research Institute, Brisbane, QLD 4102, Australia
| | - Shivashankar H. Nagaraj
- Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, QLD 4059, Australia;
- School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD 4059, Australia
- Translational Research Institute, Brisbane, QLD 4102, Australia
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20
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Mizukoshi K, Okazawa Y, Haeno H, Koyama Y, Sulidan K, Komiyama H, Saeki H, Ohtsuji N, Ito Y, Kojima Y, Goto M, Habu S, Hino O, Sakamoto K, Orimo A. Metastatic seeding of human colon cancer cell clusters expressing the hybrid epithelial/mesenchymal state. Int J Cancer 2019; 146:2547-2562. [PMID: 31506938 DOI: 10.1002/ijc.32672] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2019] [Revised: 08/05/2019] [Accepted: 08/26/2019] [Indexed: 12/15/2022]
Abstract
Emerging evidence supports the theory that tumor cell clusters efficiently metastasize to distant organs. However, the roles of epithelial-to-mesenchymal transition (EMT) in metastasizing tumor cell clusters have not yet been fully elucidated. To investigate this issue, tumor fragments were dissected from 40 colorectal cancer (CRC) patients and implanted subcutaneously into immunodeficient mice. We observed that tumors developed from the tumor fragments obtained from 28 of the 40 CRC patients. The tumors were then dissociated into cell suspensions to be orthotopically injected into secondary mice. The tumors from 13 of the 28 patients progressed. Furthermore, metastases formed spontaneously in the liver and lungs from the tumor fragments obtained from 8 of these 13 patients. Moreover, employing a mathematical analysis, we showed that tumor cell clusters seeded these metastases significantly more often than did single tumor cells. Membrane E-cadherin- and nuclear ZEB1-positive tumor cells indicating the hybrid epithelial/mesenchymal state were also detected in primary tumors of various CRC patients, and in the corresponding patient-derived xenografts (PDXs) and circulating tumor cell clusters in the bloodstreams of mice. In contrast, ZEB1 staining was barely detectable in the patient-matched liver metastases presumably developing through mesenchymal-to-epithelial transition. Inhibition of E-cadherin or ZEB1 expression by shRNA notably prevented the PDX-derived tumor organoids from colonizing the liver, when injected intrasplenically into mice, indicating E-cadherin and ZEB1 expressions to be required for their metastatic colonization. Taken together, these findings suggest that the epithelial/mesenchymal state mediates metastatic seeding of human CRC cell clusters into distant organs.
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Affiliation(s)
- Kosuke Mizukoshi
- Department of Coloproctological Surgery, Juntendo University Faculty of Medicine, Tokyo, Japan.,Department of Molecular Pathogenesis, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Yu Okazawa
- Department of Coloproctological Surgery, Juntendo University Faculty of Medicine, Tokyo, Japan.,Department of Molecular Pathogenesis, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Hiroshi Haeno
- Division of Translational Genomics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Chiba, Japan.,Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba, Japan
| | - Yu Koyama
- Department of Molecular Pathogenesis, Juntendo University Faculty of Medicine, Tokyo, Japan.,Department of Oral Pathobiological Science and Surgery, Tokyo Dental College, Tokyo, Japan
| | - Kaidiliayi Sulidan
- Department of Molecular Pathogenesis, Juntendo University Faculty of Medicine, Tokyo, Japan.,Department of Obstetrics and Gynecology, Graduate School of Medicine, Juntendo University, Tokyo, Japan
| | - Hiromitsu Komiyama
- Department of Coloproctological Surgery, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Harumi Saeki
- Department of Molecular Pathogenesis, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Naomi Ohtsuji
- Department of Molecular Pathogenesis, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Yasuhiko Ito
- Department of Molecular Pathogenesis, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Yutaka Kojima
- Department of Coloproctological Surgery, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Michitoshi Goto
- Department of Coloproctological Surgery, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Sonoko Habu
- Atopy Research Center, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Okio Hino
- Department of Molecular Pathogenesis, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Kazuhiro Sakamoto
- Department of Coloproctological Surgery, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Akira Orimo
- Department of Molecular Pathogenesis, Juntendo University Faculty of Medicine, Tokyo, Japan
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21
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Li M, Liu J, Li S, Feng Y, Yi F, Wang L, Wei S, Cao L. Autophagy-related 7 modulates tumor progression in triple-negative breast cancer. J Transl Med 2019; 99:1266-1274. [PMID: 30988371 DOI: 10.1038/s41374-019-0249-2] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2018] [Revised: 02/11/2019] [Accepted: 02/14/2019] [Indexed: 12/30/2022] Open
Abstract
The exact role of autophagy in breast cancers remains elusive. In this study, we explored the potential functions of autophagy-related 7 (Atg7) in breast cancer cell lines and tissues. Compared to normal breast tissue, a significantly lower expression of Atg7 was observed in triple-negative breast cancer (TNBC), but not other subtypes. A higher Atg7 expression was significantly associated with favorable clinicopathologic factors and better prognostic outcomes in patients with TNBC. Reflecting the clinical and pathologic observations, Atg7 was found to inhibit proliferation and migration, but promotes apoptosis in TNBC cell lines. Furthermore, Atg7 suppressed epithelial-mesenchymal transition through inhibiting aerobic glycolysis metabolism of TNBC cells. These findings provided novel molecular and clinical evidence of Atg7 in modulating the biological behavior of TNBC, thus warranting further investigation.
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Affiliation(s)
- Mingyang Li
- Key Laboratory of Medical Cell Biology, Ministry of Education; Institute of Translational Medicine, China Medical University;, Liaoning Province Collaborative Innovation Center of Aging Related Disease Diagnosis and Treatment and Prevention, Shenyang, Liaoning Province, China
| | - Jingwei Liu
- Key Laboratory of Medical Cell Biology, Ministry of Education; Institute of Translational Medicine, China Medical University;, Liaoning Province Collaborative Innovation Center of Aging Related Disease Diagnosis and Treatment and Prevention, Shenyang, Liaoning Province, China
| | - Sihui Li
- Key Laboratory of Medical Cell Biology, Ministry of Education; Institute of Translational Medicine, China Medical University;, Liaoning Province Collaborative Innovation Center of Aging Related Disease Diagnosis and Treatment and Prevention, Shenyang, Liaoning Province, China
| | - Yanling Feng
- Key Laboratory of Medical Cell Biology, Ministry of Education; Institute of Translational Medicine, China Medical University;, Liaoning Province Collaborative Innovation Center of Aging Related Disease Diagnosis and Treatment and Prevention, Shenyang, Liaoning Province, China
| | - Fei Yi
- Key Laboratory of Medical Cell Biology, Ministry of Education; Institute of Translational Medicine, China Medical University;, Liaoning Province Collaborative Innovation Center of Aging Related Disease Diagnosis and Treatment and Prevention, Shenyang, Liaoning Province, China
| | - Liang Wang
- Department of pathology, The College of Basic Medical Science, China Medical University, Shenyang, Liaoning Province, China.
| | - Shi Wei
- Section of Surgical Pathology, Comprehensive Cancer Center, The University of Alabama at Birmingham, Birmingham, AL, USA.
| | - Liu Cao
- Key Laboratory of Medical Cell Biology, Ministry of Education; Institute of Translational Medicine, China Medical University;, Liaoning Province Collaborative Innovation Center of Aging Related Disease Diagnosis and Treatment and Prevention, Shenyang, Liaoning Province, China.
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22
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Analysis of the Antiproliferative Effect of Ankaferd Hemostat on Caco-2 Colon Cancer Cells via LC/MS Shotgun Proteomics Approach. BIOMED RESEARCH INTERNATIONAL 2019; 2019:5268031. [PMID: 31240215 PMCID: PMC6556321 DOI: 10.1155/2019/5268031] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/04/2019] [Revised: 04/20/2019] [Accepted: 05/08/2019] [Indexed: 12/14/2022]
Abstract
Ankaferd hemostat (ABS), a traditional herbal extract, is a hemostatic agent used for wound healing and bleeding treatment. A standardized form of plants contains many biomolecules. In recent years, previous studies have demonstrated the antineoplastic effect of ABS. In the present work, we focused on the mechanism of its antineoplastic effect over Caco-2 colon cancer cells. The LC/MS-based proteomics method was used to understand the effect of ABS at the protein level. The results were evaluated with gene ontology, protein interaction, and pathway analysis. As shown by our results, ABS altered glucose, fatty acids, and protein metabolism. Moreover, ABS affects the cell cycle machinery. Moreover, we found that ABS induced critical cancer target and suppressor proteins such as carboxyl-terminal hydrolase 1, 60S ribosomal protein L5, Tumor protein D52-like2, karyopherin alpha 2, and protein deglycase DJ-1. In conclusion, the proteomics results indicated that ABS affects various cancer targets and suppressor proteins. Moreover ABS has systematical effect on cell metabolism and cell cycle in Caco-2 cells, suggesting that it could be used as an antineoplastic agent.
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23
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Mittal V. Epithelial Mesenchymal Transition in Tumor Metastasis. ANNUAL REVIEW OF PATHOLOGY-MECHANISMS OF DISEASE 2019; 13:395-412. [PMID: 29414248 DOI: 10.1146/annurev-pathol-020117-043854] [Citation(s) in RCA: 971] [Impact Index Per Article: 161.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Metastasis is the major cause of cancer-related deaths; therefore, the prevention and treatment of metastasis are fundamental to improving clinical outcomes. Epithelial mesenchymal transition (EMT), an evolutionarily conserved developmental program, has been implicated in carcinogenesis and confers metastatic properties upon cancer cells by enhancing mobility, invasion, and resistance to apoptotic stimuli. Furthermore, EMT-derived tumor cells acquire stem cell properties and exhibit marked therapeutic resistance. Given these attributes, the complex biological process of EMT has been heralded as a key hallmark of carcinogenesis, and targeting EMT pathways constitutes an attractive strategy for cancer treatment. However, demonstrating the necessity of EMT for metastasis in vivo has been technically challenging, and recent efforts to demonstrate a functional contribution of EMT to metastasis have yielded unexpected results. Therefore, determining the functional role of EMT in metastasis remains an area of active investigation. Studies using improved lineage tracing systems, dynamic in vivo imaging, and clinically relevant in vivo models have the potential to uncover the direct link between EMT and metastasis. This review focuses primarily on recent advances in and emerging concepts of the biology of EMT in metastasis in vivo and discusses future directions in the context of novel diagnostic and therapeutic opportunities.
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Affiliation(s)
- Vivek Mittal
- Department of Cardiothoracic Surgery, Department of Cell and Developmental Biology, and Neuberger Berman Foundation Lung Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA;
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24
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Wang J, Liu Q, Xiao H, Luo X, Liu X. Suppressive effects of Momordin Ic on HepG2 cell migration and invasion by regulating MMP-9 and adhesion molecules: Involvement of p38 and JNK pathways. Toxicol In Vitro 2019; 56:75-83. [DOI: 10.1016/j.tiv.2019.01.007] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2018] [Revised: 01/09/2019] [Accepted: 01/11/2019] [Indexed: 10/27/2022]
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25
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Non-redundant functions of EMT transcription factors. Nat Cell Biol 2019; 21:102-112. [PMID: 30602760 DOI: 10.1038/s41556-018-0196-y] [Citation(s) in RCA: 353] [Impact Index Per Article: 58.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2018] [Accepted: 08/16/2018] [Indexed: 02/07/2023]
Abstract
Epithelial-mesenchymal transition (EMT) is a crucial embryonic programme that is executed by various EMT transcription factors (EMT-TFs) and is aberrantly activated in cancer and other diseases. However, the causal role of EMT and EMT-TFs in different disease processes, especially cancer and metastasis, continues to be debated. In this Review, we identify and describe specific, non-redundant functions of the different EMT-TFs and discuss the reasons that may underlie disputes about EMT in cancer.
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26
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Stroud J. A mechanistic theory explaining hyperferritinaemia in haemophagocytic lymphohistiocytosis. Med Hypotheses 2019; 122:165-171. [DOI: 10.1016/j.mehy.2018.11.015] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2018] [Revised: 11/20/2018] [Accepted: 11/21/2018] [Indexed: 12/26/2022]
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27
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Yang X, Liang X, Zheng M, Tang Y. Cellular Phenotype Plasticity in Cancer Dormancy and Metastasis. Front Oncol 2018; 8:505. [PMID: 30456206 PMCID: PMC6230580 DOI: 10.3389/fonc.2018.00505] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2018] [Accepted: 10/16/2018] [Indexed: 02/05/2023] Open
Abstract
Cancer dormancy is a period of cancer progression in which residual tumor cells exist, but clinically remain asymptomatic for a long time, as well as resistant to conventional chemo- and radiotherapies. Cellular phenotype plasticity represents that cellular phenotype could convert between epithelial cells and cells with mesenchymal traits. Recently, this process has been shown to closely associate with tumor cell proliferation, cancer dormancy and metastasis. In this review, we have described different scenarios of how the transition from epithelial to mesenchymal morphology (EMT) and backwards (MET) are connected with the initiation of dormancy and reactivation of proliferation. These processes are fundamental for cancer cells to invade tissues and metastasize. Recognizing the mechanisms underlying the cellular phenotype plasticity as well as dormancy and targeting them is likely to increase the efficiency of traditional tumor treatment inhibiting tumor metastasis.
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Affiliation(s)
- Xiao Yang
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases and Department of OralPathology, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Xinhua Liang
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases and Department of OralPathology, West China Hospital of Stomatology, Sichuan University, Chengdu, China.,State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases and Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Min Zheng
- Department of Stomatology, Zhoushan Hospital, Wenzhou Medical University, Zhoushan, China
| | - Yaling Tang
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases and Department of OralPathology, West China Hospital of Stomatology, Sichuan University, Chengdu, China
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28
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Brown RB, Razzaque MS. Phosphate toxicity and tumorigenesis. Biochim Biophys Acta Rev Cancer 2018; 1869:303-309. [PMID: 29684520 DOI: 10.1016/j.bbcan.2018.04.007] [Citation(s) in RCA: 74] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2018] [Revised: 04/17/2018] [Accepted: 04/18/2018] [Indexed: 02/07/2023]
Abstract
In this article, we briefly summarized evidence that cellular phosphate burden from phosphate toxicity is a pathophysiological determinant of cancer cell growth. Tumor cells express more phosphate cotransporters and store more inorganic phosphate than normal cells, and dysregulated phosphate homeostasis is associated with the genesis of various human tumors. High dietary phosphate consumption causes the growth of lung and skin tumors in experimental animal models. Additional studies show that excessive phosphate burden induces growth-promoting cell signaling, stimulates neovascularization, and is associated with chromosome instability and metastasis. Studies have also shown phosphate is a mitogenic factor that affects various tumor cell growth. Among epidemiological evidence linking phosphate and tumor formation, the Health Professionals Follow-Up Study found that high dietary phosphate levels were independently associated with lethal and high-grade prostate cancer. Further research is needed to determine how excessive dietary phosphate consumption influences initiation and promotion of tumorigenesis, and to elucidate prognostic benefits of reducing phosphate burden to decrease tumor cell growth and delay metastatic progression. The results of such studies could provide the basis for therapeutic modulation of phosphate metabolism for improved patient outcome.
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Affiliation(s)
- Ronald B Brown
- School of Public Health & Health Systems, University of Waterloo, Waterloo, Ontario, Canada
| | - Mohammed S Razzaque
- Department of Oral Health Policy & Epidemiology, Harvard School of Dental Medicine, Boston, MA, USA; Department of Preventive & Community Dentistry, University of Rwanda College of Medicine & Health Sciences, School of Dentistry, Kigali, Rwanda; Department of Pathology, Lake Erie College of Osteopathic Medicine, Erie, PA, USA.
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29
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IL-13/STAT6 signaling plays a critical role in the epithelial-mesenchymal transition of colorectal cancer cells. Oncotarget 2018; 7:61183-61198. [PMID: 27533463 PMCID: PMC5308644 DOI: 10.18632/oncotarget.11282] [Citation(s) in RCA: 72] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2015] [Accepted: 08/08/2016] [Indexed: 12/17/2022] Open
Abstract
Colorectal cancer (CRC) is one of the most common causes of cancer-related death worldwide due to the distant metastases. Compelling evidence has reported that epithelial-mesenchymal transition (EMT) is involved in promoting cancer invasion and metastasis. However, the precise molecular events that initiate this complex EMT process remain poorly understood. Here, we showed that the pleiotropic cytokine interleukin-13 (IL-13) could induce an aggressive phenotype displaying EMT by enhancing the expression of EMT-promoting factor ZEB1. Importantly, STAT6 signaling inhibitor and STAT6 knockdown significantly reversed IL-13-induced EMT and ZEB1 induction in CRC cells, whereas ectopic STAT6 expression in STAT6null CRC cell line markedly promoted EMT in the present of IL-13. ChIP-PCR and Luciferase assays revealed that activated STAT6 directly bound to the promoter of ZEB1. Otherwise, we found IL-13 also up-regulated the stem cell markers (nanog, CD44, CD133 and CD166) and promoted cell migration and invasion through STAT6 pathway. We also found that siRNA-mediated knockdown of IL-13Rα1 could reverse IL-13-induced ZEB1 and EMT changes by preventing STAT6 signaling. Finally, we demonstrated positive correlation between IL-13Rα1 and ZEB1 at mRNA levels in human CRC samples. Taken together, our findings first demonstrated that IL-13/IL-13Rα1/STAT6/ZEB1 pathway plays a critical role in promoting EMT and aggressiveness of CRC.
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30
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Liu DN, Lv A, Tian ZH, Tian XY, Guan XY, Dong B, Zhao M, Hao CY. Superior mesenteric artery margin in pancreaticoduodenectomy for pancreatic adenocarcinoma. Oncotarget 2018; 8:7766-7776. [PMID: 27999192 PMCID: PMC5352359 DOI: 10.18632/oncotarget.13950] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2016] [Accepted: 12/01/2016] [Indexed: 12/15/2022] Open
Abstract
The aim of this study is trying to describe more details of superior mesenteric artery margin in pancreaticoduodenectomy for pancreatic ductal adenocarcinoma, to evaluate biological and prognostic implications of tumor budding in this margin, and to provide more evidence for evaluation of R0 surgery in pancreaticoduodenectomy. 46 patients in 5-years period are included in this study. Immunochemistry and immunofluorescence are used to analyze tumor budding and epithelial-mesenchymal transition. Superior mesenteric artery margin might be described from four aspects including location, gross appearance, microscopic appearance and tumor budding. We find that 1mm rule for R1 surgery is more appropriate to predict prognosis (P = 0.009) than 0mm rule (P = 0.141). Expression of cytokeratin in tumor budding is significantly lower than primary tumor (P = 0.001), and it suggests that tumor budding may participate the procedure of epithelial-mesenchymal transition. High-grade tumor budding and decreasing cytokeratin of tumor budding correlate with distant metastasis and has negative influence on prognosis. So superior mesenteric artery margin might be not only an area that tumor cells may invade, but also a pathway for distant metastasis. It is necessary to evaluate superior mesenteric artery margin in pancreaticoduodenectomy for pancreatic cancer.
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Affiliation(s)
- Dao-Ning Liu
- Department of Hepato-Pancreato-Biliary Surgery, Peking University Cancer Hospital and Institute, Beijing, People's Republic of China
| | - Ang Lv
- Department of Hepato-Pancreato-Biliary Surgery, Peking University Cancer Hospital and Institute, Beijing, People's Republic of China
| | - Zhi-Hua Tian
- Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Beijing, People's Republic of China
| | - Xiu-Yun Tian
- Department of Hepato-Pancreato-Biliary Surgery, Peking University Cancer Hospital and Institute, Beijing, People's Republic of China
| | - Xiao-Ya Guan
- Department of Hepato-Pancreato-Biliary Surgery, Peking University Cancer Hospital and Institute, Beijing, People's Republic of China
| | - Bin Dong
- Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Beijing, People's Republic of China
| | - Min Zhao
- Department of Pathology, Peking University Cancer Hospital and Institute, Beijing, People's Republic of China
| | - Chun-Yi Hao
- Department of Hepato-Pancreato-Biliary Surgery, Peking University Cancer Hospital and Institute, Beijing, People's Republic of China
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31
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The Predictive Value of Circulating Tumor Cells in Ovarian Cancer: A Meta Analysis. Int J Gynecol Cancer 2018; 27:1109-1117. [PMID: 25893279 DOI: 10.1097/igc.0000000000000459] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
OBJECTIVE Studies have confirmed that patients with circulating tumor cells (CTCs) in their peripheral blood (PB) or disseminated tumor cells (DTCs) in bone marrow (BM) might have bad prognosis. In this paper, we discuss whether CTCs/DTCs would be an appropriate biomarker to predict the prognosis of ovarian cancer. METHODS We systematically searched PubMed, EMBASE, Cochrane library, and Chinese National Knowledge Infrastructure to collect relevant studies published from the time the database were created to February 2014. Studies quality was assessed by Newcastle-Ottawa Scale. The effect size was estimated by hazard ratio (HR) and corresponding 95% confidence interval (95% CI). Meta-analysis was conducted with STATA Version 12.0. RESULTS Eight studies of 1184 patients were included in the final analysis. In the PB group, it showed that patients with positive CTCs had significantly shorter overall survival and disease-free survival than patients with negative CTCs (HR, 2.09; CI, 1.13-3.88 and HR, 1.72; CI, 1.32-2.25, respectively). The same result was shown with DTCs in the BM group (HR, 1.61; CI, 1.27-2.04 and HR, 1.44; CI, 1.15-1.80, respectively). We also discussed the influence of CTCs/DTCs on International Federation of Gynecology and Obstetrics stage, pathological grade with odds ratio and 95% CI. However, it did not show any statistical significance. CONCLUSIONS The CTCs/DTCs might be a new biomarker to predict the prognosis of ovarian cancer. Future studies are needed to confirm this consequence.
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32
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Wu CP, Wu P, Zhao HF, Liu WL, Li WP. Clinical Applications of and Challenges in Single-Cell Analysis of Circulating Tumor Cells. DNA Cell Biol 2018; 37:78-89. [PMID: 29265876 DOI: 10.1089/dna.2017.3981] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Affiliation(s)
- Chang-peng Wu
- Department of Neurosurgery, Shenzhen Second People's Hospital, Clinical Medicine College of Anhui Medical University, Shenzhen, China
- Department of Neurosurgery, Shenzhen Key Laboratory of Neurosurgery, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen, China
| | - Peng Wu
- The Affiliated Luohu Hospital of Shenzhen University, Shenzhen Luohu Hospital Group Department of Urology, Shenzhen, China
| | - Hua-fu Zhao
- Department of Neurosurgery, Shenzhen Key Laboratory of Neurosurgery, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen, China
- Department of Neurosurgery/Neuro-oncology, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Wen-lan Liu
- Department of Neurosurgery, Shenzhen Key Laboratory of Neurosurgery, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen, China
| | - Wei-ping Li
- Department of Neurosurgery, Shenzhen Key Laboratory of Neurosurgery, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen, China
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33
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Verhoef EI, Kolijn K, De Herdt MJ, van der Steen B, Hoogland AM, Sleddens HFBM, Looijenga LHJ, van Leenders GJLH. MET expression during prostate cancer progression. Oncotarget 2018; 7:31029-36. [PMID: 27105539 PMCID: PMC5058736 DOI: 10.18632/oncotarget.8829] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2016] [Accepted: 03/31/2016] [Indexed: 11/25/2022] Open
Abstract
Tyrosine-kinase inhibitors of the hepatocyte growth factor receptor MET are under investigation for the treatment of hormone-refractory prostate cancer (HRPC) metastasis. Analysis of MET protein expression and genetic alterations might contribute to therapeutic stratification of prostate cancer patients. Our objective was to investigate MET on protein, DNA and RNA level in clinical prostate cancer at various stages of progression. Expression of MET was analyzed in hormone-naive primary prostate cancers (N=481), lymph node (N=40) and bone (N=8) metastases, as well as HRPC (N=54) and bone metastases (N=15). MET protein expression was analyzed by immunohistochemistry (D1C2 C-terminal antibody). MET mRNA levels and MET DNA copy numbers were determined by in situ hybridization. None of the hormone-naive primary prostate cancer or lymph node metastases demonstrated MET protein or mRNA expression. In contrast, MET protein was expressed in 12/52 (23%) evaluable HRPC resections. RNA in situ demonstrated cytoplasmic signals in 14/54 (26%) of the HRPC patients, and was associated with MET protein expression (p=0.025, χ2), in absence of MET amplification or polysomy. MET protein expression was present in 7/8 (88%) hormone-naive and 10/15 (67%) HRPC bone metastases, without association of HRPC (p=0.37; χ2), with MET polysomy in 8/13 (61%) evaluable cases. In conclusion, MET was almost exclusively expressed in HRPC and prostate cancer bone metastasis, but was not related to MET amplification or polysomy. Evaluation of MET status could be relevant for therapeutic stratification of late stage prostate cancer.
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Affiliation(s)
- Esther I Verhoef
- Department of Pathology, Erasmus Medical Centre, Rotterdam, The Netherlands
| | - Kimberley Kolijn
- Department of Pathology, Erasmus Medical Centre, Rotterdam, The Netherlands
| | - Maria J De Herdt
- Othorhinolaryngology and Head and Neck Surgery, Erasmus Medical Centre, Rotterdam, The Netherlands
| | - Berdine van der Steen
- Othorhinolaryngology and Head and Neck Surgery, Erasmus Medical Centre, Rotterdam, The Netherlands
| | - A Marije Hoogland
- Department of Pathology, Erasmus Medical Centre, Rotterdam, The Netherlands
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Kim SE, Shin SH, Lee JY, Kim CH, Chung IK, Kang HM, Park HR, Park BS, Kim IR. Resveratrol Induces Mitochondrial Apoptosis and Inhibits Epithelial-Mesenchymal Transition in Oral Squamous Cell Carcinoma Cells. Nutr Cancer 2017; 70:125-135. [DOI: 10.1080/01635581.2018.1397708] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Affiliation(s)
- Seong-Eon Kim
- Department of Oral and Maxillofacial Surgery, Pusan National University Dental Hospital, Mulgeum-eup, Yangsan-si, Gyeongsangnam-do, South Korea
| | - Sang-Hun Shin
- Department of Oral and Maxillofacial Surgery, Pusan National University Dental Hospital, Mulgeum-eup, Yangsan-si, Gyeongsangnam-do, South Korea
| | - Jae-Yeol Lee
- Department of Oral and Maxillofacial Surgery, Pusan National University Dental Hospital, Mulgeum-eup, Yangsan-si, Gyeongsangnam-do, South Korea
| | - Chul-Hoon Kim
- Department of Oral and Maxillofacial Surgery, Medical Center, Dong-A University, Busan, South Korea
| | - In-Kyo Chung
- Department of Oral and Maxillofacial Surgery, Pusan National University Dental Hospital, Mulgeum-eup, Yangsan-si, Gyeongsangnam-do, South Korea
| | - Hae-Mi Kang
- Department of Oral Anatomy, School of Dentistry, Pusan National University, Busandaehak-ro, Yangsan-si, Gyeongsangnam-do, South Korea
- BK21 PLUS Project, School of Dentistry, Pusan National University, Busandaehak-ro, Yangsan-si, Gyeongsangnam-do, South Korea
| | - Hae-Ryoun Park
- Department of Oral Pathology, School of Dentistry, Pusan National University, Busandaehak-ro, Yangsan-si, Gyeongsangnam-do, South Korea
- BK21 PLUS Project, School of Dentistry, Pusan National University, Busandaehak-ro, Yangsan-si, Gyeongsangnam-do, South Korea
| | - Bong-Soo Park
- Department of Oral Anatomy, School of Dentistry, Pusan National University, Busandaehak-ro, Yangsan-si, Gyeongsangnam-do, South Korea
- BK21 PLUS Project, School of Dentistry, Pusan National University, Busandaehak-ro, Yangsan-si, Gyeongsangnam-do, South Korea
| | - In-Ryoung Kim
- Department of Oral Anatomy, School of Dentistry, Pusan National University, Busandaehak-ro, Yangsan-si, Gyeongsangnam-do, South Korea
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Role of HSPA1L as a cellular prion protein stabilizer in tumor progression via HIF-1α/GP78 axis. Oncogene 2017; 36:6555-6567. [PMID: 28759037 DOI: 10.1038/onc.2017.263] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2017] [Revised: 06/05/2017] [Accepted: 06/08/2017] [Indexed: 02/06/2023]
Abstract
The cellular prion protein (PrPC) is associated with metastasis, tumor progression and recurrence; however, the precise mechanisms underlying its action is not well understood. Our study found that PrPC degradation decreased tumor progression in colorectal cancer (CRC). In a CRC cell line and human CRC tissue exposed to hypoxia, induced heat-shock 70-kDa protein-1-like (HSPA1L) expression stabilized hypoxia-inducible factor-1α (HIF-1α) protein and promoted PrPC accumulation and tumorigenicity in vivo. PrPC was degraded via the proteasome pathway mediated by the ubiquitin-protein E3 ligase glycoprotein 78 (GP78), which interacts directly with PrPC. However, hypoxia-induced HSPA1L interacted with GP78 and inhibited its functions. HSPA1L knockdown facilitated the interaction of GP78 and PrPC, thereby increasing PrPC ubiquitination. Thus, GP78 was identified as the ubiquitinase for PrPC, thereby revealing an essential mechanism that controls PrPC levels in CRC. Our results suggest that the HSPA1L/HIF-1α/GP78 axis has a crucial role in PrPC accumulation during tumor progression.
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Epithelial-to-Mesenchymal Transition in the Pathogenesis and Therapy of Head and Neck Cancer. Cancers (Basel) 2017; 9:cancers9070076. [PMID: 28671620 PMCID: PMC5532612 DOI: 10.3390/cancers9070076] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2017] [Revised: 06/27/2017] [Accepted: 06/30/2017] [Indexed: 01/22/2023] Open
Abstract
Head and neck cancer (HNC) is one of the most prevalent human malignancies worldwide, with a high morbidity and mortality. Implementation of interdisciplinary treatment modalities has improved the quality of life, but only minor changes in overall survival have been achieved over the past decades. Main causes for treatment failure are an aggressive and invasive tumor growth in combination with a high degree of intrinsic or acquired treatment resistance. A subset of tumor cells gain these properties during malignant progression by reactivating a complex program of epithelia-to-mesenchymal transition (EMT), which is integral in embryonic development, wound healing, and stem cell behavior. EMT is mediated by a core set of key transcription factors, which are under the control of a large range of developmental signals and extracellular cues. Unraveling molecular principles that drive EMT provides new concepts to better understand tumor cell plasticity and response to established as well as new treatment modalities, and has the potential to identify new drug targets for a more effective, less toxic, and individualized therapy of HNC patients. Here, we review the most recent findings on the clinical relevance of a mesenchymal-like phenotype for HNC patients, including more rare cases of mucosal melanoma and adenoid cystic carcinoma.
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Santamaria PG, Moreno‐Bueno G, Portillo F, Cano A. EMT: Present and future in clinical oncology. Mol Oncol 2017; 11:718-738. [PMID: 28590039 PMCID: PMC5496494 DOI: 10.1002/1878-0261.12091] [Citation(s) in RCA: 177] [Impact Index Per Article: 22.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2017] [Revised: 05/31/2017] [Accepted: 06/02/2017] [Indexed: 12/12/2022] Open
Abstract
Epithelial/mesenchymal transition (EMT) has emerged as a key regulator of metastasis by facilitating tumor cell invasion and dissemination to distant organs. Recent evidences support that the reverse mesenchymal/epithelial transition (MET) is required for metastatic outgrowth; moreover, the existence of hybrid epithelial/mesenchymal (E/M) phenotypes is increasingly being reported in different tumor contexts. The accumulated data strongly support that plasticity between epithelial and mesenchymal states underlies the dissemination and metastatic potential of carcinoma cells. However, the translation into the clinics of EMT and epithelial plasticity processes presents enormous challenges and still remains a controversial issue. In this review, we will evaluate current evidences for translational applicability of EMT and depict an overview of the most recent EMT in vivo models, EMT marker analyses in human samples as well as potential EMT therapeutic approaches and ongoing clinical trials. We foresee that standardized analyses of EMT markers in solid and liquid tumor biopsies in addition to innovative tools targeting the E/M states will become promising strategies for future translation to the clinical setting.
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Affiliation(s)
- Patricia G. Santamaria
- Departamento de BioquímicaInstituto de Investigaciones Biomédicas ‘Alberto Sols’ (CSIC‐UAM)Universidad Autónoma de Madrid (UAM)IdiPAZCIBERONCMadridSpain
| | - Gema Moreno‐Bueno
- Departamento de BioquímicaInstituto de Investigaciones Biomédicas ‘Alberto Sols’ (CSIC‐UAM)Universidad Autónoma de Madrid (UAM)IdiPAZCIBERONCMadridSpain
- Fundación MD Anderson InternationalMadridSpain
| | - Francisco Portillo
- Departamento de BioquímicaInstituto de Investigaciones Biomédicas ‘Alberto Sols’ (CSIC‐UAM)Universidad Autónoma de Madrid (UAM)IdiPAZCIBERONCMadridSpain
| | - Amparo Cano
- Departamento de BioquímicaInstituto de Investigaciones Biomédicas ‘Alberto Sols’ (CSIC‐UAM)Universidad Autónoma de Madrid (UAM)IdiPAZCIBERONCMadridSpain
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38
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Cañueto J, Cardeñoso-Álvarez E, García-Hernández JL, Galindo-Villardón P, Vicente-Galindo P, Vicente-Villardón JL, Alonso-López D, De Las Rivas J, Valero J, Moyano-Sanz E, Fernández-López E, Mao JH, Castellanos-Martín A, Román-Curto C, Pérez-Losada J. MicroRNA (miR)-203 and miR-205 expression patterns identify subgroups of prognosis in cutaneous squamous cell carcinoma. Br J Dermatol 2017; 177:168-178. [PMID: 27943259 PMCID: PMC5466895 DOI: 10.1111/bjd.15236] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/03/2016] [Indexed: 01/10/2023]
Abstract
BACKGROUND Cutaneous squamous cell carcinoma (CSCC) is the second most widespread cancer in humans and its incidence is rising. These tumours can evolve as diseases of poor prognosis, and therefore it is important to identify new markers to better predict its clinical evolution. OBJECTIVES We aimed to identify the expression pattern of microRNAs (miRNAs or miRs) at different stages of skin cancer progression in a panel of murine skin cancer cell lines. Owing to the increasing importance of miRNAs in the pathogenesis of cancer, we considered the possibility that miRNAs could help to define the prognosis of CSCC and aimed to evaluate the potential use of miR-203 and miR-205 as biomarkers of prognosis in human tumours. METHODS Seventy-nine human primary CSCCs were collected at the University Hospital of Salamanca in Spain. We identified differential miRNA expression patterns at different stages of CSCC progression in a well-established panel of murine skin cancer cell lines, and then selected miR-205 and miR-203 to evaluate their association with the clinical prognosis and evolution of human CSCC. RESULTS miR-205 was expressed in tumours with pathological features recognized as indicators of poor prognosis such as desmoplasia, perineural invasion and infiltrative growth pattern. miR-205 was mainly expressed in undifferentiated areas and in the invasion front, and was associated with both local recurrence and the development of general clinical events of poor evolution. miR-205 expression was an independent variable selected to predict events of poor clinical evolution using the multinomial logistic regression model described in this study. In contrast, miR-203 was mainly expressed in tumours exhibiting the characteristics associated with a good prognosis, was mainly present in well-differentiated zones, and rarely expressed in the invasion front. Therefore, the expression and associations of miR-205 and miR-203 were mostly mutually exclusive. Finally, using a logistic biplot we identified three clusters of patients with differential prognosis based on miR-203 and miR-205 expression, and pathological tumour features. CONCLUSIONS miR-205 and miR-203 tended to exhibit mutually exclusive expression patterns in human CSCC. This work highlights the utility of miR-205 and miR-203 as prognostic markers in CSCC.
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Affiliation(s)
- J Cañueto
- Departamento de Dermatología, Hospital Universitario de Salamanca, Paseo de San Vicente, 58-182, 37007, Salamanca, Spain
- Instituto de Investigación Biomédica de Salamanca (IBSAL), Hospital Universitario de Salamanca, Paseo de San Vicente, 58-182, 37007, Salamanca, Spain
| | - E Cardeñoso-Álvarez
- Departamento de Dermatología, Hospital Virgen de la Concha, Avenida de Requejo, Zamora, Spain
| | - J L García-Hernández
- Instituto de Investigación Biomédica de Salamanca (IBSAL), Hospital Universitario de Salamanca, Paseo de San Vicente, 58-182, 37007, Salamanca, Spain
- Instituto de Biología Molecular y Celular del Cáncer (IBMCC), Centro de Investigación del Cáncer (CIC), Universidad de Salamanca/CSIC, Campus Miguel de Unamuno, s.n. 37007, Salamanca, Spain
| | - P Galindo-Villardón
- Departamento de Estadística, Universidad de Salamanca, Campus Miguel de Unamuno, s.n. 37007, Salamanca, Spain
| | - P Vicente-Galindo
- Departamento de Estadística, Universidad de Salamanca, Campus Miguel de Unamuno, s.n. 37007, Salamanca, Spain
| | - J L Vicente-Villardón
- Departamento de Estadística, Universidad de Salamanca, Campus Miguel de Unamuno, s.n. 37007, Salamanca, Spain
| | - D Alonso-López
- Instituto de Investigación Biomédica de Salamanca (IBSAL), Hospital Universitario de Salamanca, Paseo de San Vicente, 58-182, 37007, Salamanca, Spain
- Instituto de Biología Molecular y Celular del Cáncer (IBMCC), Centro de Investigación del Cáncer (CIC), Universidad de Salamanca/CSIC, Campus Miguel de Unamuno, s.n. 37007, Salamanca, Spain
- Unidad de Bioinformática, CIC-IBMCC, Salamanca, 37007, Spain
| | - J De Las Rivas
- Instituto de Investigación Biomédica de Salamanca (IBSAL), Hospital Universitario de Salamanca, Paseo de San Vicente, 58-182, 37007, Salamanca, Spain
- Instituto de Biología Molecular y Celular del Cáncer (IBMCC), Centro de Investigación del Cáncer (CIC), Universidad de Salamanca/CSIC, Campus Miguel de Unamuno, s.n. 37007, Salamanca, Spain
- Unidad de Bioinformática, CIC-IBMCC, Salamanca, 37007, Spain
| | - J Valero
- Instituto de Biología Molecular y Celular del Cáncer (IBMCC), Centro de Investigación del Cáncer (CIC), Universidad de Salamanca/CSIC, Campus Miguel de Unamuno, s.n. 37007, Salamanca, Spain
| | - E Moyano-Sanz
- Departamento de Dermatología, Hospital Universitario de Salamanca, Paseo de San Vicente, 58-182, 37007, Salamanca, Spain
| | - E Fernández-López
- Departamento de Dermatología, Hospital Universitario de Salamanca, Paseo de San Vicente, 58-182, 37007, Salamanca, Spain
- Instituto de Investigación Biomédica de Salamanca (IBSAL), Hospital Universitario de Salamanca, Paseo de San Vicente, 58-182, 37007, Salamanca, Spain
| | - J H Mao
- Life Sciences Division, Lawrence Berkeley National Laboratory, University of California, Berkeley, CA, 94720, U.S.A
| | - A Castellanos-Martín
- Instituto de Investigación Biomédica de Salamanca (IBSAL), Hospital Universitario de Salamanca, Paseo de San Vicente, 58-182, 37007, Salamanca, Spain
- Instituto de Biología Molecular y Celular del Cáncer (IBMCC), Centro de Investigación del Cáncer (CIC), Universidad de Salamanca/CSIC, Campus Miguel de Unamuno, s.n. 37007, Salamanca, Spain
| | - C Román-Curto
- Departamento de Dermatología, Hospital Universitario de Salamanca, Paseo de San Vicente, 58-182, 37007, Salamanca, Spain
- Instituto de Investigación Biomédica de Salamanca (IBSAL), Hospital Universitario de Salamanca, Paseo de San Vicente, 58-182, 37007, Salamanca, Spain
| | - J Pérez-Losada
- Instituto de Investigación Biomédica de Salamanca (IBSAL), Hospital Universitario de Salamanca, Paseo de San Vicente, 58-182, 37007, Salamanca, Spain
- Instituto de Biología Molecular y Celular del Cáncer (IBMCC), Centro de Investigación del Cáncer (CIC), Universidad de Salamanca/CSIC, Campus Miguel de Unamuno, s.n. 37007, Salamanca, Spain
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Abstract
The success of anticancer therapy is usually limited by the development of drug resistance. Such acquired resistance is driven, in part, by intratumoural heterogeneity - that is, the phenotypic diversity of cancer cells co-inhabiting a single tumour mass. The introduction of the cancer stem cell (CSC) concept, which posits the presence of minor subpopulations of CSCs that are uniquely capable of seeding new tumours, has provided a framework for understanding one dimension of intratumoural heterogeneity. This concept, taken together with the identification of the epithelial-to-mesenchymal transition (EMT) programme as a critical regulator of the CSC phenotype, offers an opportunity to investigate the nature of intratumoural heterogeneity and a possible mechanistic basis for anticancer drug resistance. In fact, accumulating evidence indicates that conventional therapies often fail to eradicate carcinoma cells that have entered the CSC state via activation of the EMT programme, thereby permitting CSC-mediated clinical relapse. In this Review, we summarize our current understanding of the link between the EMT programme and the CSC state, and also discuss how this knowledge can contribute to improvements in clinical practice.
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40
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Sulaiman A, Yao ZM, Wang LS. Re-evaluating the role of epithelial-mesenchymal-transition in cancer progression. J Biomed Res 2016; 32:81-90. [PMID: 28546516 PMCID: PMC5895572 DOI: 10.7555/jbr.31.20160124] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET) are essential for embryonic development and also important in cancer progression. In a conventional model, epithelial-like cancer cells transit to mesenchymal-like tumor cells with great motility via EMT transcription factors; these mesenchymal-like cells migrate through the circulation system, relocate to a suitable site and then convert back to an epithelial-like phenotype to regenerate the tumor. However, recent findings challenge this conventional model and support the existence of a stable hybrid epithelial/mesenchymal (E/M) tumor population. Hybrid E/M tumor cells exhibit both epithelial and mesenchymal properties, possess great metastatic and tumorigenic capacity and are associated with poorer patient prognosis. The hybrid E/M model and associated regulatory networks represent a conceptual change regarding tumor metastasis and organ colonization. It may lead to the development of novel treatment strategies to ultimately stop cancer progression and improve disease-free survival.
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Affiliation(s)
- Andrew Sulaiman
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Canada.,China-Canada Centre of Research for Digestive Diseases.,Ottawa Institute of Systems Biology, University of Ottawa, 451 Smyth Road, Ottawa, Ontario K1H 8M5, Canada
| | - Ze-Min Yao
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Canada.,China-Canada Centre of Research for Digestive Diseases.,Ottawa Institute of Systems Biology, University of Ottawa, 451 Smyth Road, Ottawa, Ontario K1H 8M5, Canada
| | - Li-Sheng Wang
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Canada.,China-Canada Centre of Research for Digestive Diseases.,Ottawa Institute of Systems Biology, University of Ottawa, 451 Smyth Road, Ottawa, Ontario K1H 8M5, Canada.,Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario K1H 8L6, Canada
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41
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Yeung KT, Yang J. Epithelial-mesenchymal transition in tumor metastasis. Mol Oncol 2016; 11:28-39. [PMID: 28085222 PMCID: PMC5242415 DOI: 10.1002/1878-0261.12017] [Citation(s) in RCA: 518] [Impact Index Per Article: 57.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2016] [Revised: 10/13/2016] [Accepted: 10/21/2016] [Indexed: 12/15/2022] Open
Abstract
The epithelial-mesenchymal transition (EMT) is a developmental program that enables stationary epithelial cells to gain the ability to migrate and invade as single cells. Tumor cells reactivate EMT to acquire molecular alterations that enable the partial loss of epithelial features and partial gain of a mesenchymal phenotype. Our understanding of the contribution of EMT to tumor invasion, migration, and metastatic outgrowth has evolved over the past decade. In this review, we provide a summary of both historic and recent studies on the role of EMT in the metastatic cascade from various experimental systems, including cancer cell lines, genetic mouse tumor models, and clinical human breast cancer tissues.
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Affiliation(s)
- Kay T Yeung
- Department of Pharmacology, University of California, San Diego, La Jolla, CA, USA.,Department of Medicine, University of California, San Diego, La Jolla, CA, USA.,Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA
| | - Jing Yang
- Department of Pharmacology, University of California, San Diego, La Jolla, CA, USA.,Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA.,Department of Pediatrics, University of California, San Diego, La Jolla, CA, USA
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42
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Qin JH, Wang L, Li QL, Liang Y, Ke ZY, Wang RA. Epithelial-mesenchymal transition as strategic microenvironment mimicry for cancer cell survival and immune escape? Genes Dis 2016; 4:16-18. [PMID: 30258903 PMCID: PMC6136597 DOI: 10.1016/j.gendis.2016.10.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2016] [Accepted: 10/10/2016] [Indexed: 12/19/2022] Open
Abstract
Epithelial-mesenchymal transition (EMT) is the phenotypic transition of epithelial cells to mesenchymal cells characterized by loss of epithelial markers, loss of intercellular adherence and acquirement of mesenchymal cell markers and increased locomotive ability. EMT is widely considered to be a gene regulated process necessary for cancer metastasis. Yet it is a highly controversial issue. We here propose that EMT is an environmentally induced cell behavior. It is the mimicry of their living environment. It is a survival strategy, a way of immune escape. We also propose here that the epithelial cell markers may functionally act as tumor antigens since in the mesenchymal surroundings there are no other structures bearing the same antigens as epithelial cells.
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Affiliation(s)
- Jun-Hui Qin
- State Key Laboratory of Cancer Biology, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, China.,Department of Pathology, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, China
| | - Li Wang
- State Key Laboratory of Cancer Biology, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, China.,Department of Pathology, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, China
| | - Qin-Long Li
- State Key Laboratory of Cancer Biology, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, China.,Department of Pathology, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, China
| | - Yuan Liang
- State Key Laboratory of Cancer Biology, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, China.,Department of Pathology, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, China
| | - Zhen-Yu Ke
- State Key Laboratory of Cancer Biology, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, China.,Department of Pathology, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, China
| | - Rui-An Wang
- State Key Laboratory of Cancer Biology, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, China.,Department of Pathology, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, China
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43
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Clark AJ, Petty HR. Protocol for Biomarker Ratio Imaging Microscopy with Specific Application to Ductal Carcinoma In situ of the Breast. Front Cell Dev Biol 2016; 4:120. [PMID: 27857940 PMCID: PMC5093143 DOI: 10.3389/fcell.2016.00120] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2016] [Accepted: 10/14/2016] [Indexed: 01/01/2023] Open
Abstract
This protocol describes the methods and steps involved in performing biomarker ratio imaging microscopy (BRIM) using formalin fixed paraffin-embedded (FFPE) samples of human breast tissue. The technique is based on the acquisition of two fluorescence images of the same microscopic field using two biomarkers and immunohistochemical tools. The biomarkers are selected such that one biomarker correlates with breast cancer aggressiveness while the second biomarker anti-correlates with aggressiveness. When the former image is divided by the latter image, a computed ratio image is formed that reflects the aggressiveness of tumor cells while increasing contrast and eliminating path-length and other artifacts from the image. For example, the aggressiveness of epithelial cells may be assessed by computing ratio images of N-cadherin and E-cadherin images or CD44 and CD24 images, which specifically reflect the mesenchymal or stem cell nature of the constituent cells, respectively. This methodology is illustrated for tissue samples of ductal carcinoma in situ (DCIS) and invasive breast cancer. This tool should be useful in tissue studies of experimental cancer as well as the management of cancer patients.
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Affiliation(s)
- Andrea J Clark
- Department of Ophthalmology and Visual Sciences, University of Michigan Medical School Ann Arbor, MI, USA
| | - Howard R Petty
- Department of Ophthalmology and Visual Sciences, University of Michigan Medical School Ann Arbor, MI, USA
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44
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Chen X, Bode AM, Dong Z, Cao Y. The epithelial-mesenchymal transition (EMT) is regulated by oncoviruses in cancer. FASEB J 2016; 30:3001-3010. [PMID: 27279361 DOI: 10.1096/fj.201600388r] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2016] [Accepted: 05/31/2016] [Indexed: 01/03/2025]
Abstract
The epithelial-mesenchymal transition (EMT), defined as transdifferentiation of epithelial cells into mesenchymal cells, is critical for embryonic development, wound healing, tissue regeneration, organ fibrosis, and cancer progression. Recently, the role of EMT in carcinogenesis has attracted much attention. Oncoviruses, including human papillomaviruses (HPVs), Epstein-Barr virus (EBV), and hepatitis B and C viruses (HBVs, HCVs), are known to be involved in the etiology of cancer and have been found to play important roles in cancer metastasis, especially in the EMT process. The HPV encoded oncoproteins E6 and E7 (E6/E7), EBV latent membrane protein-1 and -2A, EBV nuclear antigen, HBV-encoded X antigen, and nonstructural HCV protein 5A are all involved in the regulation of EMT. This review primarily focuses on the role of oncoviruses and their encoded proteins or signaling pathways in the EMT process. Understanding their roles will help us in the development of effective strategies for prevention and treatment of virus-related cancers.-Chen, X., Bode, A. M., Dong, Z., Cao, Y. The epithelial-mesenchymal transition (EMT) is regulated by oncoviruses in cancer.
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Affiliation(s)
- Xue Chen
- Molecular Imaging Center, Xiangya Hospital, Central South University, Hunan, China; Cancer Research Institute, Central South University, Hunan, China; Key Laboratory, Chinese Ministry of Education, Central South University, Hunan, China; State Key Laboratory of Carcinogenesis, Chinese Ministry of Public Health, Central South University, Hunan, China; and
| | - Ann M Bode
- The Hormel Institute, University of Minnesota, Austin, Minnesota, USA
| | - Zigang Dong
- The Hormel Institute, University of Minnesota, Austin, Minnesota, USA
| | - Ya Cao
- Molecular Imaging Center, Xiangya Hospital, Central South University, Hunan, China; Cancer Research Institute, Central South University, Hunan, China; Key Laboratory, Chinese Ministry of Education, Central South University, Hunan, China; State Key Laboratory of Carcinogenesis, Chinese Ministry of Public Health, Central South University, Hunan, China; and
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45
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Sulaiman SA, Ab Mutalib NS, Jamal R. miR-200c Regulation of Metastases in Ovarian Cancer: Potential Role in Epithelial and Mesenchymal Transition. Front Pharmacol 2016; 7:271. [PMID: 27601996 PMCID: PMC4993756 DOI: 10.3389/fphar.2016.00271] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2016] [Accepted: 08/10/2016] [Indexed: 12/20/2022] Open
Abstract
Among the gynecological malignancies, ovarian cancer is the most fatal due to its high mortality rate. Most of the identified cases are epithelial ovarian cancer (EOC) with five distinct subtypes: high-grade serous carcinoma, low-grade serous carcinoma, mucinous carcinoma, endometrioid carcinoma, and clear-cell carcinoma. Lack of an early diagnostic approach, high incidence of tumor relapse and the heterogenous characteristics between each EOC subtypes contribute to the difficulties in developing precise intervention and therapy for the patients. MicroRNAs (miRNAs) are single-stranded RNAs that have been shown to function as tumor suppressors or oncomiRs. The miR-200 family, especially miR-200c, has been shown to be implicated in the metastasis and invasion of ovarian carcinoma due to its functional regulation of epithelial-to-mesenchymal transition (EMT). This mini review is aimed to summarize the recent findings of the miR-200c functional role as well as its validated targets in the metastasis cascade of ovarian cancer, with a focus on EMT regulation. The potential of this miRNA in early diagnosis and its dual expression status are also discussed.
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Affiliation(s)
- Siti A Sulaiman
- UKM Medical Molecular Biology Institute, UKM Medical Centre, Universiti Kebangsaan Malaysia Kuala Lumpur, Malaysia
| | - Nurul-Syakima Ab Mutalib
- UKM Medical Molecular Biology Institute, UKM Medical Centre, Universiti Kebangsaan Malaysia Kuala Lumpur, Malaysia
| | - Rahman Jamal
- UKM Medical Molecular Biology Institute, UKM Medical Centre, Universiti Kebangsaan Malaysia Kuala Lumpur, Malaysia
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Gallerani G, Fabbri F. Circulating Tumor Cells in the Adenocarcinoma of the Esophagus. Int J Mol Sci 2016; 17:ijms17081266. [PMID: 27527155 PMCID: PMC5000664 DOI: 10.3390/ijms17081266] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2016] [Revised: 07/29/2016] [Accepted: 07/30/2016] [Indexed: 02/06/2023] Open
Abstract
Circulating tumor cells (CTCs) are elements of indisputable significance as they seem to be responsible for the onset of metastasis. Despite this, research into CTCs and their clinical application have been hindered by their rarity and heterogeneity at the molecular and cellular level, and also by a lack of technical standardization. Esophageal adenocarcinoma (EAC) is a highly aggressive cancer that is often diagnosed at an advanced stage. Its incidence has increased so much in recent years that new diagnostic, prognostic and predictive biomarkers are urgently needed. Preliminary findings suggest that CTCs could represent an effective, non-invasive, real-time assessable biomarker in all stages of EAC. This review provides an overview of EAC and CTC characteristics and reports the main research results obtained on CTCs in this setting. The need to carry out further basic and translational research in this area to confirm the clinical usefulness of CTCs and to provide oncologists with a tool to improve therapeutic strategies for EAC patients was herein highlighted.
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Affiliation(s)
- Giulia Gallerani
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Via P. Maroncelli 40, Meldola 47014, FC, Italy.
| | - Francesco Fabbri
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Via P. Maroncelli 40, Meldola 47014, FC, Italy.
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Clark AJ, Petty HR. Identification of lesion subtypes in biopsies of ductal carcinoma in situ of the breast using biomarker ratio imaging microscopy. Sci Rep 2016; 6:27039. [PMID: 27247112 PMCID: PMC4887986 DOI: 10.1038/srep27039] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2015] [Accepted: 05/12/2016] [Indexed: 12/19/2022] Open
Abstract
Although epidemiological studies propose aggressive and non-aggressive forms of ductal carcinoma in situ (DCIS), they cannot be identified with conventional histopathology. We now report a retrospective study of human biopsy samples using biomarker ratio imaging microscopy (BRIM). Using BRIM, micrographs of biomarkers whose expression correlates with breast cancer aggressiveness are divided by micrographs of biomarkers whose expression negatively correlates with aggressiveness to create computed micrographs reflecting aggressiveness. The biomarker pairs CD44/CD24, N-cadherin/E-cadherin, and CD74/CD59 stratified DCIS samples. BRIM identified subpopulations of DCIS lesions with ratiometric properties resembling either benign fibroadenoma or invasive carcinoma samples. Our work confirms the existence of distinct subpopulations of DCIS lesions, which will likely have utility in breast cancer research and clinical practice.
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Affiliation(s)
- Andrea J Clark
- Department of Ophthalmology and Visual Sciences, 1000 Wall Street, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Howard R Petty
- Department of Ophthalmology and Visual Sciences, 1000 Wall Street, University of Michigan Medical School, Ann Arbor, MI, USA
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Zhang C, Guan Y, Sun Y, Ai D, Guo Q. Tumor heterogeneity and circulating tumor cells. Cancer Lett 2016; 374:216-23. [DOI: 10.1016/j.canlet.2016.02.024] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2015] [Revised: 02/11/2016] [Accepted: 02/12/2016] [Indexed: 12/15/2022]
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Abstract
Primary tumors are known to constantly shed a large number of cancer cells into systemic dissemination, yet only a tiny fraction of these cells is capable of forming overt metastases. The tremendous rate of attrition during the process of metastasis implicates the existence of a rare and unique population of metastasis-initiating cells (MICs). MICs possess advantageous traits that may originate in the primary tumor but continue to evolve during dissemination and colonization, including cellular plasticity, metabolic reprogramming, the ability to enter and exit dormancy, resistance to apoptosis, immune evasion, and co-option of other tumor and stromal cells. Better understanding of the molecular and cellular hallmarks of MICs will facilitate the development and deployment of novel therapeutic strategies.
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Affiliation(s)
- Toni Celià-Terrassa
- Department of Molecular Biology, Princeton University, Princeton, New Jersey 08544, USA
| | - Yibin Kang
- Department of Molecular Biology, Princeton University, Princeton, New Jersey 08544, USA
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50
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CTCs in early breast cancer: A path worth taking. Cancer Lett 2016; 376:205-10. [PMID: 27060205 DOI: 10.1016/j.canlet.2016.03.051] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2016] [Revised: 03/24/2016] [Accepted: 03/29/2016] [Indexed: 12/21/2022]
Abstract
Circulating tumor cells (CTCs) are cellular elements of undeniable significance that spread from the tumor mass into the peripheral blood and constitute one of the main vehicles for disease diffusion. Their rarity, in addition to a number of molecular and cellular features, has severely impaired research and exploitation. CTCs have been evaluated in early breast cancer (EBC), although long from being fully accepted in this field also due to a lack of technical standardization. CTCs hold promise to be a powerful non-invasive real-time measurable biomarker in all disease stages. This hypothesis is particularly appealing in the adjuvant setting of breast cancer, as it still lacks a marker that could play a central role in monitoring disease-free intervals, predicting early relapse and guiding drug selection. This review aimed to discuss CTC characteristics and show the main results of CTC-research in EBC setting, stating the urgency to continue basic and translational research in this field to definitely translate this marker from bench to bedside.
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