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Chen S, Zhang X, Basappa B, Zhu T, Pandey V, Lobie PE. TFF3 facilitates dormancy of anti-estrogen treated ER+ mammary carcinoma. COMMUNICATIONS MEDICINE 2025; 5:45. [PMID: 39984660 PMCID: PMC11845601 DOI: 10.1038/s43856-024-00710-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Accepted: 12/13/2024] [Indexed: 02/23/2025] Open
Abstract
BACKGROUND Tumor dormancy is a substantial clinical obstacle in treatment of estrogen receptor positive mammary carcinoma (ER+MC), contributing to drug resistance, metastatic outgrowth, relapse, and consequent mortality. METHODS Preclinical models mimicking clinical anti-estrogen-induced ER+MC dormancy were generated in vivo. Function and a mechanism-based combination treatment were determined in the generated dormancy-like models in vitro, ex vivo, and in vivo. RESULTS The dormancy models display molecular features of dormancy and tumor mass and cellular dormancy with associated clinical dormancy behavior. Both serum and cancer tissue expression of Trefoil factor 3 (TFF3) are identified as prognostic indicators of dormant ER+MC with TFF3 functioning as an epigenetically regulated driver of dormancy-associated behaviors. BCL2-dependent pro-survival functions of TFF3 coupled with enhanced attributes of stemness designates TFF3 as an actionable target. Moreover, combination screening of a TFF3 small-molecule-inhibitor (AMPC) with compounds used clinically to treat anti-estrogen-resistant ER+MC identifies strong synergism between AMPC and CDK4/6 inhibitors in the dormancy-like models. The combination results in concomitant suppression of CCND1 expression and CDK4/6 kinase activity to decrease RB phosphorylation, with reduced BCL2 expression, leading to both ER + MC cell cycle arrest and apoptosis. The combined TFF3-CDK4/6 inhibition impedes metastatic outgrowth and ameliorates host animal survival in the dormancy-like models, producing a complete response in a percentage of animals. CONCLUSIONS Hence, in vivo models of anti-estrogen induced dormancy of ER+MC generated herein, identify TFF3 as a driver of this process. The combined inhibition of TFF3 and CDK4/6 may potentially alleviate the clinical challenges posed by anti-estrogen-induced dormancy in ER+MC.
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Affiliation(s)
- Shu Chen
- Precision Medicine and Healthcare Research Center, Tsinghua-Berkeley Shenzhen Institute, Tsinghua University, Shenzhen, Guangdong, PR China
- Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, Guangdong, PR China
| | - Xi Zhang
- Precision Medicine and Healthcare Research Center, Tsinghua-Berkeley Shenzhen Institute, Tsinghua University, Shenzhen, Guangdong, PR China
- Shenzhen Bay Laboratory, Shenzhen, Guangdong, PR China
| | - Basappa Basappa
- Laboratory of Chemical Biology, Department of Studies in Organic Chemistry, University of Mysore, Mysore, Karnataka, India
| | - Tao Zhu
- Shenzhen Bay Laboratory, Shenzhen, Guangdong, PR China
- Department of Oncology, The First Affiliated Hospital of USTC, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, PR China
- Key Laboratory of Immune Response and Immunotherapy, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, PR China
| | - Vijay Pandey
- Precision Medicine and Healthcare Research Center, Tsinghua-Berkeley Shenzhen Institute, Tsinghua University, Shenzhen, Guangdong, PR China.
- Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, Guangdong, PR China.
| | - Peter E Lobie
- Precision Medicine and Healthcare Research Center, Tsinghua-Berkeley Shenzhen Institute, Tsinghua University, Shenzhen, Guangdong, PR China.
- Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, Guangdong, PR China.
- Shenzhen Bay Laboratory, Shenzhen, Guangdong, PR China.
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El-Tanani M, Rabbani SA, Satyam SM, Rangraze IR, Wali AF, El-Tanani Y, Aljabali AAA. Deciphering the Role of Cancer Stem Cells: Drivers of Tumor Evolution, Therapeutic Resistance, and Precision Medicine Strategies. Cancers (Basel) 2025; 17:382. [PMID: 39941751 PMCID: PMC11815874 DOI: 10.3390/cancers17030382] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2024] [Revised: 01/17/2025] [Accepted: 01/23/2025] [Indexed: 02/16/2025] Open
Abstract
Cancer stem cells (CSCs) play a central role in tumor progression, recurrence, and resistance to conventional therapies, making them a critical focus in oncology research. This review provides a comprehensive analysis of CSC biology, emphasizing their self-renewal, differentiation, and dynamic interactions with the tumor microenvironment (TME). Key signaling pathways, including Wnt, Notch, and Hedgehog, are discussed in detail to highlight their potential as therapeutic targets. Current methodologies for isolating CSCs are critically examined, addressing their advantages and limitations in advancing precision medicine. Emerging technologies, such as CRISPR/Cas9 and single-cell sequencing, are explored for their transformative potential in unraveling CSC heterogeneity and informing therapeutic strategies. The review also underscores the pivotal role of the TME in supporting CSC survival, promoting metastasis, and contributing to therapeutic resistance. Challenges arising from CSC-driven tumor heterogeneity and dormancy are analyzed, along with strategies to mitigate these barriers, including novel therapeutics and targeted approaches. Ethical considerations and the integration of artificial intelligence in designing CSC-specific therapies are discussed as essential elements of future research. The manuscript advocates for a multi-disciplinary approach that combines innovative technologies, advanced therapeutics, and collaborative research to address the complexities of CSCs. By bridging existing gaps in knowledge and fostering advancements in personalized medicine, this review aims to guide the development of more effective cancer treatment strategies, ultimately improving patient outcomes.
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Affiliation(s)
- Mohamed El-Tanani
- RAK College of Pharmacy, Ras Al Khaimah Medical and Health Sciences University, Ras Al Khaimah P.O. Box 11172, United Arab Emirates
| | - Syed Arman Rabbani
- Department of Clinical Pharmacy, RAK College of Pharmacy, Ras Al Khaimah Medical and Health Sciences University, Ras Al Khaimah P.O. Box 11172, United Arab Emirates
| | - Shakta Mani Satyam
- Department of Pharmacology, RAK College of Medical Sciences, Ras Al Khaimah Medical and Health Sciences University, Ras Al Khaimah P.O. Box 11172, United Arab Emirates
| | - Imran Rashid Rangraze
- Department of Internal Medicine, RAK College of Medical Sciences, Ras Al Khaimah Medical and Health Sciences University, Ras Al Khaimah P.O. Box 11172, United Arab Emirates
| | - Adil Farooq Wali
- Department of Medicinal Chemistry, RAK College of Pharmacy, Ras Al Khaimah Medical and Health Sciences University, Ras Al Khaimah P.O. Box 11172, United Arab Emirates
| | | | - Alaa A. A. Aljabali
- Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Yarmouk University, Irbid 21163, Jordan
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Kabak EC, Foo SL, Rafaeva M, Martin I, Bentires-Alj M. Microenvironmental Regulation of Dormancy in Breast Cancer Metastasis: "An Ally that Changes Allegiances". ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2025; 1464:373-395. [PMID: 39821034 DOI: 10.1007/978-3-031-70875-6_18] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/19/2025]
Abstract
Breast cancer remission after treatment is sometimes long-lasting, but in about 30% of cases, there is a relapse after a so-called dormant state. Cellular cancer dormancy, the propensity of disseminated tumor cells (DTCs) to remain in a nonproliferative state for an extended period, presents an opportunity for therapeutic intervention that may prevent reawakening and the lethal consequences of metastatic outgrowth. Therefore, identification of dormant DTCs and detailed characterization of cancer cell-intrinsic and niche-specific [i.e., tumor microenvironment (TME) mediated] mechanisms influencing dormancy in different metastatic organs are of great importance in breast cancer. Several microenvironmental drivers of DTC dormancy in metastatic organs, such as the lung, bone, liver, and brain, have been identified using in vivo models and/or in vitro three-dimensional culture systems. TME induction and persistence of dormancy in these organs are mainly mediated by signals from immune cells, stromal cells, and extracellular matrix components of the TME. Alterations of the TME have been shown to reawaken dormant DTCs. Efforts to capitalize on these findings often face translational challenges due to limited availability of representative patient samples and difficulty in designing dormancy-targeting clinical trials. In this chapter, we discuss current approaches to identify dormant DTCs and provide insights into cell-extrinsic (i.e., TME) mechanisms driving breast cancer cell dormancy in distant organs.
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Affiliation(s)
- Evrim Ceren Kabak
- Laboratory of Tumor Heterogeneity, Metastasis and Resistance, Department of Biomedicine, University of Basel, University Hospital Basel, Basel, Switzerland
- Department of Biomedicine, University Hospital Basel, University of Basel, Basel, Switzerland
| | - Sok Lin Foo
- Laboratory of Tumor Heterogeneity, Metastasis and Resistance, Department of Biomedicine, University of Basel, University Hospital Basel, Basel, Switzerland
| | - Maria Rafaeva
- Laboratory of Tumor Heterogeneity, Metastasis and Resistance, Department of Biomedicine, University of Basel, University Hospital Basel, Basel, Switzerland
| | - Ivan Martin
- Department of Biomedicine, University Hospital Basel, University of Basel, Basel, Switzerland
| | - Mohamed Bentires-Alj
- Laboratory of Tumor Heterogeneity, Metastasis and Resistance, Department of Biomedicine, University of Basel, University Hospital Basel, Basel, Switzerland.
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Liu W, Kovacs AH, Hou J. Cancer Cells in Sleep Mode: Wake Them to Eliminate or Keep Them Asleep Forever? Cells 2024; 13:2022. [PMID: 39682769 PMCID: PMC11640528 DOI: 10.3390/cells13232022] [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: 09/14/2024] [Revised: 11/03/2024] [Accepted: 12/03/2024] [Indexed: 12/18/2024] Open
Abstract
Cancer cell dormancy is a critical phase in cancer development, wherein cancer cells exist in a latent state marked by temporary but reversible growth arrest. This dormancy phase contributes to anticancer drug resistance, cancer recurrence, and metastasis. Treatment strategies aimed at cancer dormancy can be categorized into two contradictory approaches: inducing cancer cells into a dormant state or eliminating dormant cells. While the former seeks to establish permanent dormancy, the latter aims at eradicating this small population of dormant cells. In this review, we explore the current advancements in therapeutic methods targeting cancer cell dormancy and discuss future strategies. The concept of cancer cell dormancy has emerged as a promising avenue for novel cancer treatments, holding the potential for breakthroughs in the future.
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Affiliation(s)
- Wenjie Liu
- Department of Chemistry, Lakehead University, 955 Oliver Rd, Thunder Bay, ON P7B 5E1, Canada; (W.L.); (A.H.K.)
- Thunder Bay Regional Health Research Institute, 980 Oliver Road, Thunder Bay, ON P7B 6V4, Canada
| | - Antal H. Kovacs
- Department of Chemistry, Lakehead University, 955 Oliver Rd, Thunder Bay, ON P7B 5E1, Canada; (W.L.); (A.H.K.)
| | - Jinqiang Hou
- Department of Chemistry, Lakehead University, 955 Oliver Rd, Thunder Bay, ON P7B 5E1, Canada; (W.L.); (A.H.K.)
- Thunder Bay Regional Health Research Institute, 980 Oliver Road, Thunder Bay, ON P7B 6V4, Canada
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Chen F, Xue Y, Zhang W, Zhou H, Zhou Z, Chen T, YinWang E, Li H, Ye Z, Gao J, Wang S. The role of mitochondria in tumor metastasis and advances in mitochondria-targeted cancer therapy. Cancer Metastasis Rev 2024; 43:1419-1443. [PMID: 39307891 PMCID: PMC11554835 DOI: 10.1007/s10555-024-10211-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Accepted: 09/08/2024] [Indexed: 11/05/2024]
Abstract
Mitochondria are central actors in diverse physiological phenomena ranging from energy metabolism to stress signaling and immune modulation. Accumulating scientific evidence points to the critical involvement of specific mitochondrial-associated events, including mitochondrial quality control, intercellular mitochondrial transfer, and mitochondrial genetics, in potentiating the metastatic cascade of neoplastic cells. Furthermore, numerous recent studies have consistently emphasized the highly significant role mitochondria play in coordinating the regulation of tumor-infiltrating immune cells and immunotherapeutic interventions. This review provides a comprehensive and rigorous scholarly investigation of this subject matter, exploring the intricate mechanisms by which mitochondria contribute to tumor metastasis and examining the progress of mitochondria-targeted cancer therapies.
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Affiliation(s)
- Fanglu Chen
- Department of Orthopedics, Musculoskeletal Tumor Center, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310009, P.R. China
- Institute of Orthopedic Research, Zhejiang University, Hangzhou, 310009, P.R. China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Yucheng Xue
- Department of Orthopedics, Musculoskeletal Tumor Center, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310009, P.R. China
- Institute of Orthopedic Research, Zhejiang University, Hangzhou, 310009, P.R. China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Wenkan Zhang
- Department of Orthopedics, Musculoskeletal Tumor Center, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310009, P.R. China
- Institute of Orthopedic Research, Zhejiang University, Hangzhou, 310009, P.R. China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Hao Zhou
- Department of Orthopedics, Musculoskeletal Tumor Center, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310009, P.R. China
- Institute of Orthopedic Research, Zhejiang University, Hangzhou, 310009, P.R. China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Zhiyi Zhou
- The First People's Hospital of Yuhang District, Hangzhou, Zhejiang, China
| | - Tao Chen
- Department of Orthopedics, Musculoskeletal Tumor Center, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310009, P.R. China
- Institute of Orthopedic Research, Zhejiang University, Hangzhou, 310009, P.R. China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Eloy YinWang
- Department of Orthopedics, Musculoskeletal Tumor Center, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310009, P.R. China
- Institute of Orthopedic Research, Zhejiang University, Hangzhou, 310009, P.R. China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Hengyuan Li
- Department of Orthopedics, Musculoskeletal Tumor Center, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310009, P.R. China
- Institute of Orthopedic Research, Zhejiang University, Hangzhou, 310009, P.R. China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Zhaoming Ye
- Department of Orthopedics, Musculoskeletal Tumor Center, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310009, P.R. China.
- Institute of Orthopedic Research, Zhejiang University, Hangzhou, 310009, P.R. China.
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, China.
| | - Junjie Gao
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China.
| | - Shengdong Wang
- Department of Orthopedics, Musculoskeletal Tumor Center, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310009, P.R. China.
- Institute of Orthopedic Research, Zhejiang University, Hangzhou, 310009, P.R. China.
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, China.
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Carpintieri S, Uyar E, Anand C, Buryk Y. Cancer History, Antiphospholipid Syndrome, and Lupus Anticoagulant: A Perfect Storm for Thrombosis. Cureus 2024; 16:e76481. [PMID: 39866992 PMCID: PMC11769576 DOI: 10.7759/cureus.76481] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/18/2024] [Indexed: 01/28/2025] Open
Abstract
Cancer and antiphospholipid syndrome (APS) independently increase thrombotic risk, and their coexistence can create a particularly hazardous prothrombotic state. This case report aims to highlight the complex challenges in managing concurrent thrombotic and hemorrhagic events in patients with a history of cancer and APS. The combination of these conditions presents a rare and difficult clinical scenario, requiring careful consideration in anticoagulation management. By presenting this case, we seek to emphasize the persistent thrombotic risk in cancer survivors and the importance of considering APS in patients with unexplained thrombotic events. This case report presents a 51-year-old male with a history of duodenal cancer in remission who experienced multiple severe thrombotic events, including an acute ischemic stroke, intracranial hemorrhages following treatment, and a pulmonary embolism. APS was diagnosed based on these events and positive laboratory findings. Management involved a delicate balance between thrombotic and hemorrhagic risks, with anticoagulation initially withheld due to intracranial hemorrhages, then cautiously initiated following the pulmonary embolism. The patient gradually improved, regaining functional independence with mild residual weakness three months post-discharge.
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Affiliation(s)
| | - Elias Uyar
- Internal Medicine, Ross University School of Medicine, Miami, USA
| | - Christian Anand
- Internal Medicine, St. George's University School of Medicine, Brooklyn, USA
| | - Yaroslav Buryk
- Pulmonary and Critical Care, Jackson Memorial Hospital, Miami, USA
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7
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Lenart NA, Rao SS. Cell-cell interactions mediating primary and metastatic breast cancer dormancy. Cancer Metastasis Rev 2024; 44:6. [PMID: 39585533 DOI: 10.1007/s10555-024-10223-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Accepted: 10/18/2024] [Indexed: 11/26/2024]
Abstract
Breast cancer remains one of the leading causes of death in women around the world. A majority of deaths from breast cancer occur due to cancer cells colonizing distant organ sites. When colonizing these distant organ sites, breast cancer cells have been known to enter into a state of dormancy for extended periods of time. However, the mechanisms that promote dormancy as well as dormant-to-proliferative switch are not fully understood. The tumor microenvironment plays a key role in mediating cancer cell phenotype including regulation of the dormant state. In this review, we highlight cell-cell interactions in the tumor microenvironment mediating breast cancer dormancy at the primary and metastatic sites. Specifically, we describe how immune cells from the lymphoid lineage, tumor-associated myeloid lineage cells, and stromal cells of non-hematopoietic origin as well as tissue resident stromal cells impact dormancy vs. proliferation in breast cancer cells as well as the associated mechanisms. In addition, we highlight the importance of developing model systems and the associated considerations that will be critical in unraveling the mechanisms that promote primary and metastatic breast cancer dormancy mediated via cell-cell interactions.
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Affiliation(s)
- Nicholas A Lenart
- Department of Chemical and Biological Engineering, The University of Alabama, Tuscaloosa, AL, 35487-0203, USA
| | - Shreyas S Rao
- Department of Chemical and Biological Engineering, The University of Alabama, Tuscaloosa, AL, 35487-0203, USA.
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Zhang WL, Fan HY, Chen BJ, Wang HF, Pang X, Li M, Liang XH, Tang YL. Cancer-associated fibroblasts-derived CXCL1 activates DEC2-mediated dormancy in oral squamous cell carcinoma. Heliyon 2024; 10:e39133. [PMID: 39469703 PMCID: PMC11513488 DOI: 10.1016/j.heliyon.2024.e39133] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2024] [Revised: 09/03/2024] [Accepted: 10/08/2024] [Indexed: 10/30/2024] Open
Abstract
Cancer-associated fibroblasts (CAFs) are known to play an important role in cancer progression, but their effects on tumor cell dormancy and the underlying mechanisms remain to be explored. Here, we aimed to dissect the intercellular communication between CAFs and oral squamous cell carcinoma (OSCC) cells under cellular dormancy. In this study, we investigated 61 OSCC patients and found that low expression of Differentiated Embryonic Chondrocyte gene 2 (DEC2) was closely associated with tumor recurrence, cisplatin chemotherapy administration, and infiltration of CAFs. Overexpression of DEC2 promoted the invasion and migration ability of OSCC cells but inhibited their proliferation and glucose metabolism, and characterized them as dormant and cisplatin-resistant cells. C-X-C motif ligand 1 (CXCL1) from CAFs was found to down-regulate DEC2 expression in OSCC cells, ultimately awakening dormant cells and leading to tumor recurrence, which was validated in vitro and in vivo. In conclusion, CAFs-derived CXCL1 downregulated DEC2 and "interrupted" DEC2-mediated OSCC cell dormancy, which may be a mechanism by which CAFs modulate OSCC cell dormancy and contribute to the development of new therapies for OSCC.
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Affiliation(s)
- Wei-long Zhang
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Dept. of Oral Pathology, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Hua-yang Fan
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Dept. of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Bin-jun Chen
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Dept. of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Hao-fan Wang
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Dept. of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Xin Pang
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Dept. of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Mao Li
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Dept. of Oral Pathology, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Xin-hua Liang
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Dept. of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Ya-ling Tang
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Dept. of Oral Pathology, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, Sichuan, China
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Li B, Zhang J, Yu Y, Li Y, Chen Y, Zhao X, Li A, Zhao L, Li M, Wang Z, Lu X, Wu W, Zhang Y, Dong Z, Liu K, Jiang Y. Dronedarone inhibits the proliferation of esophageal squamous cell carcinoma through the CDK4/CDK6-RB1 axis in vitro and in vivo. Front Med 2024; 18:896-910. [PMID: 39266905 DOI: 10.1007/s11684-024-1062-x] [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: 07/04/2023] [Accepted: 01/17/2024] [Indexed: 09/14/2024]
Abstract
Treatment options for patients with esophageal squamous cell carcinoma (ESCC) often result in poor prognosis and declining health-related quality of life. Screening FDA-approved drugs for cancer chemoprevention is a promising and cost-efficient strategy. Here, we found that dronedarone, an antiarrhythmic drug, could inhibit the proliferation of ESCC cells. Moreover, we conducted phosphorylomics analysis to investigate the mechanism of dronedarone-treated ESCC cells. Through computational docking models and pull-down assays, we demonstrated that dronedarone could directly bind to CDK4 and CDK6 kinases. We also proved that dronedarone effectively inhibited ESCC proliferation by targeting CDK4/CDK6 and blocking the G0/G1 phase through RB1 phosphorylation inhibition by in vitro kinase assays and cell cycle assays. Subsequently, we found that knocking out CDK4 and CDK6 decreased the susceptibility of ESCC cells to dronedarone. Furthermore, dronedarone suppressed the growth of ESCC in patient-derived tumor xenograft models in vivo. Thus, our study demonstrated that dronedarone could be repurposed as a CDK4/6 inhibitor for ESCC chemoprevention.
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Affiliation(s)
- Bo Li
- The Pathophysiology Department, School of Basic Medical Sciences, College of Medicine, Zhengzhou University, Zhengzhou, 450001, China
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, 450003, China
| | - Jing Zhang
- The Pathophysiology Department, School of Basic Medical Sciences, College of Medicine, Zhengzhou University, Zhengzhou, 450001, China
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, 450003, China
| | - Yin Yu
- The Pathophysiology Department, School of Basic Medical Sciences, College of Medicine, Zhengzhou University, Zhengzhou, 450001, China
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, 450003, China
| | - Yinhua Li
- The Pathophysiology Department, School of Basic Medical Sciences, College of Medicine, Zhengzhou University, Zhengzhou, 450001, China
| | - Yingying Chen
- The Pathophysiology Department, School of Basic Medical Sciences, College of Medicine, Zhengzhou University, Zhengzhou, 450001, China
| | - Xiaokun Zhao
- The Pathophysiology Department, School of Basic Medical Sciences, College of Medicine, Zhengzhou University, Zhengzhou, 450001, China
| | - Ang Li
- The Pathophysiology Department, School of Basic Medical Sciences, College of Medicine, Zhengzhou University, Zhengzhou, 450001, China
| | - Lili Zhao
- The Pathophysiology Department, School of Basic Medical Sciences, College of Medicine, Zhengzhou University, Zhengzhou, 450001, China
| | - Mingzhu Li
- The Pathophysiology Department, School of Basic Medical Sciences, College of Medicine, Zhengzhou University, Zhengzhou, 450001, China
| | - Zitong Wang
- The Pathophysiology Department, School of Basic Medical Sciences, College of Medicine, Zhengzhou University, Zhengzhou, 450001, China
| | - Xuebo Lu
- The Pathophysiology Department, School of Basic Medical Sciences, College of Medicine, Zhengzhou University, Zhengzhou, 450001, China
| | - Wenjie Wu
- The Pathophysiology Department, School of Basic Medical Sciences, College of Medicine, Zhengzhou University, Zhengzhou, 450001, China
| | - Yueteng Zhang
- The Pathophysiology Department, School of Basic Medical Sciences, College of Medicine, Zhengzhou University, Zhengzhou, 450001, China
| | - Zigang Dong
- The Pathophysiology Department, School of Basic Medical Sciences, College of Medicine, Zhengzhou University, Zhengzhou, 450001, China
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, 450003, China
- Basic Medicine Sciences Research Center, Zhengzhou University, Zhengzhou, 450052, China
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou, 450001, China
- Provincial Cooperative Innovation Center for Cancer Chemoprevention, Zhengzhou University, Zhengzhou, 450001, China
- Cancer Chemoprevention International Collaboration Laboratory, Zhengzhou, 450001, China
| | - Kangdong Liu
- The Pathophysiology Department, School of Basic Medical Sciences, College of Medicine, Zhengzhou University, Zhengzhou, 450001, China.
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, 450003, China.
- Basic Medicine Sciences Research Center, Zhengzhou University, Zhengzhou, 450052, China.
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou, 450001, China.
- Provincial Cooperative Innovation Center for Cancer Chemoprevention, Zhengzhou University, Zhengzhou, 450001, China.
- Cancer Chemoprevention International Collaboration Laboratory, Zhengzhou, 450001, China.
| | - Yanan Jiang
- The Pathophysiology Department, School of Basic Medical Sciences, College of Medicine, Zhengzhou University, Zhengzhou, 450001, China.
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, 450003, China.
- Basic Medicine Sciences Research Center, Zhengzhou University, Zhengzhou, 450052, China.
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou, 450001, China.
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10
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Yagublu V, Bayramov B, Reissfelder C, Hajibabazade J, Abdulrahimli S, Keese M. Microarray-based detection and expression analysis of drug resistance in an animal model of peritoneal metastasis from colon cancer. Clin Exp Metastasis 2024; 41:707-715. [PMID: 38609535 PMCID: PMC11499332 DOI: 10.1007/s10585-024-10283-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Accepted: 03/05/2024] [Indexed: 04/14/2024]
Abstract
Chemotherapy drugs efficiently eradicate rapidly dividing differentiated cells by inducing cell death, but poorly target slowly dividing cells, including cancer stem cells and dormant cancer cells, in the later course of treatment. Prolonged exposure to chemotherapy results in a decrease in the proportion of apoptotic cells in the tumour mass. To investigate and characterize the molecular basis of this phenomenon, microarray-based expression analysis was performed to compare tHcred2-DEVD-EGFP-caspase 3-sensor transfected C-26 tumour cells that were harvested after engraftment into mice treated with or without 5-FU. Peritoneal metastasis was induced by intraperitoneal injection of C-26 cells, which were subsequently reisolated from omental metastatic tumours after the mice were sacrificed by the end of the 10th day after tumour injection. The purity of reisolated tHcred2-DEVD-EGFP-caspase 3-sensor-expressing C-26 cells was confirmed using FLIM, and total RNA was extracted for gene expression profiling. The validation of relative transcript levels was carried out via real-time semiquantitative RT‒PCR assays. Our results demonstrated that chemotherapy induced the differential expression of mediators of cancer cell dormancy and cell survival-related genes and downregulation of both intrinsic and extrinsic apoptotic signalling pathways. Despite the fact that some differentially expressed genes, such as BMP7 and Prss11, have not been thoroughly studied in the context of chemoresistance thus far, they might be potential candidates for future studies on overcoming drug resistance.
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Affiliation(s)
- Vugar Yagublu
- Department of Surgery, Medical Faculty Mannheim, Universitätsmedizin Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany.
| | - Bayram Bayramov
- Laboratory of Human Genetics, Genetic Resources Institute of Ministry of Science and Education, Baku, Azerbaijan
- Department of Natural Sciences, Western Caspian University, AZ1001, Baku, Azerbaijan
| | - Christoph Reissfelder
- Department of Surgery, Medical Faculty Mannheim, Universitätsmedizin Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany
- Medical Faculty Mannheim, DKFZ-Hector Cancer Institute, Heidelberg University, Mannheim, Germany
| | - Javahir Hajibabazade
- Carver College of Medicine, University of Iowa, Bowen Science Building, 51 Newton Road, Iowa City, IA, 52242-1009, USA
| | - Shalala Abdulrahimli
- Department of Surgery, Medical Faculty Mannheim, Universitätsmedizin Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany
- Laboratory of Human Genetics, Genetic Resources Institute of Ministry of Science and Education, Baku, Azerbaijan
| | - Michael Keese
- Department of Vascular Surgery, Theresienkrankenhaus and St. Hedwigsklinik, Mannheim, Germany
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11
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Zheng C, Allen KO, Liu T, Solodin NM, Meyer MB, Salem K, Tsourkas PK, McIlwain SJ, Vera JM, Cromwell ER, Ozers MS, Fowler AM, Alarid ET. Elevated GRHL2 Imparts Plasticity in ER-Positive Breast Cancer Cells. Cancers (Basel) 2024; 16:2906. [PMID: 39199676 PMCID: PMC11353109 DOI: 10.3390/cancers16162906] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2024] [Revised: 08/16/2024] [Accepted: 08/17/2024] [Indexed: 09/01/2024] Open
Abstract
Estrogen receptor (ER)-positive breast cancer is characterized by late recurrences following initial treatment. The epithelial cell fate transcription factor Grainyhead-like protein 2 (GRHL2) is overexpressed in ER-positive breast cancers and is linked to poorer prognosis as compared to ER-negative breast cancers. To understand how GRHL2 contributes to progression, GRHL2 was overexpressed in ER-positive cells. We demonstrated that elevated GRHL2 imparts plasticity with stem cell- and dormancy-associated traits. RNA sequencing and immunocytochemistry revealed that high GRHL2 not only strengthens the epithelial identity but supports a hybrid epithelial to mesenchymal transition (EMT). Proliferation and tumor studies exhibited a decrease in growth and an upregulation of dormancy markers, such as NR2F1 and CDKN1B. Mammosphere assays and flow cytometry revealed enrichment of stem cell markers CD44 and ALDH1, and increased self-renewal capacity. Cistrome analyses revealed a change in transcription factor motifs near GRHL2 sites from developmental factors to those associated with disease progression. Together, these data support the idea that the plasticity and properties induced by elevated GRHL2 may provide a selective advantage to explain the association between GRHL2 and breast cancer progression.
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Affiliation(s)
- Christy Zheng
- McArdle Laboratory for Cancer Research, Department of Oncology, Carbone Comprehensive Cancer Center, University of Wisconsin-Madison, Madison, WI 53705, USA
| | - Kaelyn O. Allen
- McArdle Laboratory for Cancer Research, Department of Oncology, Carbone Comprehensive Cancer Center, University of Wisconsin-Madison, Madison, WI 53705, USA
| | - Tianrui Liu
- McArdle Laboratory for Cancer Research, Department of Oncology, Carbone Comprehensive Cancer Center, University of Wisconsin-Madison, Madison, WI 53705, USA
| | - Natalia M. Solodin
- McArdle Laboratory for Cancer Research, Department of Oncology, Carbone Comprehensive Cancer Center, University of Wisconsin-Madison, Madison, WI 53705, USA
| | - Mark B. Meyer
- Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, WI 53706, USA
| | - Kelley Salem
- Department of Radiology, University of Wisconsin-Madison, Madison, WI 53792, USA
| | - Phillipos K. Tsourkas
- Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, WI 53705, USA
| | - Sean J. McIlwain
- Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, WI 53705, USA
| | - Jessica M. Vera
- Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, WI 53705, USA
| | - Erika R. Cromwell
- Department of Radiology, University of Wisconsin-Madison, Madison, WI 53792, USA
| | - Mary Szatkowski Ozers
- McArdle Laboratory for Cancer Research, Department of Oncology, Carbone Comprehensive Cancer Center, University of Wisconsin-Madison, Madison, WI 53705, USA
- Proteovista LLC, Madison, WI 53719, USA
| | - Amy M. Fowler
- Department of Radiology, University of Wisconsin-Madison, Madison, WI 53792, USA
- Department of Medical Physics, University of Wisconsin-Madison, WI 53705, USA
- Carbone Comprehensive Cancer Center, University of Wisconsin-Madison, Madison, WI 53705, USA
| | - Elaine T. Alarid
- McArdle Laboratory for Cancer Research, Department of Oncology, Carbone Comprehensive Cancer Center, University of Wisconsin-Madison, Madison, WI 53705, USA
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12
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Škarková A, Bizzarri M, Janoštiak R, Mašek J, Rosel D, Brábek J. Educate, not kill: treating cancer without triggering its defenses. Trends Mol Med 2024; 30:673-685. [PMID: 38658206 DOI: 10.1016/j.molmed.2024.04.003] [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: 02/19/2024] [Revised: 04/02/2024] [Accepted: 04/03/2024] [Indexed: 04/26/2024]
Abstract
Traditionally, anticancer therapies focus on restraining uncontrolled proliferation. However, these cytotoxic therapies expose cancer cells to direct killing, instigating the process of natural selection favoring survival of resistant cells that become the foundation for tumor progression and therapy failure. Recognizing this phenomenon has prompted the development of alternative therapeutic strategies. Here we propose strategies targeting cancer hallmarks beyond proliferation, aiming at re-educating cancer cells towards a less malignant phenotype. These strategies include controlling cell dormancy, transdifferentiation therapy, normalizing the cancer microenvironment, and using migrastatic therapy. Adaptive resistance to these educative strategies does not confer a direct proliferative advantage to resistant cells, as non-resistant cells are not subject to eradication, thereby delaying or preventing the development of therapy-resistant tumors.
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Affiliation(s)
- Aneta Škarková
- Department of Cell Biology, BIOCEV, Faculty of Science, Charles University, Vestec, Czech Republic
| | - Mariano Bizzarri
- System Biology Group Laboratory, Sapienza University, Rome, Italy
| | - Radoslav Janoštiak
- First Faculty of Medicine, BIOCEV, Charles University, Vestec, Czech Republic
| | - Jan Mašek
- Department of Cell Biology, Faculty of Science, Charles University, Prague, Czech Republic
| | - Daniel Rosel
- Department of Cell Biology, BIOCEV, Faculty of Science, Charles University, Vestec, Czech Republic.
| | - Jan Brábek
- Department of Cell Biology, BIOCEV, Faculty of Science, Charles University, Vestec, Czech Republic.
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13
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Dong Y, Bai J, Zhou J. Developing a dormancy-associated ECM signature in TNBC that is linked to immunosuppressive tumor microenvironment and selective sensitivity to MAPK inhibitors. Heliyon 2024; 10:e32106. [PMID: 38868025 PMCID: PMC11168407 DOI: 10.1016/j.heliyon.2024.e32106] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Revised: 05/12/2024] [Accepted: 05/28/2024] [Indexed: 06/14/2024] Open
Abstract
Aims Cellular dormancy is a state of quiescence subpopulation of tumor cells, characterized by low differentiation and lack of mitotic activity. They could evade chemotherapy and targeted therapy, leading to drug resistance and disease recurrence. Recent studies have shown a correlation between dormant cancer cells and unique extracellular matrix (ECM) composition, which is critical in regulating cell behavior. However, their interacting roles in TNBC patients remains to be characterized. Main methods Dormant cancer cells in MDA-MB-231 cell line with highest PKH26 dye-retaining were FACS-sorted and gene expression was then analyzed. Dormant associated ECM (DA-ECM) signature was characterized by pathway analysis. Unsupervised hierarchical clustering was used to define distinct ECM features for TNBC patients. ECM-specific tumor biology was defined by integration of bulk RNA-seq with single-cell RNA-seq data, analysis of ligand-receptor interactions and enriched biological pathways, and in silico drug screening. We validated the sensitivity of dormant cancer cells to MAPK inhibitors by flow cytometry in vitro. Key findings We observed that dormant TNBC cells preferentially expressed ∼10 % DA-ECM genes. The DA-ECM High subtype defined by unsupervised hierarchical clustering analysis was associated with immunosuppressive tumor microenvironment. Moreover, ligand-receptor interaction and pathway analysis revealed that the DA-ECM High subtype may likely help maintain tumor cell dormancy through MAPK, Hedgehog and Notch signaling pathways. Finally, in silico drug screening against the DA-ECM signature and in vitro assay showed dormant cancer cells were relatively sensitive to the MAPK pathway inhibitors, which may represent a potential therapeutic strategy for treating TNBC. Significance Collectively, our research revealed that dormancy-associated ECM characterized tumor cells possess significant ECM remodeling capacity, and treatment strategies towards these cells could improve TNBC patient outcome.
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Affiliation(s)
- Yang Dong
- Research Center for Translational Medicine, Cancer Stem Cell Institute, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai 200120, China
| | - Jin Bai
- Department of Oncology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai 200120, China
| | - Jianjun Zhou
- Research Center for Translational Medicine, Cancer Stem Cell Institute, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai 200120, China
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14
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TAHIYA EC, ISLAM AA, HATTA M, LUSIKOOY RE, PRIHANTONO P, RUDIMAN R, WIDIANA IK, PATELONGI I, BUKHARI AS. 5-Fluorouracil for colorectal cancer: mechanism of action and metabolism. GAZZETTA MEDICA ITALIANA ARCHIVIO PER LE SCIENZE MEDICHE 2024; 183. [DOI: 10.23736/s0393-3660.23.05249-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2025]
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15
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Zingoni A, Antonangeli F, Sozzani S, Santoni A, Cippitelli M, Soriani A. The senescence journey in cancer immunoediting. Mol Cancer 2024; 23:68. [PMID: 38561826 PMCID: PMC10983694 DOI: 10.1186/s12943-024-01973-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2023] [Accepted: 02/28/2024] [Indexed: 04/04/2024] Open
Abstract
Cancer progression is continuously controlled by the immune system which can identify and destroy nascent tumor cells or inhibit metastatic spreading. However, the immune system and its deregulated activity in the tumor microenvironment can also promote tumor progression favoring the outgrowth of cancers capable of escaping immune control, in a process termed cancer immunoediting. This process, which has been classified into three phases, i.e. "elimination", "equilibrium" and "escape", is influenced by several cancer- and microenvironment-dependent factors. Senescence is a cellular program primed by cells in response to different pathophysiological stimuli, which is based on long-lasting cell cycle arrest and the secretion of numerous bioactive and inflammatory molecules. Because of this, cellular senescence is a potent immunomodulatory factor promptly recruiting immune cells and actively promoting tissue remodeling. In the context of cancer, these functions can lead to both cancer immunosurveillance and immunosuppression. In this review, the authors will discuss the role of senescence in cancer immunoediting, highlighting its context- and timing-dependent effects on the different three phases, describing how senescent cells promote immune cell recruitment for cancer cell elimination or sustain tumor microenvironment inflammation for immune escape. A potential contribution of senescent cells in cancer dormancy, as a mechanism of therapy resistance and cancer relapse, will be discussed with the final objective to unravel the immunotherapeutic implications of senescence modulation in cancer.
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Affiliation(s)
- Alessandra Zingoni
- Department of Molecular Medicine, Laboratory Affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Sapienza University of Rome, Rome, 00161, Italy
| | - Fabrizio Antonangeli
- Institute of Molecular Biology and Pathology, National Research Council (CNR), Rome, 00185, Italy
| | - Silvano Sozzani
- Department of Molecular Medicine, Laboratory Affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Sapienza University of Rome, Rome, 00161, Italy
| | - Angela Santoni
- Department of Molecular Medicine, Laboratory Affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Sapienza University of Rome, Rome, 00161, Italy
- IRCCS Neuromed, Pozzilli, 86077, Italy
| | - Marco Cippitelli
- Department of Molecular Medicine, Laboratory Affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Sapienza University of Rome, Rome, 00161, Italy.
| | - Alessandra Soriani
- Department of Molecular Medicine, Laboratory Affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Sapienza University of Rome, Rome, 00161, Italy.
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16
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Aleksandrova KV, Vorobev ML, Suvorova II. mTOR pathway occupies a central role in the emergence of latent cancer cells. Cell Death Dis 2024; 15:176. [PMID: 38418814 PMCID: PMC10902345 DOI: 10.1038/s41419-024-06547-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2023] [Revised: 01/18/2024] [Accepted: 02/07/2024] [Indexed: 03/02/2024]
Abstract
The current focus in oncology research is the translational control of cancer cells as a major mechanism of cellular plasticity. Recent evidence has prompted a reevaluation of the role of the mTOR pathway in cancer development leading to new conclusions. The mechanistic mTOR inhibition is well known to be a tool for generating quiescent stem cells and cancer cells. In response to mTOR suppression, quiescent cancer cells dynamically change their proteome, triggering alternative non-canonical translation mechanisms. The shift to selective translation may have clinical relevance, since quiescent tumor cells can acquire new phenotypical features. This review provides new insights into the patterns of mTOR functioning in quiescent cancer cells, enhancing our current understanding of the biology of latent metastasis.
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Affiliation(s)
| | - Mikhail L Vorobev
- Institute of Cytology, Russian Academy of Sciences, St. Petersburg, Russian Federation
| | - Irina I Suvorova
- Institute of Cytology, Russian Academy of Sciences, St. Petersburg, Russian Federation.
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17
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Maleki EH, Bahrami AR, Matin MM. Cancer cell cycle heterogeneity as a critical determinant of therapeutic resistance. Genes Dis 2024; 11:189-204. [PMID: 37588236 PMCID: PMC10425754 DOI: 10.1016/j.gendis.2022.11.025] [Citation(s) in RCA: 37] [Impact Index Per Article: 37.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Revised: 10/20/2022] [Accepted: 11/16/2022] [Indexed: 01/15/2023] Open
Abstract
Intra-tumor heterogeneity is now arguably one of the most-studied topics in tumor biology, as it represents a major obstacle to effective cancer treatment. Since tumor cells are highly diverse at genetic, epigenetic, and phenotypic levels, intra-tumor heterogeneity can be assumed as an important contributing factor to the nullification of chemotherapeutic effects, and recurrence of the tumor. Based on the role of heterogeneous subpopulations of cancer cells with varying cell-cycle dynamics and behavior during cancer progression and treatment; herein, we aim to establish a comprehensive definition for adaptation of neoplastic cells against therapy. We discuss two parallel and yet distinct subpopulations of tumor cells that play pivotal roles in reducing the effects of chemotherapy: "resistant" and "tolerant" populations. Furthermore, this review also highlights the impact of the quiescent phase of the cell cycle as a survival mechanism for cancer cells. Beyond understanding the mechanisms underlying the quiescence, it provides an insightful perspective on cancer stem cells (CSCs) and their dual and intertwined functions based on their cell cycle state in response to treatment. Moreover, CSCs, epithelial-mesenchymal transformed cells, circulating tumor cells (CTCs), and disseminated tumor cells (DTCs), which are mostly in a quiescent state of the cell cycle are proved to have multiple biological links and can be implicated in our viewpoint of cell cycle heterogeneity in tumors. Overall, increasing our knowledge of cell cycle heterogeneity is a key to identifying new therapeutic solutions, and this emerging concept may provide us with new opportunities to prevent the dreadful cancer recurrence.
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Affiliation(s)
- Ebrahim H. Maleki
- Department of Biology, Faculty of Science, Ferdowsi University of Mashhad, 9177948974 Mashhad, Iran
- Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, 31-007 Krakow, Poland
- Doctoral School of Exact and Natural Sciences, Jagiellonian University, 30-348 Krakow, Poland
| | - Ahmad Reza Bahrami
- Department of Biology, Faculty of Science, Ferdowsi University of Mashhad, 9177948974 Mashhad, Iran
- Industrial Biotechnology Research Group, Institute of Biotechnology, Ferdowsi University of Mashhad, 9177948974 Mashhad, Iran
| | - Maryam M. Matin
- Department of Biology, Faculty of Science, Ferdowsi University of Mashhad, 9177948974 Mashhad, Iran
- Novel Diagnostics and Therapeutics Research Group, Institute of Biotechnology, Ferdowsi University of Mashhad, 9177948974 Mashhad, Iran
- Stem Cell and Regenerative Medicine Research Group, Iranian Academic Center for Education, Culture and Research (ACECR), Khorasan Razavi Branch, 917751376 Mashhad, Iran
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18
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Vail E, Choubey AP, Alexander HR, August DA, Berry A, Boland PM, Eskander MF, Grandhi MS, Haliani B, In H, Kennedy TJ, Langan RC, Maggi JC, Pitt HA, Ganesan S, Ecker BL. Recurrence-free survival dynamics following adjuvant chemotherapy for resected colorectal cancer: A systematic review of randomized controlled trials. Cancer Med 2024; 13:e6884. [PMID: 38186327 PMCID: PMC10807601 DOI: 10.1002/cam4.6884] [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: 07/13/2023] [Revised: 11/15/2023] [Accepted: 12/17/2023] [Indexed: 01/09/2024] Open
Abstract
BACKGROUND Several cytotoxic chemotherapies have demonstrated efficacy in improving recurrence-free survival (RFS) following resection of Stage II-IV colorectal cancer (CRC). However, the temporal dynamics of response to such adjuvant therapy have not been systematically quantified. METHODS The Cochrane Central Register of Trials, Medline (PubMed) and Web of Science were queried from database inception to February 23, 2023 for Phase III randomized controlled trials (RCTs) where there was a significant difference in RFS between adjuvant chemotherapy and surgery only arms. Summary data were extracted from published Kaplan-Meier curves using DigitizeIT. Absolute differences in RFS event rates were compared at matched intervals using multiple paired t-tests. RESULTS The initial search yielded 1469 manuscripts. After screening, 18 RCTs were eligible (14 Stage II/III; 4 Stage IV), inclusive of 16,682 patients. In the absence of adjuvant chemotherapy, the greatest rate of recurrence was observed in the first year (mean RFS event rate; 0-0.5 years: 0.22 ± 0.21; 0.5-1 years: 0.20 ± 0.09). Adjuvant chemotherapy was associated with significant decreases in the RFS event rates for the intervals 0-0.5 years (0.09 ± 0.09 vs. 0.22 ± 0.21, p < 0.001) and 0.5-1 years (0.14 ± 0.11 vs. 0.20 ± 0.09, p = 0.001) after randomization, but not at later intervals (1-5 years). In Stage IV trials, RFS event rates significantly differed for the interval 0-0.5 years (p = 0.012), corresponding with adjuvant treatment durations of 6 months. In Stage II/III trials, which included therapies of 6-24 months duration, there were marked differences in the RFS event rates between surgery and chemotherapy arms for the intervals 0-0.5 years (p < 0.001) and 0.5-1 years (p < 0.001) with smaller differences in the RFS event rates for the intervals 1-2 years (p = 0.012) and 2-3 years (p = 0.010). CONCLUSIONS In a systematic review of positive RCTs comparing adjuvant chemotherapy to surgery alone for Stage II-IV CRC, observed RFS improvements were driven by early divergences that occurred primarily during active cytotoxic chemotherapy. Late recurrence dynamics were not influenced by adjuvant therapy use. Such observations may have implications for the use of chemotherapy for micrometastatic clones detectable by cell-free DNA-based methodologies.
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Affiliation(s)
- Emma Vail
- Division of Surgical OncologyRutgers Cancer Institute of New Jersey, Rutgers HealthNew BrunswickNew JerseyUSA
| | - Ankur P. Choubey
- Division of Surgical OncologyRutgers Cancer Institute of New Jersey, Rutgers HealthNew BrunswickNew JerseyUSA
- Rutgers Robert Wood Johnson University Medical SchoolNew BrunswickNew JerseyUSA
| | - H. Richard Alexander
- Division of Surgical OncologyRutgers Cancer Institute of New Jersey, Rutgers HealthNew BrunswickNew JerseyUSA
- Rutgers Robert Wood Johnson University Medical SchoolNew BrunswickNew JerseyUSA
| | - David A. August
- Division of Surgical OncologyRutgers Cancer Institute of New Jersey, Rutgers HealthNew BrunswickNew JerseyUSA
- Rutgers Robert Wood Johnson University Medical SchoolNew BrunswickNew JerseyUSA
| | - Abril Berry
- Cooperman Barnabas Medical CenterLivingstonNew JerseyUSA
| | - Patrick M. Boland
- Rutgers Robert Wood Johnson University Medical SchoolNew BrunswickNew JerseyUSA
- Division of Medical OncologyRutgers Cancer Institute of New Jersey, Rutgers HealthNew BrunswickNew JerseyUSA
| | - Mariam F. Eskander
- Division of Surgical OncologyRutgers Cancer Institute of New Jersey, Rutgers HealthNew BrunswickNew JerseyUSA
- Rutgers Robert Wood Johnson University Medical SchoolNew BrunswickNew JerseyUSA
| | - Miral S. Grandhi
- Division of Surgical OncologyRutgers Cancer Institute of New Jersey, Rutgers HealthNew BrunswickNew JerseyUSA
- Rutgers Robert Wood Johnson University Medical SchoolNew BrunswickNew JerseyUSA
| | | | - Haejin In
- Division of Surgical OncologyRutgers Cancer Institute of New Jersey, Rutgers HealthNew BrunswickNew JerseyUSA
- Rutgers Robert Wood Johnson University Medical SchoolNew BrunswickNew JerseyUSA
| | - Timothy J. Kennedy
- Division of Surgical OncologyRutgers Cancer Institute of New Jersey, Rutgers HealthNew BrunswickNew JerseyUSA
- Rutgers Robert Wood Johnson University Medical SchoolNew BrunswickNew JerseyUSA
| | - Russell C. Langan
- Division of Surgical OncologyRutgers Cancer Institute of New Jersey, Rutgers HealthNew BrunswickNew JerseyUSA
- Rutgers Robert Wood Johnson University Medical SchoolNew BrunswickNew JerseyUSA
- Cooperman Barnabas Medical CenterLivingstonNew JerseyUSA
| | - Jason C. Maggi
- Division of Surgical OncologyRutgers Cancer Institute of New Jersey, Rutgers HealthNew BrunswickNew JerseyUSA
- Cooperman Barnabas Medical CenterLivingstonNew JerseyUSA
| | - Henry A. Pitt
- Division of Surgical OncologyRutgers Cancer Institute of New Jersey, Rutgers HealthNew BrunswickNew JerseyUSA
- Rutgers Robert Wood Johnson University Medical SchoolNew BrunswickNew JerseyUSA
| | - Shridar Ganesan
- Rutgers Robert Wood Johnson University Medical SchoolNew BrunswickNew JerseyUSA
- Division of Medical OncologyRutgers Cancer Institute of New Jersey, Rutgers HealthNew BrunswickNew JerseyUSA
| | - Brett L. Ecker
- Division of Surgical OncologyRutgers Cancer Institute of New Jersey, Rutgers HealthNew BrunswickNew JerseyUSA
- Rutgers Robert Wood Johnson University Medical SchoolNew BrunswickNew JerseyUSA
- Cooperman Barnabas Medical CenterLivingstonNew JerseyUSA
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19
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Quartieri M, Puspitasari A, Vitacchio T, Durante M, Tinganelli W. The role of hypoxia and radiation in developing a CTCs-like phenotype in murine osteosarcoma cells. Front Cell Dev Biol 2023; 11:1222809. [PMID: 38033871 PMCID: PMC10687637 DOI: 10.3389/fcell.2023.1222809] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Accepted: 10/11/2023] [Indexed: 12/02/2023] Open
Abstract
Introduction: Cancer treatment has evolved significantly, yet concerns about tumor recurrence and metastasis persist. Within the dynamic tumor microenvironment, a subpopulation of mesenchymal tumor cells, known as Circulating Cancer Stem Cells (CCSCs), express markers like CD133, TrkB, and CD47, making them radioresistant and pivotal to metastasis. Hypoxia intensifies their stemness, complicating their identification in the bloodstream. This study investigates the interplay of acute and chronic hypoxia and radiation exposure in selecting and characterizing cells with a CCSC-like phenotype. Methods: LM8 murine osteosarcoma cells were cultured and subjected to normoxic (21% O2) and hypoxic (1% O2) conditions. We employed Sphere Formation and Migration Assays, Western Blot analysis, CD133 Cell Sorting, and CD133+ Fluorescent Activated Cell Sorting (FACS) analysis with a focus on TrkB antibody to assess the effects of acute and chronic hypoxia, along with radiation exposure. Results: Our findings demonstrate that the combination of radiation and acute hypoxia enhances stemness, while chronic hypoxia imparts a cancer stem-like phenotype in murine osteosarcoma cells, marked by increased migration and upregulation of CCSC markers, particularly TrkB and CD47. These insights offer a comprehensive understanding of the interactions between radiation, hypoxia, and cellular responses in the context of cancer treatment. Discussion: This study elucidates the complex interplay among radiation, hypoxia, and cellular responses, offering valuable insights into the intricacies and potential advancements in cancer treatment.
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Affiliation(s)
- Martina Quartieri
- Biophysics Department, GSI Helmholtzzentrum für Schwerionenforschung GmbH, Darmstadt, Germany
| | - Anggraeini Puspitasari
- Biophysics Department, GSI Helmholtzzentrum für Schwerionenforschung GmbH, Darmstadt, Germany
- Biology Division, Gunma University Heavy Ion Medical Center, Maebashi, Japan
| | - Tamara Vitacchio
- Biophysics Department, GSI Helmholtzzentrum für Schwerionenforschung GmbH, Darmstadt, Germany
| | - Marco Durante
- Biophysics Department, GSI Helmholtzzentrum für Schwerionenforschung GmbH, Darmstadt, Germany
- Institut für Festkörperphysik, Technische Universität Darmstadt, Darmstadt, Germany
| | - Walter Tinganelli
- Biophysics Department, GSI Helmholtzzentrum für Schwerionenforschung GmbH, Darmstadt, Germany
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20
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Khromov T, Fischer L, Leha A, Bremmer F, Fischer A, Schliephake H, Rahat MA, Brockmeyer P. Combined Biomarker System Predicts Prognosis in Patients with Metastatic Oral Squamous Cell Carcinoma. Cancers (Basel) 2023; 15:4924. [PMID: 37894290 PMCID: PMC10605069 DOI: 10.3390/cancers15204924] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Revised: 09/27/2023] [Accepted: 10/09/2023] [Indexed: 10/29/2023] Open
Abstract
BACKGROUND Metastatic oral squamous cell carcinoma (OSCC) is associated with poor patient prognosis. Metastasis is a complex process involving various proteins, tumor cell alterations, including changes attributable to the epithelial-to-mesenchymal transition (EMT) process, and interactions with the tumor microenvironment (TME). In this study, we investigate a combined protein marker system consisting of connexin 43 (Cx43), EMMPRIN (CD147), E-cadherin, and vimentin, with a focus on their roles in the invasive metastatic progression of OSCC and their potential utility in predicting prognosis. METHODS We conducted an immunohistochemical analysis to assess the protein expression profiles of Cx43, EMMPRIN, E-cadherin, and vimentin using tissue samples obtained from 24 OSCC patients. The metastatic process was mapped through different regions of interest (ROIs), including adjacent healthy oral mucosa (OM), center of primary OSCC, invasive front (IF), and local cervical lymph node metastases (LNM). The primary clinical endpoints were disease-free survival (DFS) and overall survival (OS). RESULTS Substantial changes in the expression profiles of the different marker proteins were observed among the different ROIs, with all p-values < 0.05, signifying statistical significance. Multivariable Cox regression analysis results showed a significant effect of increased EMMPRIN expression toward the IF on DFS (p = 0.019) and OS (p = 0.023). Furthermore, the combined predictive analysis showed a significant predictive value of the marker system for DFS (p = 0.0017) and OS (p = 0.00044). CONCLUSIONS The combined marker system exhibited a significant ability to predict patient prognosis. An increase in EMMPRIN expression toward the IF showed the strongest effect and could be an interesting new antimetastatic therapy approach.
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Affiliation(s)
- Tatjana Khromov
- Department of Clinical Chemistry, University Medical Center Goettingen, 37075 Goettingen, Germany; (T.K.); (A.F.)
| | - Lucas Fischer
- Department of Urology, University Medical Center Goettingen, 37075 Goettingen, Germany;
| | - Andreas Leha
- Department of Medical Statistics, University Medical Center Goettingen, 37075 Goettingen, Germany;
| | - Felix Bremmer
- Institute of Pathology, University Medical Center Goettingen, 37075 Goettingen, Germany;
| | - Andreas Fischer
- Department of Clinical Chemistry, University Medical Center Goettingen, 37075 Goettingen, Germany; (T.K.); (A.F.)
| | - Henning Schliephake
- Department of Oral and Maxillofacial Surgery, University Medical Center Goettingen, 37075 Goettingen, Germany;
| | - Michal Amit Rahat
- Immunotherapy Laboratory, Carmel Medical Center, Haifa 3436212, Israel;
- Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 3109601, Israel
| | - Phillipp Brockmeyer
- Department of Oral and Maxillofacial Surgery, University Medical Center Goettingen, 37075 Goettingen, Germany;
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21
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Wieder R. Awakening of Dormant Breast Cancer Cells in the Bone Marrow. Cancers (Basel) 2023; 15:cancers15113021. [PMID: 37296983 DOI: 10.3390/cancers15113021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2023] [Revised: 05/23/2023] [Accepted: 05/26/2023] [Indexed: 06/12/2023] Open
Abstract
Up to 40% of patients with breast cancer (BC) have metastatic cells in the bone marrow (BM) at the initial diagnosis of localized disease. Despite definitive systemic adjuvant therapy, these cells survive in the BM microenvironment, enter a dormant state and recur stochastically for more than 20 years. Once they begin to proliferate, recurrent macrometastases are not curable, and patients generally succumb to their disease. Many potential mechanisms for initiating recurrence have been proposed, but no definitive predictive data have been generated. This manuscript reviews the proposed mechanisms that maintain BC cell dormancy in the BM microenvironment and discusses the data supporting specific mechanisms for recurrence. It addresses the well-described mechanisms of secretory senescence, inflammation, aging, adipogenic BM conversion, autophagy, systemic effects of trauma and surgery, sympathetic signaling, transient angiogenic bursts, hypercoagulable states, osteoclast activation, and epigenetic modifications of dormant cells. This review addresses proposed approaches for either eliminating micrometastases or maintaining a dormant state.
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Affiliation(s)
- Robert Wieder
- Rutgers New Jersey Medical School and the Cancer Institute of New Jersey, 185 South Orange Avenue, MSB F671, Newark, NJ 07103, USA
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22
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Selvaggi F, Catalano T, Lattanzio R, Cotellese R, Aceto GM. Wingless/It/β-catenin signaling in liver metastasis from colorectal cancer: A focus on biological mechanisms and therapeutic opportunities. World J Gastroenterol 2023; 29:2764-2783. [PMID: 37274070 PMCID: PMC10237106 DOI: 10.3748/wjg.v29.i18.2764] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Revised: 02/28/2023] [Accepted: 04/17/2023] [Indexed: 05/11/2023] Open
Abstract
The liver is the most common site of metastases in patients with colorectal cancer. Colorectal liver metastases (CRLMs) are the result of molecular mechanisms that involve different cells of the liver microenvironment. The aberrant activation of Wingless/It (Wnt)/β-catenin signals downstream of Wnt ligands initially drives the oncogenic transformation of the colon epithelium, but also the progression of metastatization through the epithelial-mesenchymal transition/mesenchymal-epithelial transition interactions. In liver microenvironment, metastatic cells can also survive and adapt through dormancy, which makes them less susceptible to pro-apoptotic signals and therapies. Treatment of CRLMs is challenging due to its variability and heterogeneity. Advances in surgery and oncology have been made in the last decade and a pivotal role for Wnt/β-catenin pathway has been re-cognized in chemoresistance. At the state of art, there is a lack of clear understanding of why and how this occurs and thus where exactly the opportunities for developing anti-CRLMs therapies may lie. In this review, current knowledge on the involvement of Wnt signaling in the development of CRLMs was considered. In addition, an overview of useful biomarkers with a revision of surgical and non-surgical therapies currently accepted in the clinical practice for colorectal liver metastasis patients were provided.
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Affiliation(s)
- Federico Selvaggi
- Department of Surgical, ASL2 Lanciano-Vasto-Chieti, Ospedale Clinicizzato SS Annunziata of Chieti, Chieti 66100, Italy
| | - Teresa Catalano
- Department of Clinical and Experimental Medicine, University of Messina, Messina 98125, Italy
| | - Rossano Lattanzio
- Department of Innovative Technologies in Medicine & Dentistry, University “G. d’Annunzio” Chieti-Pescara, Chieti 66100, Italy
| | - Roberto Cotellese
- Department of Medical, Oral and Biotechnological Sciences, University “G. d’Annunzio” Chieti-Pescara, Chieti 66100, Italy
- Villa Serena Foundation for Research, Villa Serena - Del Dott. L. Petruzzi, Città Sant’Angelo 65013, Pescara, Italy
| | - Gitana Maria Aceto
- Department of Medical, Oral and Biotechnological Sciences, “G. d’Annunzio” University of Chieti-Pescara, Chieti 66100, Italy
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23
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Feigelman G, Simanovich E, Brockmeyer P, Rahat MA. Knocking-Down CD147/EMMPRIN Expression in CT26 Colon Carcinoma Forces the Cells into Cellular and Angiogenic Dormancy That Can Be Reversed by Interactions with Macrophages. Biomedicines 2023; 11:biomedicines11030768. [PMID: 36979746 PMCID: PMC10044868 DOI: 10.3390/biomedicines11030768] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Revised: 02/27/2023] [Accepted: 02/28/2023] [Indexed: 03/06/2023] Open
Abstract
Metastasis in colorectal cancer is responsible for most of the cancer-related deaths. For metastasis to occur, tumor cells must first undergo the epithelial-to-mesenchymal transition (EMT), which is driven by the transcription factors (EMT-TFs) Snail, Slug twist1, or Zeb1, to promote their migration. In the distant organs, tumor cells may become dormant for years, until signals from their microenvironment trigger and promote their outgrowth. Here we asked whether CD147/EMMPRIN controls entry and exit from dormancy in the aggressive and proliferative (i.e., non-dormant) CT26 mouse colon carcinoma cells, in its wild-type form (CT26-WT cells). To this end, we knocked down EMMPRIN expression in CT26 cells (CT26-KD), and compared their EMT and cellular dormancy status (e.g., proliferation, pERK/pP38 ratio, vimentin expression, expression of EMT-TFs and dormancy markers), and angiogenic dormancy (e.g., VEGF and MMP-9 secretion, healing of the wounded bEND3 mouse endothelial cells), to the parental cells (CT26-WT). We show that knocking-down EMMPRIN expression reduced the pERK/pP38 ratio, enhanced the expression of vimentin, the EMT-TFs and the dormancy markers, and reduced the proliferation and angiogenic potential, cumulatively indicating that cells were pushed towards dormancy. When macrophages were co-cultured with both types of CT26 cells, the CT26-WT cells increased their angiogenic potential, but did not change their proliferation, state of EMT, or dormancy, whereas the CT26-KD cells exhibited values mostly similar to those of the co-cultured CT26-WT cells. Addition of recombinant TGFβ or EMMPRIN that simulated the presence of macrophages yielded similar results. Combinations of low concentrations of TGFβ and EMMPRIN had a minimal additive effect only in the CT26-KD cells, suggesting that they work along the same signaling pathway. We conclude that EMMPRIN is important as a gatekeeper that prevents cells from entering a dormant state, and that macrophages can promote an exit from dormancy.
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Affiliation(s)
- Gabriele Feigelman
- Immunotherapy Laboratory, Carmel Medical Center, Haifa 3436212, Israel
- Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 3109601, Israel
| | - Elina Simanovich
- Immunotherapy Laboratory, Carmel Medical Center, Haifa 3436212, Israel
| | - Phillipp Brockmeyer
- Department of Oral and Maxillofacial Surgery, University Medical Center Göttingen, 37073 Göttingen, Germany
| | - Michal A. Rahat
- Immunotherapy Laboratory, Carmel Medical Center, Haifa 3436212, Israel
- Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 3109601, Israel
- Correspondence:
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24
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Therapeutic targeting of dormant cancer stem cells in solid tumors. GENE REPORTS 2023. [DOI: 10.1016/j.genrep.2022.101717] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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25
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Chan AML, Cheah JM, Lokanathan Y, Ng MH, Law JX. Natural Killer Cell-Derived Extracellular Vesicles as a Promising Immunotherapeutic Strategy for Cancer: A Systematic Review. Int J Mol Sci 2023; 24:ijms24044026. [PMID: 36835438 PMCID: PMC9964266 DOI: 10.3390/ijms24044026] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2022] [Revised: 01/30/2023] [Accepted: 02/03/2023] [Indexed: 02/19/2023] Open
Abstract
Cancer is the second leading contributor to global deaths caused by non-communicable diseases. The cancer cells are known to interact with the surrounding non-cancerous cells, including the immune cells and stromal cells, within the tumor microenvironment (TME) to modulate the tumor progression, metastasis and resistance. Currently, chemotherapy and radiotherapy are the standard treatments for cancers. However, these treatments cause a significant number of side effects, as they damage both the cancer cells and the actively dividing normal cells indiscriminately. Hence, a new generation of immunotherapy using natural killer (NK) cells, cytotoxic CD8+ T-lymphocytes or macrophages was developed to achieve tumor-specific targeting and circumvent the adverse effects. However, the progression of cell-based immunotherapy is hindered by the combined action of TME and TD-EVs, which render the cancer cells less immunogenic. Recently, there has been an increase in interest in using immune cell derivatives to treat cancers. One of the highly potential immune cell derivatives is the NK cell-derived EVs (NK-EVs). As an acellular product, NK-EVs are resistant to the influence of TME and TD-EVs, and can be designed for "off-the-shelf" use. In this systematic review, we examine the safety and efficacy of NK-EVs to treat various cancers in vitro and in vivo.
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Affiliation(s)
- Alvin Man Lung Chan
- Centre for Tissue Engineering and Regenerative Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur 56000, Malaysia
- Ming Medical Sdn Bhd, D3-3 (2nd Floor), Block D3 Dana 1 Commercial Centre, Jalan PJU 1a/22, Petaling Jaya 47101, Malaysia
| | - Jin Min Cheah
- Ming Medical Sdn Bhd, D3-3 (2nd Floor), Block D3 Dana 1 Commercial Centre, Jalan PJU 1a/22, Petaling Jaya 47101, Malaysia
| | - Yogeswaran Lokanathan
- Centre for Tissue Engineering and Regenerative Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur 56000, Malaysia
| | - Min Hwei Ng
- Centre for Tissue Engineering and Regenerative Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur 56000, Malaysia
| | - Jia Xian Law
- Centre for Tissue Engineering and Regenerative Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur 56000, Malaysia
- Correspondence: ; Tel.: +60-391-457677
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26
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Alhaddad L, Nofal Z, Pustovalova M, Osipov AN, Leonov S. Long-Term Cultured Human Glioblastoma Multiforme Cells Demonstrate Increased Radiosensitivity and Senescence-Associated Secretory Phenotype in Response to Irradiation. Int J Mol Sci 2023; 24:ijms24032002. [PMID: 36768320 PMCID: PMC9916727 DOI: 10.3390/ijms24032002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Revised: 01/14/2023] [Accepted: 01/17/2023] [Indexed: 01/20/2023] Open
Abstract
The overall effect of senescence on cancer progression and cancer cell resistance to X-ray radiation (IR) is still not fully understood and remains controversial. How to induce tumor cell senescence and which senescent cell characteristics will ensure the safest therapeutic strategy for cancer treatment are under extensive investigation. While the evidence for passage number-related effects on malignant primary cells or cell lines is compelling, much less is known about how the changes affect safety and Senescence-Associated Secretory Phenotype (SASP), both of which are needed for the senescence cell-based vaccine to be effective against cancer. The present study aimed to investigate the effects of repeated passaging on the biological (self-renewal capacity and radioresistance) and functional (senescence) characteristics of the different populations of short- and long-term passaging glioblastoma multiforme (GBM) cells responding to senescence-inducing DNA-damaging IR stress. For this purpose, we compared radiobiological effects of X-ray exposure on two isogenic human U87 cell lines: U87L, minimally cultured cells (<15 passages after obtaining from the ATCC) and U87H, long-term cultured cells (>3 years of continuous culturing after obtaining from the ATCC). U87L cells displayed IR dose-related changes in the signs of IR stress-induced premature senescence. These included an increase in the proportion of senescence-associated β-galactosidase (SA-β-Gal)-positive cells, and concomitant decrease in the proportion of Ki67-positive cells and metabolically active cells. However, reproductive survival of irradiated short-term cultured U87L cells was higher compared to long-term cultured U87H cells, as the clonogenic activity results demonstrated. In contrast, the irradiated long-term cultured U87H cells possessed dose-related increases in the proportion of multinucleated giant cancer cells (MGCCs), while demonstrating higher radiosensitivity (lower self-renewal) and a significantly reduced fraction of DNA-replicating cells compared to short-term cultured U87L cells. Conditioned culture medium from U87H cells induced a significant rise of SA-β-Gal staining in U87L cells in a paracrine manner suggesting inherent SASP. Our data suggested that low-dose irradiated long-term cultured GBM cells might be a safer candidate for a recently proposed senescence cell-based vaccine against cancer.
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Affiliation(s)
- Lina Alhaddad
- School of Biological and Medical Physics, Moscow Institute of Physics and Technology (National Research University), 141701 Dolgoprudny, Russia
- Department of Environmental Sciences, Faculty of Sciences, Damascus University, Damascus P.O. Box 30621, Syria
| | - Zain Nofal
- School of Biological and Medical Physics, Moscow Institute of Physics and Technology (National Research University), 141701 Dolgoprudny, Russia
| | - Margarita Pustovalova
- School of Biological and Medical Physics, Moscow Institute of Physics and Technology (National Research University), 141701 Dolgoprudny, Russia
- State Research Center—Burnasyan Federal Medical Biophysical Center of Federal Medical Biological Agency (SRC-FMBC), 123098 Moscow, Russia
| | - Andreyan N. Osipov
- School of Biological and Medical Physics, Moscow Institute of Physics and Technology (National Research University), 141701 Dolgoprudny, Russia
- State Research Center—Burnasyan Federal Medical Biophysical Center of Federal Medical Biological Agency (SRC-FMBC), 123098 Moscow, Russia
- N.N. Semenov Federal Research Center for Chemical Physics, Russian Academy of Sciences, 119991 Moscow, Russia
- Correspondence:
| | - Sergey Leonov
- School of Biological and Medical Physics, Moscow Institute of Physics and Technology (National Research University), 141701 Dolgoprudny, Russia
- Institute of Cell Biophysics, Russian Academy of Sciences, 142290 Pushchino, Russia
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27
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Castaneda M, den Hollander P, Kuburich NA, Rosen JM, Mani SA. Mechanisms of cancer metastasis. Semin Cancer Biol 2022; 87:17-31. [PMID: 36354098 DOI: 10.1016/j.semcancer.2022.10.006] [Citation(s) in RCA: 75] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Revised: 10/10/2022] [Accepted: 10/25/2022] [Indexed: 11/09/2022]
Abstract
Metastatic cancer is almost always terminal, and more than 90% of cancer deaths result from metastatic disease. Combating cancer metastasis and post-therapeutic recurrence successfully requires understanding each step of metastatic progression. This review describes the current state of knowledge of the etiology and mechanism of cancer progression from primary tumor growth to the formation of new tumors in other parts of the body. Open questions, avenues for future research, and therapeutic approaches with the potential to prevent or inhibit metastasis through personalization to each patient's mutation and/or immune profile are also highlighted.
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Affiliation(s)
- Maria Castaneda
- Translational Molecular Pathology, MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Petra den Hollander
- Translational Molecular Pathology, MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Pathology and Lab Medicine, Brown University, Providence, RI 02912, USA; Legoretta Cancer Center, Brown University, Providence, RI 021912, USA
| | - Nick A Kuburich
- Translational Molecular Pathology, MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Pathology and Lab Medicine, Brown University, Providence, RI 02912, USA; Legoretta Cancer Center, Brown University, Providence, RI 021912, USA
| | - Jeffrey M Rosen
- Molecular & Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
| | - Sendurai A Mani
- Translational Molecular Pathology, MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Pathology and Lab Medicine, Brown University, Providence, RI 02912, USA; Legoretta Cancer Center, Brown University, Providence, RI 021912, USA.
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28
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Bryl R, Piwocka O, Kawka E, Mozdziak P, Kempisty B, Knopik-Skrocka A. Cancer Stem Cells-The Insight into Non-Coding RNAs. Cells 2022; 11:cells11223699. [PMID: 36429127 PMCID: PMC9688207 DOI: 10.3390/cells11223699] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Revised: 11/11/2022] [Accepted: 11/15/2022] [Indexed: 11/23/2022] Open
Abstract
Since their initial identification three decades ago, there has been extensive research regarding cancer stem cells (CSCs). It is important to consider the biology of cancer stem cells with a particular focus on their phenotypic and metabolic plasticity, the most important signaling pathways, and non-coding RNAs (ncRNAs) regulating these cellular entities. Furthermore, the current status of therapeutic approaches against CSCs is an important consideration regarding employing the technology to improve human health. Cancer stem cells have claimed to be one of the most important group of cells for the development of several common cancers as they dictate features, such as resistance to radio- and chemotherapy, metastasis, and secondary tumor formation. Therapies which could target these cells may develop into an effective strategy for tumor eradication and a hope for patients for whom this disease remains uncurable.
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Affiliation(s)
- Rut Bryl
- Section of Regenerative Medicine and Cancer Research, Natural Sciences Club, Faculty of Biology, Adam Mickiewicz University, 61-614 Poznań, Poland
| | - Oliwia Piwocka
- Section of Regenerative Medicine and Cancer Research, Natural Sciences Club, Faculty of Biology, Adam Mickiewicz University, 61-614 Poznań, Poland
- Department of Electroradiology, Poznan University of Medical Sciences, 61-701 Poznań, Poland
- Doctoral School, Poznan University of Medical Sciences, 61-701 Poznań, Poland
| | - Emilia Kawka
- Section of Regenerative Medicine and Cancer Research, Natural Sciences Club, Faculty of Biology, Adam Mickiewicz University, 61-614 Poznań, Poland
| | - Paul Mozdziak
- Prestage Department of Poultry Science, North Carolina State University, Raleigh, NC 27695, USA
| | - Bartosz Kempisty
- Prestage Department of Poultry Science, North Carolina State University, Raleigh, NC 27695, USA
- Department of Human Morphology and Embryology, Division of Anatomy, Medical University of Wrocław, 50-367 Wroclaw, Poland
- Department of Veterinary Surgery, Institute of Veterinary Medicine, Nicolaus Copernicus University, 87-100 Torun, Poland
- Correspondence: or
| | - Agnieszka Knopik-Skrocka
- Section of Regenerative Medicine and Cancer Research, Natural Sciences Club, Faculty of Biology, Adam Mickiewicz University, 61-614 Poznań, Poland
- Department of Cell Biology, Faculty of Biology, Adam Mickiewicz University, 61-614 Poznań, Poland
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29
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Smolkova B, Kataki A, Earl J, Ruz-Caracuel I, Cihova M, Urbanova M, Buocikova V, Tamargo S, Rovite V, Niedra H, Schrader J, Kohl Y. Liquid biopsy and preclinical tools for advancing diagnosis and treatment of patients with pancreatic neuroendocrine neoplasms. Crit Rev Oncol Hematol 2022; 180:103865. [PMID: 36334880 DOI: 10.1016/j.critrevonc.2022.103865] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Accepted: 10/31/2022] [Indexed: 11/06/2022] Open
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30
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The Role of Indoleamine 2, 3-Dioxygenase 1 in Regulating Tumor Microenvironment. Cancers (Basel) 2022; 14:cancers14112756. [PMID: 35681736 PMCID: PMC9179436 DOI: 10.3390/cancers14112756] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Revised: 05/19/2022] [Accepted: 05/27/2022] [Indexed: 02/05/2023] Open
Abstract
Indoleamine 2, 3-dioxygenase 1 (IDO1) is a rate-limiting enzyme that metabolizes an essential amino acid tryptophan (Trp) into kynurenine (Kyn), and it promotes the occurrence of immunosuppressive effects by regulating the consumption of Trp and the accumulation of Kyn in the tumor microenvironment (TME). Recent studies have shown that the main cellular components of TME interact with each other through this pathway to promote the formation of tumor immunosuppressive microenvironment. Here, we review the role of the immunosuppression mechanisms mediated by the IDO1 pathway in tumor growth. We discuss obstacles encountered in using IDO1 as a new tumor immunotherapy target, as well as the current clinical research progress.
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31
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Fane ME, Chhabra Y, Alicea GM, Maranto DA, Douglass SM, Webster MR, Rebecca VW, Marino GE, Almeida F, Ecker BL, Zabransky DJ, Hüser L, Beer T, Tang HY, Kossenkov A, Herlyn M, Speicher DW, Xu W, Xu X, Jaffee EM, Aguirre-Ghiso JA, Weeraratna AT. Stromal changes in the aged lung induce an emergence from melanoma dormancy. Nature 2022; 606:396-405. [PMID: 35650435 PMCID: PMC9554951 DOI: 10.1038/s41586-022-04774-2] [Citation(s) in RCA: 100] [Impact Index Per Article: 33.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Accepted: 04/19/2022] [Indexed: 12/14/2022]
Abstract
Disseminated cancer cells from primary tumours can seed in distal tissues, but may take several years to form overt metastases, a phenomenon that is termed tumour dormancy. Despite its importance in metastasis and residual disease, few studies have been able to successfully characterize dormancy within melanoma. Here we show that the aged lung microenvironment facilitates a permissive niche for efficient outgrowth of dormant disseminated cancer cells-in contrast to the aged skin, in which age-related changes suppress melanoma growth but drive dissemination. These microenvironmental complexities can be explained by the phenotype switching model, which argues that melanoma cells switch between a proliferative cell state and a slower-cycling, invasive state1-3. It was previously shown that dermal fibroblasts promote phenotype switching in melanoma during ageing4-8. We now identify WNT5A as an activator of dormancy in melanoma disseminated cancer cells within the lung, which initially enables the efficient dissemination and seeding of melanoma cells in metastatic niches. Age-induced reprogramming of lung fibroblasts increases their secretion of the soluble WNT antagonist sFRP1, which inhibits WNT5A in melanoma cells and thereby enables efficient metastatic outgrowth. We also identify the tyrosine kinase receptors AXL and MER as promoting a dormancy-to-reactivation axis within melanoma cells. Overall, we find that age-induced changes in distal metastatic microenvironments promote the efficient reactivation of dormant melanoma cells in the lung.
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Affiliation(s)
- Mitchell E Fane
- Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
- Department of Oncology, Sidney Kimmel Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Yash Chhabra
- Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
- Department of Oncology, Sidney Kimmel Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Gretchen M Alicea
- Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
- Department of Oncology, Sidney Kimmel Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Devon A Maranto
- Department of Oncology, Sidney Kimmel Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Stephen M Douglass
- Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
- Department of Oncology, Sidney Kimmel Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | | | - Vito W Rebecca
- Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
- Department of Oncology, Sidney Kimmel Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Gloria E Marino
- Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
- Department of Oncology, Sidney Kimmel Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | | | - Brett L Ecker
- The Wistar Institute, Philadelphia, PA, USA
- Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Daniel J Zabransky
- Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
- Department of Oncology, Sidney Kimmel Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Laura Hüser
- Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
- Department of Oncology, Sidney Kimmel Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA
- Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany
| | | | | | | | | | | | - Wei Xu
- Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Xiaowei Xu
- Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Elizabeth M Jaffee
- Department of Oncology, Sidney Kimmel Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Julio A Aguirre-Ghiso
- Department of Cell Biology, Albert Einstein Cancer Center, Albert Einstein College of Medicine, New York, NY, USA
- Cancer Dormancy and Tumor Microenvironment Institute, Albert Einstein Cancer Center, Albert Einstein College of Medicine, New York, NY, USA
- Gruss-Lipper Biophotonics Center, Albert Einstein Cancer Center, Albert Einstein College of Medicine, New York, NY, USA
- Ruth L. and David S. Gottesman Institute for Stem Cell Research and Regenerative Medicine, Institute for Aging Research, Albert Einstein College of Medicine, New York, NY, USA
| | - Ashani T Weeraratna
- Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
- Department of Oncology, Sidney Kimmel Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA.
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Palmisciano P, Ferini G, Barone F, Chavda V, Romano F, Amico P, Emmanuele D, Nicoletti GF, Pompili G, Giammalva GR, Maugeri R, Iacopino DG, Strigari L, Yeo TT, Cicero S, Scalia G, Umana GE. Extra-Neural Metastases From Primary Intracranial Ependymomas: A Systematic Review. Front Oncol 2022; 12:831016. [PMID: 35574408 PMCID: PMC9093681 DOI: 10.3389/fonc.2022.831016] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Accepted: 03/28/2022] [Indexed: 11/13/2022] Open
Abstract
Background Primary intracranial ependymomas (IE) are rare brain tumors rarely metastasizing outside the central nervous system. We systematically reviewed the literature on extra-neural metastases from primary IEs. Methods PubMed, Scopus, Web-of-Science, and Cochrane were searched following the PRISMA guidelines to include studies of extra-neural metastases from primary IEs. Clinical features, management strategies, and survival were analyzed. Results We collected 48 patients from 43 studies. Median age was 13 years (range, 2-65). Primary IEs were frequently located in the parietal (22.9%) and frontal (16.7%) lobes, and mostly treated with resection (95.8%) and/or radiotherapy (62.5%). Most IEs were of grade-III (79.1%), and few of grade-I (6.3%) or grade-II (14.6%). 45 patients experienced intracranial recurrences, mostly treated with resection (86.7%), radiotherapy (60%), and/or chemotherapy (24.4%). Median time-interval from primary IEs was 28 months (range, 0-140). Most extra-neural metastases were diagnosed at imaging (37.5%) or autopsy (35.4%). Extra-neural metastases were multifocal in 38 patients (79.1%), mostly involving cervical or hilar lymph-nodes (66.7%), lung/pleura (47.9%), and/or scalp (29.1%). Surgical resection (31.3%), chemotherapy (31.3%) and locoregional radiotherapy (18.8%) were the most common treatments for extra-neural metastases, but 28 (58.3%) patients were not treated. At last follow-up, 37 patients died with median overall-survivals from primary IEs of 36 months (range, 1-239), and from extra-neural metastases of 3 months (range, 0.1-36). Overall-survival was significantly longer in patients with grade-I and II IEs (P=0.040). Conclusion Extra-neural metastases from primary IEs are rare, but mostly occur at later disease stages. Multidisciplinary management strategies should be intended mostly for palliation.
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Affiliation(s)
- Paolo Palmisciano
- Department of Neurosurgery, Trauma Center, Gamma Knife Center, Cannizzaro Hospital, Catania, Italy
| | - Gianluca Ferini
- Department of Radiation Oncology, REM Radioterapia srl, Viagrande, Italy
| | - Fabio Barone
- Department of Neurosurgery, Trauma Center, Gamma Knife Center, Cannizzaro Hospital, Catania, Italy
| | - Vishal Chavda
- Department of Pathology, Stanford School of Medicine, Stanford University Medical Center, Palo Alto, CA, United States
| | | | - Paolo Amico
- Department of Pathological Anatomy, Cannizzaro Hospital, Catania, Italy
| | | | - Giovanni F. Nicoletti
- Department of Neurosurgery, Highly Specialized Hospital of National Importance “Garibaldi”, Catania, Italy
| | | | - Giuseppe Roberto Giammalva
- Unit of Neurosurgery, Department of Biomedical Neurosciences and Advanced Diagnostics, University of Palermo, Palermo, Italy
| | - Rosario Maugeri
- Unit of Neurosurgery, Department of Biomedical Neurosciences and Advanced Diagnostics, University of Palermo, Palermo, Italy
| | - Domenico Gerardo Iacopino
- Unit of Neurosurgery, Department of Biomedical Neurosciences and Advanced Diagnostics, University of Palermo, Palermo, Italy
| | - Lidia Strigari
- Department of Medical Physics, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Tseng T. Yeo
- Department of Surgery, Division of Neurosurgery, National University Hospital, Singapore, Singapore
| | - Salvatore Cicero
- Department of Neurosurgery, Trauma Center, Gamma Knife Center, Cannizzaro Hospital, Catania, Italy
| | - Gianluca Scalia
- Department of Neurosurgery, Highly Specialized Hospital of National Importance “Garibaldi”, Catania, Italy
| | - Giuseppe Emmanuele Umana
- Department of Neurosurgery, Trauma Center, Gamma Knife Center, Cannizzaro Hospital, Catania, Italy
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Resveratrol Contrasts IL-6 Pro-Growth Effects and Promotes Autophagy-Mediated Cancer Cell Dormancy in 3D Ovarian Cancer: Role of miR-1305 and of Its Target ARH-I. Cancers (Basel) 2022; 14:cancers14092142. [PMID: 35565270 PMCID: PMC9101105 DOI: 10.3390/cancers14092142] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Revised: 04/22/2022] [Accepted: 04/22/2022] [Indexed: 01/18/2023] Open
Abstract
Tumor dormancy is the extended period during which patients are asymptomatic before recurrence, and it represents a difficult phenomenon to target pharmacologically. The relapse of tumors, for instance arising from the interruption of dormant metastases, is frequently observed in ovarian cancer patients and determines poor survival. Inflammatory cytokines present in the tumor microenvironment likely contribute to such events. Cancer cell dormancy and autophagy are interconnected at the molecular level through ARH-I (DIRAS3) and BECLIN-1, two tumor suppressors often dysregulated in ovarian cancers. IL-6 disrupts autophagy in ovarian cancer cells via miRNAs downregulation of ARH-I, an effect contrasted by the nutraceutical protein restriction mimetic resveratrol (RV). By using three ovarian cancer cell lines with different genetic background in 2D and 3D models, the latter mimicking the growth of peritoneal metastases, we show that RV keeps the cancer cells in a dormant-like quiescent state contrasting the IL-6 growth-promoting activity. Mechanistically, this effect is mediated by BECLIN-1-dependent autophagy and relies on the availability of ARH-I. We also show that ARH-I (DIRAS3) is a bona fide target of miR-1305, a novel oncomiRNA upregulated by IL-6 and downregulated by RV. Clinically relevant, bioinformatic analysis of a transcriptomic database showed that the high expression of DIRAS3 and MAP1LC3B mRNAs together with that of CDKN1A, directing a cellular dormant phenotype, predicts better overall survival in ovarian cancer patients, and this correlates with MIR1305 downregulation. The possibility of maintaining a permanent cell dormancy in ovarian cancer by the chronic administration of RV should be considered as a therapeutic option to prevent the "awakening" of cancer cells in response to a permissive microenvironment, thus limiting the risk of tumor relapse and metastasis.
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Janowska A, Iannone M, Fidanzi C, Romanelli M, Filippi L, Del Re M, Martins M, Dini V. The Genetic Basis of Dormancy and Awakening in Cutaneous Metastatic Melanoma. Cancers (Basel) 2022; 14:2104. [PMID: 35565234 PMCID: PMC9102235 DOI: 10.3390/cancers14092104] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Revised: 04/19/2022] [Accepted: 04/21/2022] [Indexed: 01/27/2023] Open
Abstract
Immune dysregulation, in combination with genetic and epigenetic alterations, induces an excessive proliferation of uncontrolled melanoma cells followed by dissemination of the tumor cells to distant sites, invading organs and creating metastasis. Although immunotherapy, checkpoint inhibitors and molecular targeted therapies have been developed as treatment options for advanced melanoma, there are specific mechanisms by which cancer cells can escape treatment. One of the main factors associated with reduced response to therapy is the ability of residual tumor cells to persist in a dormant state, without proliferation. This comprehensive review aimed at understanding the genetic basis of dormancy/awakening phenomenon in metastatic melanoma will help identify the possible therapeutical strategies that might eliminate melanoma circulating tumor cells (CTCs) or keep them in the dormant state forever, thereby repressing tumor relapse and metastatic spread.
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Affiliation(s)
- Agata Janowska
- Unit of Dermatology, University of Pisa, 56126 Pisa, Italy; (M.I.); (C.F.); (M.R.); (M.M.); (V.D.)
| | - Michela Iannone
- Unit of Dermatology, University of Pisa, 56126 Pisa, Italy; (M.I.); (C.F.); (M.R.); (M.M.); (V.D.)
| | - Cristian Fidanzi
- Unit of Dermatology, University of Pisa, 56126 Pisa, Italy; (M.I.); (C.F.); (M.R.); (M.M.); (V.D.)
| | - Marco Romanelli
- Unit of Dermatology, University of Pisa, 56126 Pisa, Italy; (M.I.); (C.F.); (M.R.); (M.M.); (V.D.)
| | - Luca Filippi
- Unit of Neonatology, University of Pisa, 56126 Pisa, Italy;
| | - Marzia Del Re
- Unit of Clinical Pharmacology and Pharmacogenetics, University of Pisa, 56126 Pisa, Italy;
| | - Manuella Martins
- Unit of Dermatology, University of Pisa, 56126 Pisa, Italy; (M.I.); (C.F.); (M.R.); (M.M.); (V.D.)
| | - Valentina Dini
- Unit of Dermatology, University of Pisa, 56126 Pisa, Italy; (M.I.); (C.F.); (M.R.); (M.M.); (V.D.)
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Micieli JA, Dhoot AS, Micieli R, Montanera W, Assaad D, Krizova A. Recurrence of Thin Cutaneous Melanoma in the Optic Nerve After Over a Decade of Clinical Cure. J Neuroophthalmol 2022; 42:e343-e346. [PMID: 34417774 DOI: 10.1097/wno.0000000000001399] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Affiliation(s)
- Jonathan A Micieli
- Department of Ophthalmology and Vision Sciences (JAM), University of Toronto, Toronto, Canada ; Faculty of Medicine (ASD), University of Toronto, Toronto, Canada ; Department of Medicine (RM, DA), Division of Dermatology, University of Toronto, Toronto, Canada ; Diagnostic and Therapeutic Neuroradiology (WM), Department of Medical Imaging, St. Michael's Hospital, University of Toronto, Toronto, Canada; and Department of Pathology and Laboratory Medicine (AK), St. Michael's Hospital, University of Toronto, Toronto, Canada
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You B, Xia T, Gu M, Zhang Z, Zhang Q, Shen J, Fan Y, Yao H, Pan S, Lu Y, Cheng T, Yang Z, He X, Zhang H, Shi M, Liu D, You Y. AMPK-mTOR-Mediated Activation of Autophagy Promotes Formation of Dormant Polyploid Giant Cancer Cells. Cancer Res 2022; 82:846-858. [PMID: 34965934 PMCID: PMC9359740 DOI: 10.1158/0008-5472.can-21-2342] [Citation(s) in RCA: 47] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2021] [Revised: 11/20/2021] [Accepted: 12/27/2021] [Indexed: 01/07/2023]
Abstract
Dormant cancer cells that survive anticancer therapy can lead to cancer recurrence and disseminated metastases that prove fatal in most cases. Recently, specific dormant polyploid giant cancer cells (PGCC) have drawn our attention because of their association with the clinical risk of nasopharyngeal carcinoma (NPC) recurrence, as demonstrated by previous clinical data. In this study, we report the biological properties of PGCC, including mitochondrial alterations, and reveal that autophagy is a critical mechanism of PGCC induction. Moreover, pharmacologic or genetic inhibition of autophagy greatly impaired PGCC formation, significantly suppressing metastasis and improving survival in a mouse model. Mechanistically, chemotherapeutic drugs partly damaged mitochondria, which then produced low ATP levels and activated autophagy via the AMPK-mTOR pathway to promote PGCC formation. Analysis of the transcriptional and epigenetic landscape of PGCC revealed overexpression of RIPK1, and the scaffolding function of RIPK1 was required for AMPK-mTOR pathway-induced PGCC survival. High numbers of PGCCs correlated with shorter recurrence time and worse survival outcomes in patients with NPC. Collectively, these findings suggest a therapeutic approach of targeting dormant PGCCs in cancer. SIGNIFICANCE Pretreatment with an autophagy inhibitor before chemotherapy could prevent formation of therapy-induced dormant polyploid giant cancer cells, thereby reducing recurrence and metastasis of nasopharyngeal carcinoma.
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Affiliation(s)
- Bo You
- Department of Otorhinolaryngology Head and Neck Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province, China.,Institute of Otolaryngology Head and Neck Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province, China.,College of Medicine, Nantong, Jiangsu Province, China
| | - Tian Xia
- Department of Otorhinolaryngology Head and Neck Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province, China.,Institute of Otolaryngology Head and Neck Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province, China.,College of Medicine, Nantong, Jiangsu Province, China
| | - Miao Gu
- Department of Otorhinolaryngology Head and Neck Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province, China.,Institute of Otolaryngology Head and Neck Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province, China.,College of Medicine, Nantong, Jiangsu Province, China
| | - Zhenxin Zhang
- Department of Otorhinolaryngology Head and Neck Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province, China.,Institute of Otolaryngology Head and Neck Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province, China.,College of Medicine, Nantong, Jiangsu Province, China
| | - Qicheng Zhang
- Department of Otorhinolaryngology Head and Neck Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province, China.,Institute of Otolaryngology Head and Neck Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province, China.,College of Medicine, Nantong, Jiangsu Province, China
| | - Jianhong Shen
- Clinical Medical Research Center, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province, China
| | - Yue Fan
- Department of Otorhinolaryngology Head and Neck Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province, China.,Institute of Otolaryngology Head and Neck Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province, China.,College of Medicine, Nantong, Jiangsu Province, China
| | - Hui Yao
- Department of Otorhinolaryngology Head and Neck Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province, China.,Institute of Otolaryngology Head and Neck Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province, China.,College of Medicine, Nantong, Jiangsu Province, China
| | - Si Pan
- Department of Otorhinolaryngology Head and Neck Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province, China.,Institute of Otolaryngology Head and Neck Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province, China.,College of Medicine, Nantong, Jiangsu Province, China
| | - Yingna Lu
- Department of Otorhinolaryngology Head and Neck Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province, China.,Institute of Otolaryngology Head and Neck Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province, China.,College of Medicine, Nantong, Jiangsu Province, China
| | - Tianyi Cheng
- Department of Otorhinolaryngology Head and Neck Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province, China.,Institute of Otolaryngology Head and Neck Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province, China.,College of Medicine, Nantong, Jiangsu Province, China
| | - Zhiyuan Yang
- Department of Otorhinolaryngology Head and Neck Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province, China.,Institute of Otolaryngology Head and Neck Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province, China.,College of Medicine, Nantong, Jiangsu Province, China
| | - Xin He
- Department of Pathology, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province, China
| | - Hao Zhang
- Institute of Otolaryngology Head and Neck Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province, China.,College of Medicine, Nantong, Jiangsu Province, China
| | - Muqi Shi
- Institute of Otolaryngology Head and Neck Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province, China.,College of Medicine, Nantong, Jiangsu Province, China
| | - Dong Liu
- Nantong Laboratory of Development and Diseases, School of Life Sciences, Co-Innovation Center of Neuroregeneration, Key Laboratory of Neuroregeneration of Jiangsu and MOE, Nantong University, Nantong, Jiangsu Province, China.,Corresponding Authors: Yiwen You, Department of Otorhinolaryngology Head and Neck Surgery, Affiliated Hospital of Nantong University, 40 Qing Nian Dong Lu, Chongchuan District, Nantong, Jiangsu Province, China, 226007, China. Phone: 135-8522-9333; E-mail: ; and Dong Liu, Nantong Laboratory of Development and Diseases, School of Life Sciences, Co-Innovation Center of Neuroregeneration, Key Laboratory of Neuroregeneration of Jiangsu and MOE, Nantong University, 9 Siyuan Road, Chongchuan District, Nantong, Jiangsu Province, China, 226019, China. Phone: 8618-6051-33927; E-mail:
| | - Yiwen You
- Department of Otorhinolaryngology Head and Neck Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province, China.,Institute of Otolaryngology Head and Neck Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province, China.,College of Medicine, Nantong, Jiangsu Province, China.,Corresponding Authors: Yiwen You, Department of Otorhinolaryngology Head and Neck Surgery, Affiliated Hospital of Nantong University, 40 Qing Nian Dong Lu, Chongchuan District, Nantong, Jiangsu Province, China, 226007, China. Phone: 135-8522-9333; E-mail: ; and Dong Liu, Nantong Laboratory of Development and Diseases, School of Life Sciences, Co-Innovation Center of Neuroregeneration, Key Laboratory of Neuroregeneration of Jiangsu and MOE, Nantong University, 9 Siyuan Road, Chongchuan District, Nantong, Jiangsu Province, China, 226019, China. Phone: 8618-6051-33927; E-mail:
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Zaragoza-Ojeda M, Torres-Flores U, Rodríguez-Leviz A, Arenas-Huertero F. Benzo[ghi]perylene induces cellular dormancy signaling and endoplasmic reticulum stress in NL-20 human bronchial epithelial cells. Toxicol Appl Pharmacol 2022; 439:115925. [PMID: 35182551 DOI: 10.1016/j.taap.2022.115925] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Revised: 01/25/2022] [Accepted: 02/14/2022] [Indexed: 12/22/2022]
Abstract
Benzo[ghi]perylene (BghiP) is produced by the incomplete combustion of gasoline and it is a marker of high vehicular flow in big cities. Nowadays, it is known that BghiP functions as ligand for the aryl hydrocarbon receptor (AhR), which can cause several molecular responses. For this reason, the aim of the present study was to assess the in vitro effects of the exposure to BghiP, specifically, the induction of cellular dormancy and endoplasmic reticulum stress (ER stress) in NL-20 human cells. Our results proved that a 24 h exposure of BghiP, increased the expression of NR2F1 (p < 0.05). NR2F1 is the main activator of cell dormancy, therefore, we analyzed the expression of its target genes SOX9 and p27 showing an increase of the transcripts (p < 0.05), suggesting a pathway that could produce a cell cycle arrest. Interestingly, this effect was only observed with BghiP exposure, and not with a classic AhR ligand: benzo[a]pyrene. Moreover, in the presence of the AhR antagonist, CH223191, or when the expression of AhR was knock-down using dsiRNAs, the cellular dormancy signaling pathway was blocked. Morphological and ultrastructure analysis demonstrated that BghiP also induces ER stress, characterized by the dilated ER cisternae and the overexpression of PERK and CHOP genes (p < 0.05). Moreover, the halt of cell proliferation and the ER stress are both associated to the increase of pro-inflammatory cytokines (IL-6 and IL-8) and the cell survival in response to microenvironmental cues. These responses induced by BghiP on bronchial cells open new horizons on the research of other biological effects induced by environmental pollutants.
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Affiliation(s)
- Montserrat Zaragoza-Ojeda
- Laboratorio de Investigación en Patología Experimental, Hospital Infantil de México Federico Gómez, Mexico City 06720, Mexico; Posgrado en Ciencias Biológicas, Facultad de Medicina, Universidad Nacional Autónoma de México (UNAM), Mexico City 04510, Mexico
| | - Ulises Torres-Flores
- Laboratorio de Investigación en Patología Experimental, Hospital Infantil de México Federico Gómez, Mexico City 06720, Mexico
| | - Alejandra Rodríguez-Leviz
- Laboratorio de Microscopía Electrónica, Patología Clínica y Experimental, Hospital Infantil de México Federico Gómez, Mexico City 06720, Mexico
| | - Francisco Arenas-Huertero
- Laboratorio de Investigación en Patología Experimental, Hospital Infantil de México Federico Gómez, Mexico City 06720, Mexico.
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Shmakova AA, Klimovich PS, Rysenkova KD, Popov VS, Gorbunova AS, Karpukhina AA, Karagyaur MN, Rubina KA, Tkachuk VA, Semina EV. Urokinase Receptor uPAR Downregulation in Neuroblastoma Leads to Dormancy, Chemoresistance and Metastasis. Cancers (Basel) 2022; 14:cancers14040994. [PMID: 35205745 PMCID: PMC8870350 DOI: 10.3390/cancers14040994] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2022] [Revised: 02/05/2022] [Accepted: 02/12/2022] [Indexed: 02/04/2023] Open
Abstract
Simple Summary uPAR is a membrane receptor that contributes to extracellular matrix remodeling and controls cellular adhesion, proliferation, survival, and migration. We demonstrate that the initially high uPAR expression predicts poor survival in neuroblastoma. However, relapsed neuroblastomas have a significantly decreased uPAR expression. uPAR downregulation in neuroblastoma cells leads to dormancy and resistance to chemotherapeutic drugs. In mice, low uPAR-expressing neuroblastoma cells formed smaller primary tumors but more frequent metastasis. Abstract uPAR is a membrane receptor that binds extracellular protease urokinase, contributes to matrix remodeling and plays a crucial role in cellular adhesion, proliferation, survival, and migration. uPAR overexpression in tumor cells promotes mitogenesis, opening a prospective avenue for targeted therapy. However, uPAR targeting in cancer has potential risks. We have recently shown that uPAR downregulation in neuroblastoma promotes epithelial-mesenchymal transition (EMT), potentially associated with metastasis and chemoresistance. We used data mining to evaluate the role of uPAR expression in primary and relapsed human neuroblastomas. To model the decreased uPAR expression, we targeted uPAR using CRISPR/Cas9 and shRNA in neuroblastoma Neuro2a cells and evaluated their chemosensitivity in vitro as well as tumor growth and metastasis in vivo. We demonstrate that the initially high PLAUR expression predicts poor survival in human neuroblastoma. However, relapsed neuroblastomas have a significantly decreased PLAUR expression. uPAR targeting in neuroblastoma Neuro2a cells leads to p38 activation and an increased p21 expression (suggesting a dormant phenotype). The dormancy in neuroblastoma cells can be triggered by the disruption of uPAR-integrin interaction. uPAR-deficient cells are less sensitive to cisplatin and doxorubicin treatment and exhibit lower p53 activation. Finally, low uPAR-expressing Neuro2a cells formed smaller primary tumors, but more frequent metastasis in mice. To the best of our knowledge, this is the first study revealing the pathological role of dormant uPAR-deficient cancer cells having a chemoresistant and motile phenotype.
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Affiliation(s)
- Anna A. Shmakova
- National Cardiology Research Center of the Ministry of Health of the Russian Federation, Institute of Experimental Cardiology, 121552 Moscow, Russia; (A.A.S.); (P.S.K.); (K.D.R.); (V.A.T.)
- Faculty of Medicine, Lomonosov Moscow State University, 119192 Moscow, Russia; (V.S.P.); (A.S.G.); (M.N.K.); (K.A.R.)
| | - Polina S. Klimovich
- National Cardiology Research Center of the Ministry of Health of the Russian Federation, Institute of Experimental Cardiology, 121552 Moscow, Russia; (A.A.S.); (P.S.K.); (K.D.R.); (V.A.T.)
- Faculty of Medicine, Lomonosov Moscow State University, 119192 Moscow, Russia; (V.S.P.); (A.S.G.); (M.N.K.); (K.A.R.)
| | - Karina D. Rysenkova
- National Cardiology Research Center of the Ministry of Health of the Russian Federation, Institute of Experimental Cardiology, 121552 Moscow, Russia; (A.A.S.); (P.S.K.); (K.D.R.); (V.A.T.)
- Faculty of Medicine, Lomonosov Moscow State University, 119192 Moscow, Russia; (V.S.P.); (A.S.G.); (M.N.K.); (K.A.R.)
| | - Vladimir S. Popov
- Faculty of Medicine, Lomonosov Moscow State University, 119192 Moscow, Russia; (V.S.P.); (A.S.G.); (M.N.K.); (K.A.R.)
| | - Anna S. Gorbunova
- Faculty of Medicine, Lomonosov Moscow State University, 119192 Moscow, Russia; (V.S.P.); (A.S.G.); (M.N.K.); (K.A.R.)
| | - Anna A. Karpukhina
- Koltzov Institute of Developmental Biology, Russian Academy of Science, 117334 Moscow, Russia;
| | - Maxim N. Karagyaur
- Faculty of Medicine, Lomonosov Moscow State University, 119192 Moscow, Russia; (V.S.P.); (A.S.G.); (M.N.K.); (K.A.R.)
| | - Kseniya A. Rubina
- Faculty of Medicine, Lomonosov Moscow State University, 119192 Moscow, Russia; (V.S.P.); (A.S.G.); (M.N.K.); (K.A.R.)
| | - Vsevolod A. Tkachuk
- National Cardiology Research Center of the Ministry of Health of the Russian Federation, Institute of Experimental Cardiology, 121552 Moscow, Russia; (A.A.S.); (P.S.K.); (K.D.R.); (V.A.T.)
- Faculty of Medicine, Lomonosov Moscow State University, 119192 Moscow, Russia; (V.S.P.); (A.S.G.); (M.N.K.); (K.A.R.)
| | - Ekaterina V. Semina
- National Cardiology Research Center of the Ministry of Health of the Russian Federation, Institute of Experimental Cardiology, 121552 Moscow, Russia; (A.A.S.); (P.S.K.); (K.D.R.); (V.A.T.)
- Faculty of Medicine, Lomonosov Moscow State University, 119192 Moscow, Russia; (V.S.P.); (A.S.G.); (M.N.K.); (K.A.R.)
- Correspondence:
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Angstadt S, Zhu Q, Jaffee EM, Robinson DN, Anders RA. Pancreatic Ductal Adenocarcinoma Cortical Mechanics and Clinical Implications. Front Oncol 2022; 12:809179. [PMID: 35174086 PMCID: PMC8843014 DOI: 10.3389/fonc.2022.809179] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Accepted: 01/05/2022] [Indexed: 12/23/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers due to low therapeutic response rates and poor prognoses. Majority of patients present with symptoms post metastatic spread, which contributes to its overall lethality as the 4th leading cause of cancer-related deaths. Therapeutic approaches thus far target only one or two of the cancer specific hallmarks, such as high proliferation rate, apoptotic evasion, or immune evasion. Recent genomic discoveries reveal that genetic heterogeneity, early micrometastases, and an immunosuppressive tumor microenvironment contribute to the inefficacy of current standard treatments and specific molecular-targeted therapies. To effectively combat cancers like PDAC, we need an innovative approach that can simultaneously impact the multiple hallmarks driving cancer progression. Here, we present the mechanical properties generated by the cell’s cortical cytoskeleton, with a spotlight on PDAC, as an ideal therapeutic target that can concurrently attack multiple systems driving cancer. We start with an introduction to cancer cell mechanics and PDAC followed by a compilation of studies connecting the cortical cytoskeleton and mechanical properties to proliferation, metastasis, immune cell interactions, cancer cell stemness, and/or metabolism. We further elaborate on the implications of these findings in disease progression, therapeutic resistance, and clinical relapse. Manipulation of the cancer cell’s mechanical system has already been shown to prevent metastasis in preclinical models, but it has greater potential for target exploration since it is a foundational property of the cell that regulates various oncogenic behaviors.
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Affiliation(s)
- Shantel Angstadt
- Department of Pathology Johns Hopkins University School of Medicine, Baltimore, MD, United States
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
- Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Qingfeng Zhu
- Department of Pathology Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Elizabeth M. Jaffee
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Douglas N. Robinson
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
- Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
- *Correspondence: Douglas N. Robinson, ; Robert A. Anders,
| | - Robert A. Anders
- Department of Pathology Johns Hopkins University School of Medicine, Baltimore, MD, United States
- *Correspondence: Douglas N. Robinson, ; Robert A. Anders,
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40
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He L, Wick N, Germans SK, Peng Y. The Role of Breast Cancer Stem Cells in Chemoresistance and Metastasis in Triple-Negative Breast Cancer. Cancers (Basel) 2021; 13:cancers13246209. [PMID: 34944829 PMCID: PMC8699562 DOI: 10.3390/cancers13246209] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Revised: 12/05/2021] [Accepted: 12/08/2021] [Indexed: 02/05/2023] Open
Abstract
Triple negative breast cancer (TNBC) remains an aggressive disease due to the lack of targeted therapies and low rate of response to chemotherapy that is currently the main treatment modality for TNBC. Breast cancer stem cells (BCSCs) are a small subpopulation of breast tumors and recognized as drivers of tumorigenesis. TNBC tumors are characterized as being enriched for BCSCs. Studies have demonstrated the role of BCSCs as the source of metastatic disease and chemoresistance in TNBC. Multiple targets against BCSCs are now under investigation, with the considerations of either selectively targeting BCSCs or co-targeting BCSCs and non-BCSCs (majority of tumor cells). This review article provides a comprehensive overview of recent advances in the role of BCSCs in TNBC and the identification of cancer stem cell biomarkers, paving the way for the development of new targeted therapies. The review also highlights the resultant discovery of cancer stem cell targets in TNBC and the ongoing clinical trials treating chemoresistant breast cancer. We aim to provide insights into better understanding the mutational landscape of BCSCs and exploring potential molecular signaling pathways targeting BCSCs to overcome chemoresistance and prevent metastasis in TNBC, ultimately to improve the overall survival of patients with this devastating disease.
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Affiliation(s)
- Lin He
- Department of Pathology, University of Texas Southwestern Medical Center, 6201 Harry Hines Blvd, Dallas, TX 75235, USA; (L.H.); (N.W.); (S.K.G.)
| | - Neda Wick
- Department of Pathology, University of Texas Southwestern Medical Center, 6201 Harry Hines Blvd, Dallas, TX 75235, USA; (L.H.); (N.W.); (S.K.G.)
| | - Sharon Koorse Germans
- Department of Pathology, University of Texas Southwestern Medical Center, 6201 Harry Hines Blvd, Dallas, TX 75235, USA; (L.H.); (N.W.); (S.K.G.)
| | - Yan Peng
- Department of Pathology, University of Texas Southwestern Medical Center, 6201 Harry Hines Blvd, Dallas, TX 75235, USA; (L.H.); (N.W.); (S.K.G.)
- Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75235, USA
- Correspondence:
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41
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Chernosky NM, Tamagno I. The Role of the Innate Immune System in Cancer Dormancy and Relapse. Cancers (Basel) 2021; 13:5621. [PMID: 34830776 PMCID: PMC8615859 DOI: 10.3390/cancers13225621] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Revised: 11/04/2021] [Accepted: 11/08/2021] [Indexed: 12/12/2022] Open
Abstract
Metastatic spread and recurrence are intimately linked to therapy failure, which remains an overarching clinical challenge for patients with cancer. Cancer cells often disseminate early in the disease process and can remain dormant for years or decades before re-emerging as metastatic disease, often after successful treatment. The interactions of dormant cancer cells and their metastatic niche, comprised of various stromal and immune cells, can determine the length of time that cancer cells remain dormant, as well as when they reactivate. New studies are defining how innate immune cells in the primary tumor may be corrupted to help facilitate many aspects of dissemination and re-emergence from a dormant state. Although the scientific literature has partially shed light on the drivers of immune escape in cancer, the specific mechanisms regulating metastasis and dormancy in the context of anti-tumor immunity are still mostly unknown. This review follows the journey of metastatic cells from dissemination to dormancy and the onset of metastatic outgrowth and recurrent tumor development, with emphasis on the role of the innate immune system. To this end, further research identifying how immune cells interact with cancer cells at each step of cancer progression will pave the way for new therapies that target the reactivation of dormant cancer cells into recurrent, metastatic cancers.
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Affiliation(s)
- Noah M. Chernosky
- Department of Pathology, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA;
- Case Comprehensive Cancer Center, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Ilaria Tamagno
- Department of Pathology, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA;
- Case Comprehensive Cancer Center, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA
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Alhasan BA, Gordeev SA, Knyazeva AR, Aleksandrova KV, Margulis BA, Guzhova IV, Suvorova II. The mTOR Pathway in Pluripotent Stem Cells: Lessons for Understanding Cancer Cell Dormancy. MEMBRANES 2021; 11:858. [PMID: 34832087 PMCID: PMC8620939 DOI: 10.3390/membranes11110858] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 11/02/2021] [Accepted: 11/04/2021] [Indexed: 11/16/2022]
Abstract
Currently, the success of targeted anticancer therapies largely depends on the correct understanding of the dormant state of cancer cells, since it is increasingly regarded to fuel tumor recurrence. The concept of cancer cell dormancy is often considered as an adaptive response of cancer cells to stress, and, therefore, is limited. It is possible that the cancer dormant state is not a privilege of cancer cells but the same reproductive survival strategy as diapause used by embryonic stem cells (ESCs). Recent advances reveal that high autophagy and mTOR pathway reduction are key mechanisms contributing to dormancy and diapause. ESCs, sharing their main features with cancer stem cells, have a delicate balance between the mTOR pathway and autophagy activity permissive for diapause induction. In this review, we discuss the functioning of the mTOR signaling and autophagy in ESCs in detail that allows us to deepen our understanding of the biology of cancer cell dormancy.
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Affiliation(s)
| | | | | | | | | | | | - Irina I. Suvorova
- Institute of Cytology, Russian Academy of Sciences, 194064 St. Petersburg, Russia; (B.A.A.); (S.A.G.); (A.R.K.); (K.V.A.); (B.A.M.); (I.V.G.)
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43
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Kemp JA, Kwon YJ. Cancer nanotechnology: current status and perspectives. NANO CONVERGENCE 2021; 8:34. [PMID: 34727233 PMCID: PMC8560887 DOI: 10.1186/s40580-021-00282-7] [Citation(s) in RCA: 91] [Impact Index Per Article: 22.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Accepted: 10/05/2021] [Indexed: 05/09/2023]
Abstract
Modern medicine has been waging a war on cancer for nearly a century with no tangible end in sight. Cancer treatments have significantly progressed, but the need to increase specificity and decrease systemic toxicities remains. Early diagnosis holds a key to improving prognostic outlook and patient quality of life, and diagnostic tools are on the cusp of a technological revolution. Nanotechnology has steadily expanded into the reaches of cancer chemotherapy, radiotherapy, diagnostics, and imaging, demonstrating the capacity to augment each and advance patient care. Nanomaterials provide an abundance of versatility, functionality, and applications to engineer specifically targeted cancer medicine, accurate early-detection devices, robust imaging modalities, and enhanced radiotherapy adjuvants. This review provides insights into the current clinical and pre-clinical nanotechnological applications for cancer drug therapy, diagnostics, imaging, and radiation therapy.
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Affiliation(s)
- Jessica A Kemp
- Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University of California, Irvine, CA, 92697, USA
| | - Young Jik Kwon
- Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University of California, Irvine, CA, 92697, USA.
- Department of Chemical and Biomolecular Engineering, School of Engineering, University of California, Irvine, CA, 92697, USA.
- Department of Biomedical Engineering, School of Engineering, University of California, Irvine, CA, 92697, USA.
- Department of Molecular Biology and Biochemistry, School of Biological Sciences, University of California, Irvine, CA, 92697, USA.
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44
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Zhao L, Zhang K, He H, Yang Y, Li W, Liu T, Li J. The Relationship Between Mesenchymal Stem Cells and Tumor Dormancy. Front Cell Dev Biol 2021; 9:731393. [PMID: 34712663 PMCID: PMC8545891 DOI: 10.3389/fcell.2021.731393] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2021] [Accepted: 09/13/2021] [Indexed: 12/12/2022] Open
Abstract
Tumor dormancy, a state of tumor, is clinically undetectable and the outgrowth of dormant tumor cells into overt metastases is responsible for cancer-associated deaths. However, the dormancy-related molecular mechanism has not been clearly described. Some researchers have proposed that cancer stem cells (CSCs) and disseminated tumor cells (DTCs) can be seen as progenitor cells of tumor dormancy, both of which can remain dormant in a non-permissive soil/niche. Nowadays, research interest in the cancer biology field is skyrocketing as mesenchymal stem cells (MSCs) are capable of regulating tumor dormancy, which will provide a unique therapeutic window to cure cancer. Although the influence of MSCs on tumor dormancy has been investigated in previous studies, there is no thorough review on the relationship between MSCs and tumor dormancy. In this paper, the root of tumor dormancy is analyzed and dormancy-related molecular mechanisms are summarized. With an emphasis on the role of the MSCs during tumor dormancy, new therapeutic strategies to prevent metastatic disease are proposed, whose clinical application potentials are discussed, and some challenges and prospects of the studies of tumor dormancy are also described.
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Affiliation(s)
- Linxian Zhao
- Department of General Surgery, The Second Hospital of Jilin University, Changchun, China
| | - Kai Zhang
- Department of General Surgery, The Second Hospital of Jilin University, Changchun, China
| | - Hongyu He
- Operating Theater and Department of Anesthesiology, The Second Hospital of Jilin University, Changchun, China
| | - Yongping Yang
- Department of General Surgery, The Second Hospital of Jilin University, Changchun, China
| | - Wei Li
- Department of General Surgery, The Second Hospital of Jilin University, Changchun, China
| | - Tongjun Liu
- Department of General Surgery, The Second Hospital of Jilin University, Changchun, China
| | - Jiannan Li
- Department of General Surgery, The Second Hospital of Jilin University, Changchun, China
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45
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Yang C, Ng CT, Li D, Zhang L. Targeting Indoleamine 2,3-Dioxygenase 1: Fighting Cancers via Dormancy Regulation. Front Immunol 2021; 12:725204. [PMID: 34539663 PMCID: PMC8446437 DOI: 10.3389/fimmu.2021.725204] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Accepted: 08/12/2021] [Indexed: 12/14/2022] Open
Abstract
The connection between indoleamine 2,3-dioxygenase 1 (IDO1) and tumour dormancy – a quiescent state of tumour cells which has been consistently linked to metastasis and cancer recurrence – is rarely discussed despite the pivotal role of IDO1 in cancer development and progression. Whilst the underlying mechanisms of IDO1-mediated dormancy are elusive, we summarize the IDO1 pathways which potentially contribute to dormancy in this review. Critically, distinct IDO1 activities are involved in dormancy initiation and maintenance; factors outside the well-studied IDO1/kynurenine/aryl hydrocarbon receptor axis, including the mammalian target of rapamycin and general control nonderepressible 2, appear to be implicated in dormancy. We also discuss various strategies for cancer treatment via regulating IDO1-dependent dormancy and suggest the application of nanotechnology to deliver effective treatment.
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Affiliation(s)
- Chao Yang
- National Engineering Research Center For Marine Aquaculture, Institute of Innovation & Application, Zhejiang Ocean University, Zhoushan, China
| | - Chan-Tat Ng
- Department of Psychology, National Chengchi University, Taipei, Taiwan.,Department of English, National Chengchi University, Taipei, Taiwan
| | - Dan Li
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Lei Zhang
- Sericultural Research Institute, College of Biotechnology, Jiangsu University of Science and Technology, Zhenjiang, China.,Department of Chemical Engineering, Waterloo Institute for Nanotechnology, University of Waterloo, Waterloo, ON, Canada
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46
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Chen X, Xie H, Wang X, Zheng Z, Jin S. CIRBP Knockdown Attenuates Tumourigenesis and Improves the Chemosensitivity of Pancreatic Cancer via the Downregulation of DYRK1B. Front Cell Dev Biol 2021; 9:667551. [PMID: 34490236 PMCID: PMC8417580 DOI: 10.3389/fcell.2021.667551] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2021] [Accepted: 08/02/2021] [Indexed: 12/09/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies worldwide with very limited treatment options. Cold-inducible RNA binding protein (CIRBP) plays promoting roles in several types of cancers, but its function remains unclear in PDAC. Here, we found that the expression of CIRBP was upregulated in PDAC tumor tissues and was significantly associated with poor prognosis. Knockdown of CIRBP in PANC-1 and SW1990 cells inhibited proliferation, migration and invasion in vitro and suppressed tumor growth in vivo. Moreover, CIRBP knockdown enhanced the antitumour effects of gemcitabine treatment in PANC-1 and SW1990 cells, whereas CIRBP overexpression exerted the opposite effects. Mechanistically, CIRBP promoted PDAC malignancy and chemoresistance via upregulation of dual-specificity tyrosine-Y-phosphorylation regulated kinase 1B (DYRK1B). Indeed, knockdown of CIRBP sensitized pancreatic tumors to gemcitabine treatment by diminishing DYRK1B expression and increasing the ratio of ERK/p38 activity. Our findings suggest that CIRBP overexpression facilitates PDAC progression and gemcitabine resistance by upregulating DYRK1B expression and inhibiting the ERK/p38 signaling pathway, highlighting CIRBP as a potential new therapeutic target for PDAC.
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Affiliation(s)
- Xiang Chen
- Department of Anesthesia, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Hongyu Xie
- Department of Anesthesia, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xin Wang
- Department of Anesthesia, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Zhinan Zheng
- Department of Anesthesia, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Sanqing Jin
- Department of Anesthesia, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
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47
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Uzuner D, Akkoç Y, Peker N, Pir P, Gözüaçık D, Çakır T. Transcriptional landscape of cellular networks reveal interactions driving the dormancy mechanisms in cancer. Sci Rep 2021; 11:15806. [PMID: 34349126 PMCID: PMC8339123 DOI: 10.1038/s41598-021-94005-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Accepted: 06/28/2021] [Indexed: 11/22/2022] Open
Abstract
Primary cancer cells exert unique capacity to disseminate and nestle in distant organs. Once seeded in secondary sites, cancer cells may enter a dormant state, becoming resistant to current treatment approaches, and they remain silent until they reactivate and cause overt metastases. To illuminate the complex mechanisms of cancer dormancy, 10 transcriptomic datasets from the literature enabling 21 dormancy–cancer comparisons were mapped on protein–protein interaction networks and gene-regulatory networks to extract subnetworks that are enriched in significantly deregulated genes. The genes appearing in the subnetworks and significantly upregulated in dormancy with respect to proliferative state were scored and filtered across all comparisons, leading to a dormancy–interaction network for the first time in the literature, which includes 139 genes and 1974 interactions. The dormancy interaction network will contribute to the elucidation of cellular mechanisms orchestrating cancer dormancy, paving the way for improvements in the diagnosis and treatment of metastatic cancer.
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Affiliation(s)
- Dilara Uzuner
- Department of Bioengineering, Gebze Technical University, 41400, Kocaeli, Turkey
| | - Yunus Akkoç
- Koç University Research Center for Translational Medicine (KUTTAM), Zeytinburnu, 34010, Istanbul, Turkey
| | - Nesibe Peker
- Koç University Research Center for Translational Medicine (KUTTAM), Zeytinburnu, 34010, Istanbul, Turkey
| | - Pınar Pir
- Department of Bioengineering, Gebze Technical University, 41400, Kocaeli, Turkey
| | - Devrim Gözüaçık
- Koç University Research Center for Translational Medicine (KUTTAM), Zeytinburnu, 34010, Istanbul, Turkey.,Koç University School of Medicine, Sarıyer , 34450, Istanbul, Turkey.,SUNUM Nanotechnology Research and Application Center, Tuzla, 34956, Istanbul, Turkey
| | - Tunahan Çakır
- Department of Bioengineering, Gebze Technical University, 41400, Kocaeli, Turkey.
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48
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Mathios D, Srivastava S, Kim T, Bettegowda C, Lim M. Emerging Technologies for Non-invasive Monitoring of Treatment Response to Immunotherapy for Brain Tumors. Neuromolecular Med 2021; 24:74-87. [PMID: 34297308 DOI: 10.1007/s12017-021-08677-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Accepted: 07/10/2021] [Indexed: 12/19/2022]
Abstract
Glioblastoma is the most common primary malignant brain tumor and one of the most aggressive tumors across all cancer types with remarkable resistance to any treatment. While immunotherapy has shown a robust clinical benefit in systemic cancers, its benefit is still under investigation in brain cancers. The broader use of immunotherapy in clinical trials for glioblastoma has highlighted the challenges of traditional methods of monitoring progression via imaging. Development of new guidelines, advanced imaging techniques, and immune profiling have emerged to counter premature diagnoses of progressive disease. However, these approaches do not provide a timely diagnosis and are costly and time consuming. Surgery is currently the standard of care for diagnosis of pseudoprogression in cases where MRI is equivocal. However, it is invasive, risky, and disruptive to patient's lives and their oncological treatment. With its increased vascularity, glioblastoma is continually shedding tumor components into the vasculature including tumor cells, genetic material, and extracellular vesicles. These elements can be isolated from routine blood draws and provide a real-time non-invasive indicator of tumor progression. Liquid biopsy therefore presents as an attractive alternative to current methods to guide treatment. While the initial evaluation of liquid biopsy for brain tumors via identification of mutations in the plasma was disappointing, novel technologies and use of alternatives to plasma cell-free DNA analytes provide promise for an effective liquid biopsy approach in brain tumors. This review aims to summarize developments in the use of liquid biopsy to monitor glioblastoma, especially in the context of immunotherapy.
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Affiliation(s)
- Dimitrios Mathios
- Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Siddhartha Srivastava
- Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Timothy Kim
- Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Chetan Bettegowda
- Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Michael Lim
- Department of Neurosurgery, Stanford University School of Medicine, Palo Alto, CA, USA.
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Kostecka LG, Pienta KJ, Amend SR. Polyaneuploid Cancer Cell Dormancy: Lessons From Evolutionary Phyla. Front Ecol Evol 2021. [DOI: 10.3389/fevo.2021.660755] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Dormancy is a key survival strategy in many organisms across the tree of life. Organisms that utilize some type of dormancy (hibernation, aestivation, brumation, diapause, and quiescence) are able to survive in habitats that would otherwise be uninhabitable. Induction into dormant states is typically caused by environmental stress. While organisms are dormant, their physical activity is minimal, and their metabolic rates are severely depressed (hypometabolism). These metabolic reductions allow for the conservation and distribution of energy while conditions in the environment are poor. When conditions are more favorable, the organisms are then able to come out of dormancy and reengage in their environment. Polyaneuploid cancer cells (PACCs), proposed mediators of cancer metastasis and resistance, access evolutionary programs and employ dormancy as a survival mechanism in response to stress. Quiescence, the type of dormancy observed in PACCs, allows these cells the ability to survive stressful conditions (e.g., hypoxia in the microenvironment, transiting the bloodstream during metastasis, and exposure to chemotherapy) by downregulating and altering metabolic function, but then increasing metabolic activities again once stress has passed. We can gain insights regarding the mechanisms underlying PACC dormancy by looking to the evolution of dormancy in different organisms.
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50
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Inhibition of CCL7 derived from Mo-MDSCs prevents metastatic progression from latency in colorectal cancer. Cell Death Dis 2021; 12:484. [PMID: 33986252 PMCID: PMC8119947 DOI: 10.1038/s41419-021-03698-5] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2020] [Revised: 03/25/2021] [Accepted: 04/07/2021] [Indexed: 02/07/2023]
Abstract
In colorectal cancer (CRC), overt metastases often appear after years of latency. But the signals that cause micro-metastatic cells to remain indolent, thereby enabling them to survive for extended periods of time, are unclear. Immunofluorescence and co-immunoprecipitation assays were used to explore the co-localization of CCL7 and CCR2. Immunohistochemical (IHC) assays were employed to detect the characters of metastatic HT29 cells in mice liver. Flow cytometry assays were performed to detect the immune cells. Bruberin vivo MS FX Pro Imager was used to observe the liver metastasis of CRC in mice. Quantitative real-time PCR (qRT-PCR) and western blot were employed to detect the expressions of related proteins. Trace RNA sequencing was employed to identify differentially expressed genes in MDSCs from liver micro-M and macro-M of CRC in mice. Here, we firstly constructed the vitro dormant cell models and metastatic dormant animal models of colorectal cancer. Then we found that myeloid-derived suppressor cells (MDSCs) were increased significantly from liver micro-metastases to macro-metastases of CRC in mice. Moreover, monocytic MDSCs (Mo-MDSC) significantly promoted the dormant activation of micro-metastatic cells compared to polymorphonuclear MDSCs (PMN-MDSC). Mechanistically, CCL7 secreted by Mo-MDSCs bound with membrane protein CCR2 of micro-metastatic cells and then stimulated the JAK/STAT3 pathway to activate the dormant cells. Low-dose administration of CCL7 and MDSCs inhibitors in vivo could significantly maintain the CRC metastatic cells dormant status for a long time to reduce metastasis or recurrence after radical operation. Clinically, the level of CCL7 in blood was positively related to the number of Mo-MDSCs in CCR patients, and highly linked with the short-time recurrence and distant metastasis. CCL7 secreted by Mo-MDSCs plays an important role in initiating the outgrowth of metastatic latent CRC cells. Inhibition of CCL7 might provide a potential therapeutic strategy for the prevention of metastasis recurrence.
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