|
1
|
Tavaglione F, Pennisi G, Pelusi S. PNPLA3 I148M and Hepatocellular Carcinoma. Liver Int 2025; 45:e70051. [PMID: 40029157 DOI: 10.1111/liv.70051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Revised: 02/20/2025] [Accepted: 02/21/2025] [Indexed: 03/05/2025]
Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. With the widespread implementation of HBV vaccination and the availability of highly effective antiviral therapies, the incidence of metabolic dysfunction-associated steatotic liver disease (MASLD)-related HCC has proportionally increased. Notably, up to 20%-30% of MASLD-related HCC cases develop in the absence of overt cirrhosis. Several genetic variants, primarily in genes related to lipid metabolism, play a key role in HCC development in individuals with MASLD and alcohol-related liver disease. Among these, the rs738409 C>G polymorphism (I148M) in the patatin-like phospholipase domain-containing protein 3 (PNPLA3) gene is the strongest genetic factor predisposing to the entire spectrum of MASLD conditions, including cirrhosis and HCC. Importantly, combining PNPLA3 I148M with multiple genetic variants robustly associated with progressive liver disease (i.e., polygenic risk scores) improves risk stratification and prediction of HCC in at-risk individuals compared to the single variant alone. In this review, we will discuss the latest evidence on the epidemiology of HCC and the contribution of PNPLA3 and PNPLA3-based polygenic risk scores to the development of HCC in at-risk individuals.
Collapse
Affiliation(s)
- Federica Tavaglione
- Division of Gastroenterology and Hepatology, MASLD Research Center, University of California at San Diego, La Jolla, California, USA
| | - Grazia Pennisi
- Section of Gastroenterology and Hepatology, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, Palermo, Italy
| | - Serena Pelusi
- Transfusion Medicine Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| |
Collapse
|
|
2
|
Guevara Lopez ML, Gebo A, Parodi M, Persano S, Maus-Conn J, Mingari MC, Loiacono F, Orecchia P, Sivori S, Cantoni C, Gentili M, Facchinetti F, Ferracini R, Vallera DA, Felices M, Bertolini G, Pravetoni M, Roz L, Vitale M. CD56 bright cytokine-induced memory-like NK cells and NK-cell engagers synergize against non-small cell lung cancer cancer-stem cells. J Immunother Cancer 2025; 13:e010205. [PMID: 39939140 PMCID: PMC11822435 DOI: 10.1136/jitc-2024-010205] [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: 07/26/2024] [Accepted: 01/24/2025] [Indexed: 02/14/2025] Open
Abstract
BACKGROUND Due to their enhanced responsiveness and persistence, cytokine-induced memory-like (CIML)-natural killer (NK) cells have emerged as new immunotherapeutic tools against malignancies. However, their effects on tumor-cell spread and metastases in solid tumors remain poorly investigated. Moreover, a clear identification of the most effective CIML-NK subsets, especially in controlling cancer stem cells (CSC), is still lacking. METHODS We performed combined phenotypical and functional analyses of CIML-NK cell subsets, either selected by flow-cytometry gating, or generated from sorted CD56bright/CD56dim NK cells.By co-culture experiments, we analyzed the effect of CIML-NK cells on non-small cell lung cancer (NSCLC) cell spheroids, or patient-derived xenografts (PDX), assessing changes in their CSC content, tumorigenicity, and/or tumor disseminating capability in vivo. CIML-NK cells were also infused in PDX-bearing mice to validate their effect on the CSC dissemination from the PDX to the lungs.Finally, we generated and functionally analyzed CIML-NK cells from patients with stages I/III NSCLC (n=6). RESULTS We show that CIML-NK cells exert antitumor activity mostly through their CD56bright cell subset, which greatly expands during CIML differentiation. Compared with NK cells conventionally activated with interleukin-2, CIML-NK cells express lower levels of check-point receptors, TIGIT and TIM3, and higher effector functions against NSCLC cells from PDX, and against in vitro-generated tumor spheroids. Remarkably, CIML-NK cells also significantly reduce the CSC-containing CD133+ cell subpopulation within spheroids and PDX, and limit tumor cell tumorigenicity and ability to disseminate CSCs from primary tumors to distant sites. Sorting experiments on CIML or tumor cell subsets reveal that CD56bright cells drive most of this anti-CSC activity, and suggest that such functional advantage could be related to increased expression of LFA-1 and ICAM-1 on CD56bright cells and CSCs, respectively. We also show that the tri-specific killer cell engager (TriKE) 1615133 significantly enhances CIML-NK cell activity against CSCs. Finally, we demonstrate that CIML-NK cells, capable of killing autologous tumor cells and responding to the 1615133 TriKE, could be induced from patients with NSCLC. CONCLUSIONS Our study discloses for the first time the therapeutic potential of CIML-NK cells in controlling CSCs and metastatic spread, highlighting the role of the CD56bright subset expansion and 1615133 TriKE for optimizing CIML-NK-based therapies against metastatic tumors.
Collapse
Affiliation(s)
- Maria L Guevara Lopez
- Department of Experimental Medicine (DIMES), University of Genoa, Genova, Italy
- Department of Pharmacology, University of Minnesota, Minneapolis, Minnesota, USA
- Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy
| | - Ann Gebo
- Department of Pharmacology, University of Minnesota, Minneapolis, Minnesota, USA
| | - Monica Parodi
- IRCCS Ospedale Policlinico San Martino, Genova, Italy
| | - Stefano Persano
- Department of Pharmacology, University of Minnesota, Minneapolis, Minnesota, USA
| | - Josephine Maus-Conn
- Department of Pharmacology, University of Minnesota, Minneapolis, Minnesota, USA
| | | | | | | | - Simona Sivori
- Department of Experimental Medicine (DIMES), University of Genoa, Genova, Italy
- IRCCS Ospedale Policlinico San Martino, Genova, Italy
| | - Claudia Cantoni
- Department of Experimental Medicine (DIMES), University of Genoa, Genova, Italy
- Laboratory of Clinical and Experimental Imunology Department of Services, IRCCS Istituto Giannina Gaslini, Genova, Italy
| | - Marco Gentili
- Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy
| | | | - Riccardo Ferracini
- Ospedale Koelliker, Turin, Italy
- Department of Integrated Surgical and Diagnostic Sciences, University of Genoa, Genova, Italy
| | - Daniel A Vallera
- Department of Radiation Oncology, University of Minnesota, Minneapolis, Minnesota, USA
| | - Martin Felices
- Hematology, Oncology, and Transplantation, University of Minnesota, Minneapolis, Minnesota, USA
| | | | - Marco Pravetoni
- Department of Pharmacology, University of Minnesota, Minneapolis, Minnesota, USA
- Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington, USA
| | - Luca Roz
- Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy
| | | |
Collapse
|
|
3
|
Park J, Lee YT, Agopian VG, Liu JS, Koltsova EK, You S, Zhu Y, Tseng HR, Yang JD. Liquid biopsy in hepatocellular carcinoma: Challenges, advances, and clinical implications. Clin Mol Hepatol 2025; 31:S255-S284. [PMID: 39604328 PMCID: PMC11925447 DOI: 10.3350/cmh.2024.0541] [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: 07/10/2024] [Revised: 11/15/2024] [Accepted: 11/25/2024] [Indexed: 11/29/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is an aggressive primary liver malignancy often diagnosed at an advanced stage, resulting in a poor prognosis. Accurate risk stratification and early detection of HCC are critical unmet needs for improving outcomes. Several blood-based biomarkers and imaging tests are available for early detection, prediction, and monitoring of HCC. However, serum protein biomarkers such as alpha-fetoprotein have shown relatively low sensitivity, leading to inaccurate performance. Imaging studies also face limitations related to suboptimal accuracy, high cost, and limited implementation. Recently, liquid biopsy techniques have gained attention for addressing these unmet needs. Liquid biopsy is non-invasive and provides more objective readouts, requiring less reliance on healthcare professional's skills compared to imaging. Circulating tumor cells, cell-free DNA, and extracellular vesicles are targeted in liquid biopsies as novel biomarkers for HCC. Despite their potential, there are debates regarding the role of these novel biomarkers in the HCC care continuum. This review article aims to discuss the technical challenges, recent technical advancements, advantages and disadvantages of these liquid biopsies, as well as their current clinical application and future directions of liquid biopsy in HCC.
Collapse
Affiliation(s)
- Jaeho Park
- Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Yi-Te Lee
- Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Vatche G. Agopian
- Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA, USA
- Department of Surgery, University of California Los Angeles, Los Angeles, CA, USA
| | - Jessica S Liu
- Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL, USA
| | - Ekaterina K. Koltsova
- Smidt Heart Institute, Department of Medicine, Department of Biomedical Sciences, 8700 Beverly Blvd, Los Angeles, CA, USA
| | - Sungyong You
- Department of Urology and Computational Biomedicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Yazhen Zhu
- Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA, USA
- California NanoSystems Institute, Crump Institute for Molecular Imaging, Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA, USA
- Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA, USA
| | - Hsian-Rong Tseng
- Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA, USA
- California NanoSystems Institute, Crump Institute for Molecular Imaging, Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA, USA
| | - Ju Dong Yang
- Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| |
Collapse
|
|
4
|
Janjua D, Chaudhary A, Joshi U, Tripathi T, Bharti AC. Circulating tumor cells in solid malignancies: From advanced isolation technologies to biological understanding and clinical relevance in early diagnosis and prognosis. Biochim Biophys Acta Rev Cancer 2025; 1880:189236. [PMID: 39662757 DOI: 10.1016/j.bbcan.2024.189236] [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: 09/17/2024] [Revised: 12/03/2024] [Accepted: 12/03/2024] [Indexed: 12/13/2024]
Abstract
Circulating tumor cells (CTCs) are shed from primary tumors and travel through the body via circulation, eventually settling to form micrometastases under favorable conditions. Numerous studies have identified CTCs as a negative prognostic indicator for survival across various cancer types. CTCs mirror the current heterogeneity and genetic and biological state of tumors, making their study invaluable for understanding tumor progression, cell senescence, and cancer dormancy. However, their isolation and characterization still poses a major challenge that limits their clinical translation. A wide array of methods, each with different levels of specificity, utility, cost, and sensitivity, have been developed to isolate and characterize CTCs. Moreover, innovative techniques are emerging to address the limitations of existing methods. In this review, we provide insights into CTC biology addressing spectra of markers employed for molecular analysis and functional characterization. It also emphasizes current label-dependent and label-independent isolation procedures, addressing their strengths and limitations. SIGNIFICANCE: A comprehensive overview of CTC biology, their molecular and functional characterization, along with their current clinical utility will help in understanding the present-day extent to which the clinical potential of CTCs is getting tapped in personalized medicine.
Collapse
Affiliation(s)
- Divya Janjua
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi (North Campus), New Delhi, India
| | - Apoorva Chaudhary
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi (North Campus), New Delhi, India
| | - Udit Joshi
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi (North Campus), New Delhi, India
| | - Tanya Tripathi
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi (North Campus), New Delhi, India
| | - Alok Chandra Bharti
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi (North Campus), New Delhi, India.
| |
Collapse
|
|
5
|
Niu Q, Ye S, Zhao L, Qian Y, Liu F. The role of liver cancer stem cells in hepatocellular carcinoma metastasis. Cancer Biol Ther 2024; 25:2321768. [PMID: 38393655 PMCID: PMC10896152 DOI: 10.1080/15384047.2024.2321768] [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: 06/08/2023] [Accepted: 02/18/2024] [Indexed: 02/25/2024] Open
Abstract
Metastasis accounts for the vast majority of cancer deaths; however, this complex process has yet to be fully explained. To form metastases, cancer cells must undergo a series of steps, known as the "Metastatic cascade", each of which requires a specific functional transformation. Cancer stem cells (CSCs) play a vital role in tumor metastasis, but their dynamic behavior and regulatory mechanisms have not been fully elucidated. Based on the "Metastatic cascade" theory, this review summarizes the effect of liver CSCs on the metastatic biological programs that underlie the dissemination and metastatic growth of cancer cells. Liver CSCs have the capacity to initiate distant organ metastasis via EMT, and the microenvironment transformation that supports the ability of these cells to disseminate, evade immune surveillance, dormancy, and regenerate metastasis. Understanding the heterogeneity and traits of liver CSCs in these processes is critical for developing strategies to prevent and treat metastasis of advanced hepatocellular carcinoma (HCC).
Collapse
Affiliation(s)
- Qinghui Niu
- Liver Disease Center, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Susu Ye
- Liver Disease Center, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Liu Zhao
- Liver Disease Center, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Yanzhi Qian
- School Hospital, Qingdao University of Science and Technology, Qingdao, China
| | - Fengchao Liu
- Liver Disease Center, The Affiliated Hospital of Qingdao University, Qingdao, China
| |
Collapse
|
|
6
|
Wang Z, Li R, Yang G, Wang Y. Cancer stem cell biomarkers and related signalling pathways. J Drug Target 2024; 32:33-44. [PMID: 38095181 DOI: 10.1080/1061186x.2023.2295222] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Accepted: 12/10/2023] [Indexed: 12/20/2023]
Abstract
Cancer stem cells (CSCs) represent a distinct subset of neoplastic cells characterised by their heightened capacity for tumorigenesis. These cells are implicated in the facilitation of cancer metastasis, recurrence, and resistance to conventional therapeutic interventions. Extensive scientific research has been devoted to the identification of biomarkers and the elucidation of molecular mechanisms in order to improve targeted therapeutic approaches. Accurate identification of cancer stem cells based on biomarkers can provide a theoretical basis for drug combinations of malignant tumours. Targeted biomarker-based therapies also offer a silver lining for patients with advanced malignancies. This review aims comprehensively to consolidate the latest findings on CSCs biomarkers, targeted agents as well as biomarkers associated signalling pathways in well-established cancer types, thereby contributing to improved prognostic outcomes.
Collapse
Affiliation(s)
- Zhe Wang
- School of Medicine, Southern University of Science and Technology, Shenzhen, China
- Department of Infectious Disease, The First Affiliated Hospital, Southern University of Science and Technology, Shenzhen, China
| | - Rui Li
- School of Medicine, Southern University of Science and Technology, Shenzhen, China
| | - Guilin Yang
- Department of Infectious Disease, The First Affiliated Hospital, Southern University of Science and Technology, Shenzhen, China
| | - Yijin Wang
- School of Medicine, Southern University of Science and Technology, Shenzhen, China
| |
Collapse
|
|
7
|
Sarabia-Sánchez MA, Tinajero-Rodríguez JM, Ortiz-Sánchez E, Alvarado-Ortiz E. Cancer Stem Cell markers: Symphonic masters of chemoresistance and immune evasion. Life Sci 2024; 355:123015. [PMID: 39182567 DOI: 10.1016/j.lfs.2024.123015] [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: 04/21/2024] [Revised: 08/21/2024] [Accepted: 08/22/2024] [Indexed: 08/27/2024]
Abstract
Cancer Stem Cells (CSCs) are highly tumorigenic, chemoresistant, and immune evasive. They emerge as a central driver that gives rise to the bulk of tumoral mass, modifies the tumor microenvironment (TME), and exploits it, leading to poor clinical outcomes for patients with cancer. The existence of CSCs thus accounts for the failure of conventional therapies and immune surveillance. Identifying CSCs in solid tumors remains a significant challenge in modern oncology, with the use of cell surface markers being the primary strategy for studying, isolating, and enriching these cells. In this review, we explore CSC markers, focusing on the underlying signaling pathways that drive CSC self-renewal, which simultaneously makes them intrinsically chemoresistant and immune system evaders. We comprehensively discuss the autonomous and non-autonomous functions of CSCs, with particular emphasis on their interactions with the tumor microenvironment, especially immune cells. This reciprocal network enhances CSCs malignancy while compromising the surrounding niche, ultimately defining therapeutic vulnerabilities associated with each CSC marker. The most common CSCs surface markers addressed in this review-CD44, CD133, ICAM1/CD54, and LGR5-provide insights into the interplay between chemoresistance and immune evasion, two critically important phenomena in disease eradication. This new perspective on the state-of-the-art of CSCs will undoubtedly open new avenues for therapy.
Collapse
Affiliation(s)
- Miguel Angel Sarabia-Sánchez
- Subdirección de Investigación Básica, Instituto Nacional de Cancerología, Secretaría de Salud, Ciudad de México, México; Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México, México
| | - José Manuel Tinajero-Rodríguez
- Subdirección de Investigación Básica, Instituto Nacional de Cancerología, Secretaría de Salud, Ciudad de México, México; Tecnológico Nacional de México, Tecnológico de Estudios Superiores de Huixquilucan, México
| | - Elizabeth Ortiz-Sánchez
- Subdirección de Investigación Básica, Instituto Nacional de Cancerología, Secretaría de Salud, Ciudad de México, México
| | - Eduardo Alvarado-Ortiz
- Programa de Posgrado en Ciencias Biológicas, Universidad Nacional Autónoma de México, México; Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México, México.
| |
Collapse
|
|
8
|
Balaji N, Kukal S, Bhat A, Pradhan N, Minocha S, Kumar S. A quartet of cancer stem cell niches in hepatocellular carcinoma. Cytokine Growth Factor Rev 2024; 79:39-51. [PMID: 39217065 DOI: 10.1016/j.cytogfr.2024.08.007] [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: 07/03/2024] [Revised: 08/20/2024] [Accepted: 08/20/2024] [Indexed: 09/04/2024]
Abstract
Hepatocellular Carcinoma (HCC), the most prevalent type of primary liver cancer, is known for its aggressive behavior and poor prognosis. The Cancer Stem Cell theory, which postulates the presence of a small population of self-renewing cells called Cancer Stem Cells (CSCs), provides insights into various clinical and molecular features of HCC such as tumor heterogeneity, metabolic adaptability, therapy resistance, and recurrence. These CSCs are nurtured in the tumor microenvironment (TME), where a mix of internal and external factors creates a tumor-supportive niche that is continuously evolving both spatially and temporally, thus enhancing the tumor's complexity. This review details the origins of hepatic CSCs (HCSCs) and the factors influencing their stem-like qualities. It highlights the reciprocal crosstalk between HCSCs and the TME (hypoxic, vascular, invasive, and immune niches), exploring the signaling pathways involved and how these interactions control the malignant traits of CSCs. Additionally, it discusses potential therapeutic approaches targeting the HCSC niche and their possible uses in clinical practice.
Collapse
Affiliation(s)
- Neha Balaji
- Kusuma School of Biological Sciences, Indian Institute of Technology Delhi, 110016, India
| | - Samiksha Kukal
- Kusuma School of Biological Sciences, Indian Institute of Technology Delhi, 110016, India
| | - Anjali Bhat
- Kusuma School of Biological Sciences, Indian Institute of Technology Delhi, 110016, India
| | - Nikita Pradhan
- Kusuma School of Biological Sciences, Indian Institute of Technology Delhi, 110016, India
| | - Shilpi Minocha
- Kusuma School of Biological Sciences, Indian Institute of Technology Delhi, 110016, India.
| | - Saran Kumar
- Kusuma School of Biological Sciences, Indian Institute of Technology Delhi, 110016, India.
| |
Collapse
|
|
9
|
Ma Y, Lv H, Xing F, Xiang W, Wu Z, Feng Q, Wang H, Yang W. Cancer stem cell-immune cell crosstalk in the tumor microenvironment for liver cancer progression. Front Med 2024; 18:430-445. [PMID: 38600350 DOI: 10.1007/s11684-023-1049-z] [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: 06/09/2023] [Accepted: 11/15/2023] [Indexed: 04/12/2024]
Abstract
Crosstalk between cancer cells and the immune microenvironment is determinant for liver cancer progression. A tumor subpopulation called liver cancer stem cells (CSCs) significantly accounts for the initiation, metastasis, therapeutic resistance, and recurrence of liver cancer. Emerging evidence demonstrates that the interaction between liver CSCs and immune cells plays a crucial role in shaping an immunosuppressive microenvironment and determining immunotherapy responses. This review sheds light on the bidirectional crosstalk between liver CSCs and immune cells for liver cancer progression, as well as the underlying molecular mechanisms after presenting an overview of liver CSCs characteristic and their microenvironment. Finally, we discuss the potential application of liver CSCs-targeted immunotherapy for liver cancer treatment.
Collapse
Affiliation(s)
- Yue Ma
- Cancer Research Center, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China
- National Center for Liver Cancer, Naval Medical University (Second Military Medical University), Shanghai, 201805, China
| | - Hongwei Lv
- Cancer Research Center, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China
- National Center for Liver Cancer, Naval Medical University (Second Military Medical University), Shanghai, 201805, China
- International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Naval Medical University (Second Military Medical University), Shanghai, 200438, China
| | - Fuxue Xing
- Cancer Research Center, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China
- National Center for Liver Cancer, Naval Medical University (Second Military Medical University), Shanghai, 201805, China
| | - Wei Xiang
- Cancer Research Center, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China
- National Center for Liver Cancer, Naval Medical University (Second Military Medical University), Shanghai, 201805, China
| | - Zixin Wu
- Cancer Research Center, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China
- National Center for Liver Cancer, Naval Medical University (Second Military Medical University), Shanghai, 201805, China
| | - Qiyu Feng
- Cancer Research Center, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China
- National Center for Liver Cancer, Naval Medical University (Second Military Medical University), Shanghai, 201805, China
| | - Hongyang Wang
- Cancer Research Center, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China.
- National Center for Liver Cancer, Naval Medical University (Second Military Medical University), Shanghai, 201805, China.
- International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Naval Medical University (Second Military Medical University), Shanghai, 200438, China.
- Shanghai Key Laboratory of Hepato-biliary Tumor Biology, Shanghai, 200438, China.
- Key Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer, Ministry of Education, Shanghai, 200438, China.
| | - Wen Yang
- Cancer Research Center, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China.
- National Center for Liver Cancer, Naval Medical University (Second Military Medical University), Shanghai, 201805, China.
- International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Naval Medical University (Second Military Medical University), Shanghai, 200438, China.
- Shanghai Key Laboratory of Hepato-biliary Tumor Biology, Shanghai, 200438, China.
- Key Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer, Ministry of Education, Shanghai, 200438, China.
| |
Collapse
|
|
10
|
Ryan AT, Kim M, Lim K. Immune Cell Migration to Cancer. Cells 2024; 13:844. [PMID: 38786066 PMCID: PMC11120175 DOI: 10.3390/cells13100844] [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: 03/23/2024] [Revised: 04/27/2024] [Accepted: 05/03/2024] [Indexed: 05/25/2024] Open
Abstract
Immune cell migration is required for the development of an effective and robust immune response. This elegant process is regulated by both cellular and environmental factors, with variables such as immune cell state, anatomical location, and disease state that govern differences in migration patterns. In all cases, a major factor is the expression of cell surface receptors and their cognate ligands. Rapid adaptation to environmental conditions partly depends on intrinsic cellular immune factors that affect a cell's ability to adjust to new environment. In this review, we discuss both myeloid and lymphoid cells and outline key determinants that govern immune cell migration, including molecules required for immune cell adhesion, modes of migration, chemotaxis, and specific chemokine signaling. Furthermore, we summarize tumor-specific elements that contribute to immune cell trafficking to cancer, while also exploring microenvironment factors that can alter these cellular dynamics within the tumor in both a pro and antitumor fashion. Specifically, we highlight the importance of the secretome in these later aspects. This review considers a myriad of factors that impact immune cell trajectory in cancer. We aim to highlight the immunotherapeutic targets that can be harnessed to achieve controlled immune trafficking to and within tumors.
Collapse
Affiliation(s)
- Allison T. Ryan
- Department of Microbiology and Immunology, University of Rochester, Rochester, NY 14642, USA; (A.T.R.); (M.K.)
- David H. Smith Center for Vaccine Biology and Immunology, University of Rochester, Rochester, NY 14642, USA
| | - Minsoo Kim
- Department of Microbiology and Immunology, University of Rochester, Rochester, NY 14642, USA; (A.T.R.); (M.K.)
- David H. Smith Center for Vaccine Biology and Immunology, University of Rochester, Rochester, NY 14642, USA
| | - Kihong Lim
- Department of Microbiology and Immunology, University of Rochester, Rochester, NY 14642, USA; (A.T.R.); (M.K.)
- David H. Smith Center for Vaccine Biology and Immunology, University of Rochester, Rochester, NY 14642, USA
| |
Collapse
|
|
11
|
Uong TNT, Yoon M, Chung IJ, Nam TK, Ahn SJ, Jeong JU, Song JY, Kim YH, Nguyen HPQ, Cho D, Chu TH, Dang GC, Nguyen NPNM. Direct Tumor Irradiation Potentiates Adoptive NK Cell Targeting Against Parental and Stemlike Cancer in Human Liver Cancer Models. Int J Radiat Oncol Biol Phys 2024; 119:234-250. [PMID: 37981041 DOI: 10.1016/j.ijrobp.2023.11.023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2023] [Revised: 10/09/2023] [Accepted: 11/11/2023] [Indexed: 11/21/2023]
Abstract
PURPOSE Radiation therapy (RT) has been shown to effectively induce the expression of intercellular adhesion molecule-1 (ICAM-1), which is recognized by lymphocyte function-associated antigen 1 (LFA-1) expressed on natural killer (NK) cells. However, the potential synergistic antitumor immune response of tumor irradiation and administered NK cells has not been explored in intractable human liver cancers. Furthermore, NK cell targeting against both parental and cancer stemness has never been investigated. METHODS AND MATERIALS Highly activated ex vivo NK cells were administered into the human liver tumor-bearing mice. Tumor direct RT was optimized according to tumor bearing site. HepG2 and Hep3B ICAM-1 knockout cells were generated using CRISPR/CAS9. Stemness tumor spheres were generated. NK cell cytolysis against parental and tumor sphere was evaluated using flow cytometry and real-time cytotoxicity assay. RESULTS A combination of adoptive NK cell therapy with RT significantly improved therapeutic efficacy over monotherapies against subcutaneous, orthotopic, and metastatic human liver tumor models. Direct tumor irradiation potentiated NK cell recognition and conjugation against liver cancer through the LFA-1/ICAM-1 axis. Suppression of immune synapse formation on NK cells using high-affinity LFA-1 inhibitors or ICAM-1 knockout liver cancer induced "outside-in" signal blocking in NK cells, resulting in failure to eliminate liver tumor despite the combination therapy. NK cells effectively recognized and targeted triple-high epithelial cell adhesion molecule+CD133+CD24+ liver cancer expressing upregulated ICAM-1 in the irradiated tumor microenvironment, which led to prevention of the initiation of metastasis, improving survival in a metastatic model. In addition, the LFA-1/ICAM-1 axis interruption between NK cells and stemness liver tumor spheres significantly diminished NK cell cytolysis. Consistent with our preclinical data, the LFA-1/ICAM-1 axis correlated with survival outcomes in patients with metastatic cancer from the The Cancer Genome Atlas databases. CONCLUSIONS NK cells in combination with tumor irradiation can provide synergistic therapeutic effects for NK cell recognition and elimination against both parental and stemlike liver cancer through LFA-1/ICAM-1.
Collapse
Affiliation(s)
- Tung Nguyen Thanh Uong
- Department of Radiation Oncology, Chonnam National University Hwasun Hospital, Chonnam National University Medical School, Gwangju, Republic of Korea; Department of Biomedical Science, Chonnam National University Graduate School, Gwangju, Republic of Korea
| | - Meesun Yoon
- Department of Radiation Oncology, Chonnam National University Hwasun Hospital, Chonnam National University Medical School, Gwangju, Republic of Korea; Department of Biomedical Science, Chonnam National University Graduate School, Gwangju, Republic of Korea; Immunotherapy Innovation Center, Chonnam National University Medical School, Hwasun, Republic of Korea.
| | - Ik-Joo Chung
- Immunotherapy Innovation Center, Chonnam National University Medical School, Hwasun, Republic of Korea; Department of Hematology and Oncology, Chonnam National University Medical School and Hwasun Hospital, Hwasun, Republic of Korea
| | - Taek-Keun Nam
- Department of Radiation Oncology, Chonnam National University Hwasun Hospital, Chonnam National University Medical School, Gwangju, Republic of Korea
| | - Sung-Ja Ahn
- Department of Radiation Oncology, Chonnam National University Hwasun Hospital, Chonnam National University Medical School, Gwangju, Republic of Korea
| | - Jae-Uk Jeong
- Department of Radiation Oncology, Chonnam National University Hwasun Hospital, Chonnam National University Medical School, Gwangju, Republic of Korea
| | - Ju-Young Song
- Department of Radiation Oncology, Chonnam National University Hwasun Hospital, Chonnam National University Medical School, Gwangju, Republic of Korea
| | - Yong-Hyub Kim
- Department of Radiation Oncology, Chonnam National University Hwasun Hospital, Chonnam National University Medical School, Gwangju, Republic of Korea
| | - Huy Phuoc Quang Nguyen
- Department of Radiation Oncology, Chonnam National University Hwasun Hospital, Chonnam National University Medical School, Gwangju, Republic of Korea; Department of Biomedical Science, Chonnam National University Graduate School, Gwangju, Republic of Korea
| | - Duck Cho
- Department of Laboratory Medicine & Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Tan-Huy Chu
- Department of Hematology, Pham Ngoc Thach University of Medicine, Vietnam
| | - Giang Chau Dang
- Department of Biomedical Science, Chonnam National University Graduate School, Gwangju, Republic of Korea; Department of Microbiology and Combinatorial Tumor Immunotherapy Research Center, Chonnam National University Medical School, Gwangju, Republic of Korea
| | - Nhat Phuoc Nguong Minh Nguyen
- Department of Radiation Oncology, Chonnam National University Hwasun Hospital, Chonnam National University Medical School, Gwangju, Republic of Korea; Department of Biomedical Science, Chonnam National University Graduate School, Gwangju, Republic of Korea
| |
Collapse
|
|
12
|
Zhao H, Ling Y, He J, Dong J, Mo Q, Wang Y, Zhang Y, Yu H, Tang C. Potential targets and therapeutics for cancer stem cell-based therapy against drug resistance in hepatocellular carcinoma. Drug Resist Updat 2024; 74:101084. [PMID: 38640592 DOI: 10.1016/j.drup.2024.101084] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Revised: 03/22/2024] [Accepted: 04/06/2024] [Indexed: 04/21/2024]
Abstract
Hepatocellular carcinoma (HCC) is the most common digestive malignancyin the world, which is frequently diagnosed at late stage with a poor prognosis. For most patients with advanced HCC, the therapeutic options arelimiteddue to cancer occurrence of drug resistance. Hepatic cancer stem cells (CSCs) account for a small subset of tumor cells with the ability of self-renewal and differentiationin HCC. It is widely recognized that the presence of CSCs contributes to primary and acquired drug resistance. Therefore, hepatic CSCs-targeted therapy is considered as a promising strategy to overcome drug resistance and improve therapeutic outcome in HCC. In this article, we review drug resistance in HCC and provide a summary of potential targets for CSCs-based therapy. In addition, the development of CSCs-targeted therapeuticsagainst drug resistance in HCC is summarized in both preclinical and clinical trials. The in-depth understanding of CSCs-related drug resistance in HCC will favor optimization of the current therapeutic strategies and gain encouraging therapeutic outcomes.
Collapse
Affiliation(s)
- Hongxing Zhao
- Department of Radiology, First affiliated Hospital of Huzhou University, Huzhou, Zhejiang Province, China
| | - Yuhang Ling
- Central Laboratory, First affiliated Hospital of Huzhou University, Huzhou, Zhejiang Province, China; Huzhou Key Laboratory of Translational Medicine, First affiliated Hospital of Huzhou University, Huzhou, Zhejiang Province, China
| | - Jie He
- Department of Hepatology, First affiliated Hospital of Huzhou University, Huzhou, Zhejiang Province, China
| | - Jinling Dong
- Department of Hepatology, First affiliated Hospital of Huzhou University, Huzhou, Zhejiang Province, China
| | - Qinliang Mo
- Department of Hepatopancreatobiliary Surgery, First affiliated Hospital of Huzhou University, Huzhou, Zhejiang Province, China
| | - Yao Wang
- Department of Hepatopancreatobiliary Surgery, First affiliated Hospital of Huzhou University, Huzhou, Zhejiang Province, China
| | - Ying Zhang
- Central Laboratory, First affiliated Hospital of Huzhou University, Huzhou, Zhejiang Province, China; Department of Hepatology, First affiliated Hospital of Huzhou University, Huzhou, Zhejiang Province, China
| | - Hongbin Yu
- Department of General Surgery, First affiliated Hospital of Huzhou University, Huzhou, Zhejiang Province, China
| | - Chengwu Tang
- Huzhou Key Laboratory of Translational Medicine, First affiliated Hospital of Huzhou University, Huzhou, Zhejiang Province, China; Department of Hepatopancreatobiliary Surgery, First affiliated Hospital of Huzhou University, Huzhou, Zhejiang Province, China.
| |
Collapse
|
|
13
|
Zhan Q, Liu B, Situ X, Luo Y, Fu T, Wang Y, Xie Z, Ren L, Zhu Y, He W, Ke Z. New insights into the correlations between circulating tumor cells and target organ metastasis. Signal Transduct Target Ther 2023; 8:465. [PMID: 38129401 PMCID: PMC10739776 DOI: 10.1038/s41392-023-01725-9] [Citation(s) in RCA: 31] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Revised: 12/07/2023] [Accepted: 12/08/2023] [Indexed: 12/23/2023] Open
Abstract
Organ-specific metastasis is the primary cause of cancer patient death. The distant metastasis of tumor cells to specific organs depends on both the intrinsic characteristics of the tumor cells and extrinsic factors in their microenvironment. During an intermediate stage of metastasis, circulating tumor cells (CTCs) are released into the bloodstream from primary and metastatic tumors. CTCs harboring aggressive or metastatic features can extravasate to remote sites for continuous colonizing growth, leading to further lesions. In the past decade, numerous studies demonstrated that CTCs exhibited huge clinical value including predicting distant metastasis, assessing prognosis and monitoring treatment response et al. Furthermore, increasingly numerous experiments are dedicated to identifying the key molecules on or inside CTCs and exploring how they mediate CTC-related organ-specific metastasis. Based on the above molecules, more and more inhibitors are being developed to target CTCs and being utilized to completely clean CTCs, which should provide promising prospects to administer advanced tumor. Recently, the application of various nanomaterials and microfluidic technologies in CTCs enrichment technology has assisted to improve our deep insights into the phenotypic characteristics and biological functions of CTCs as a potential therapy target, which may pave the way for us to make practical clinical strategies. In the present review, we mainly focus on the role of CTCs being involved in targeted organ metastasis, especially the latest molecular mechanism research and clinical intervention strategies related to CTCs.
Collapse
Affiliation(s)
- Qinru Zhan
- Department of Pathology, The First Affiliated Hospital of Sun Yat-sen University, 510000, Guangzhou, Guangdong, P.R. China
| | - Bixia Liu
- Department of Pathology, The First Affiliated Hospital of Sun Yat-sen University, 510000, Guangzhou, Guangdong, P.R. China
| | - Xiaohua Situ
- Department of Pathology, The First Affiliated Hospital of Sun Yat-sen University, 510000, Guangzhou, Guangdong, P.R. China
| | - Yuting Luo
- Department of Pathology, The First Affiliated Hospital of Sun Yat-sen University, 510000, Guangzhou, Guangdong, P.R. China
| | - Tongze Fu
- Department of Pathology, The First Affiliated Hospital of Sun Yat-sen University, 510000, Guangzhou, Guangdong, P.R. China
- Institute of Precision Medicine, The First Affiliated Hospital of Sun Yat-sen University, 510000, Guangzhou, Guangdong, P.R. China
| | - Yanxia Wang
- Zhongshan School of Medicine, Sun Yat-sen University, 510000, Guangzhou, Guangdong, P.R. China
| | - Zhongpeng Xie
- Zhongshan School of Medicine, Sun Yat-sen University, 510000, Guangzhou, Guangdong, P.R. China
| | - Lijuan Ren
- Department of Pathology, The First Affiliated Hospital of Sun Yat-sen University, 510000, Guangzhou, Guangdong, P.R. China
| | - Ying Zhu
- Department of Radiology, The First Affiliated Hospital of Sun Yat-sen University, 510000, Guangzhou, Guangdong, P.R. China.
| | - Weiling He
- Department of Microbiology and Immunology, Weill Cornell Medicine, New York, NY, 10065, USA.
- School of Medicine, Xiang'an Hospital of Xiamen University, Xiamen University, 361000, Xiamen, Fujian, P.R. China.
| | - Zunfu Ke
- Department of Pathology, The First Affiliated Hospital of Sun Yat-sen University, 510000, Guangzhou, Guangdong, P.R. China.
- Institute of Precision Medicine, The First Affiliated Hospital of Sun Yat-sen University, 510000, Guangzhou, Guangdong, P.R. China.
| |
Collapse
|
|
14
|
Kong R, Wei W, Man Q, Chen L, Jia Y, Zhang H, Liu Z, Cheng K, Mao C, Liu S. Hypoxia-induced circ-CDYL-EEF1A2 transcriptional complex drives lung metastasis of cancer stem cells from hepatocellular carcinoma. Cancer Lett 2023; 578:216442. [PMID: 37852428 DOI: 10.1016/j.canlet.2023.216442] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Revised: 09/24/2023] [Accepted: 10/11/2023] [Indexed: 10/20/2023]
Abstract
Hepatocellular carcinoma (HCC) is often associated with poor outcomes due to lung metastasis. ICAM-1+ circulating tumor cells, termed circulating cancer stem cells (CCSCs), possess stem cell-like characteristics. However, it is still unexplored how their presence indicates lung metastasis tendency, and particularly, what mechanism drives their lung metastasis. Here, we demonstrated that a preoperative CCSC count in 5 mL of blood (CCSC5) of >3 was a risk factor for lung metastasis in clinical HCC patients. The CSCs overexpressed with circ-CDYL entered the bloodstream and developed lung metastases in mice. Mechanistically, circ-CDYL promoted COL14A1 expression and thus ERK signaling to facilitate epithelial-mesenchymal transition. Furthermore, we uncovered that an RNA-binding protein, EEF1A2, acted as a novel transcriptional (co-) factor to cooperate with circ-CDYL and initiate COL14A1 transcription. A high circ-CDYL level is caused by HIF-1⍺-mediated transcriptional upregulation of its parental gene CDYL and splicing factor EIF4A3 under a hypoxia microenvironment. Hence, the hypoxia microenvironment enables the high-tendency lung metastasis of ICAM-1+ CCSCs through the HIF-1⍺/circ-CDYL-EEF1A2/COL14A1 axis, potentially allowing clinicians to preoperatively detect ICAM-1+ CCSCs as a real-time biomarker for precisely deciding HCC treatment strategies.
Collapse
Affiliation(s)
- Ruijiao Kong
- Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai, 200434, China; School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.
| | - Wenxin Wei
- Clinical Research Institute and Department of Hepatic Surgery, The Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, 200438, China
| | - Qiuhong Man
- Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai, 200434, China
| | - Liang Chen
- Department of Laboratory and Diagnosis, Changhai Hospital, Naval Medical University, Shanghai, 200433, China; No. 904 Hospital of the PLA Joint Logistics Support Force, Wuxi, 214000, China
| | - Yin Jia
- Department of Laboratory and Diagnosis, Changhai Hospital, Naval Medical University, Shanghai, 200433, China
| | - Hui Zhang
- Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai, 200434, China
| | - Zixin Liu
- Department of Hepatobiliary Pancreatic Surgery, Changhai Hospital, Naval Medical University, Shanghai, 200433, China
| | - Kai Cheng
- Department of Laboratory Medicine, Wusong Branch, Zhongshan Hospital, Fudan University, Shanghai, 200433, China
| | - Chuanbin Mao
- Department of Biomedical Engineering, The Chinese University of Hong Kong, Sha Tin, Hong Kong SAR, China; School of Materials Science & Engineering, Zhejiang University, Hangzhou, 310027, China.
| | - Shanrong Liu
- Department of Laboratory and Diagnosis, Changhai Hospital, Naval Medical University, Shanghai, 200433, China.
| |
Collapse
|
|
15
|
Abdellateif MS, Zekri ARN. Stem cell therapy for hepatocellular carcinoma and end-stage liver disease. J Egypt Natl Canc Inst 2023; 35:35. [PMID: 37926787 DOI: 10.1186/s43046-023-00194-z] [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: 12/19/2022] [Accepted: 10/20/2023] [Indexed: 11/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a major health problem worldwide, especially for patients who are suffering from end-stage liver disease (ESLD). The ESLD is considered a great challenge for clinicians due to the limited chance for liver transplantation, which is the only curative treatment for those patients. Stem cell-based therapy as a part of regenerative medicine represents a promising application for ESLD patients. Many clinical trials were performed to assess the utility of bone marrow-derived stem cells as a potential therapy for patients with liver diseases. The aim of the present study is to present and review the various types of stem cell-based therapy, including the mesenchymal stem cells (MSCs), BM-derived mononuclear cells (BM-MNCs), CD34 + hematopoietic stem cells (HSCs), induced pluripotent stem cells (iPSCs), and cancer stem cells.Though this type of therapy achieved promising results for the treatment of ESLD, however still there is a confounding data regarding its clinical application. A large body of evidence is highly required to evaluate the stem cell-based therapy after long-term follow-up, with respect to the incidence of toxicity, immunogenicity, and tumorigenesis that developed in many patients.
Collapse
Affiliation(s)
- Mona S Abdellateif
- Medical Biochemistry and Molecular Biology, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, 11976, Egypt.
| | - Abdel-Rahman N Zekri
- Molecular Virology and Immunology Unit, Cancer Biology Department, NCI, Cairo University, Cairo, 11976, Egypt
| |
Collapse
|
|
16
|
Zhang Q, Kong D, Yang Z, Li G, Cheng S, Feng L, Zhang K, Zhang W. Prognostic value of stem-like circulating tumor cells in patients with cancer: a systematic review and meta-analysis. Clin Exp Med 2023; 23:1933-1944. [PMID: 36735207 DOI: 10.1007/s10238-023-01009-0] [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: 11/09/2022] [Accepted: 01/23/2023] [Indexed: 02/04/2023]
Abstract
Despite increasing interest in the study of circulating tumor cells (CTC) subsets, especially epithelial-mesenchymal transition (EMT) and stem cells subsets of CTC that play a key role in tumor recurrence and metastasis, there is no evidence from meta-analyses that shows the correlation between stem-like CTCs and prognosis in cancer patients. Thus, we performed a meta-analysis to assess its prognostic value. Sixteen articles were screened by searching the PubMed, Embase, Cochrane, China National Knowledge Internet (CNKI) and Wanfang databases. The hazard ratio (HR) and 95% confidence interval (95% CI) extracted from each article were summarized. Patients with positive stem-like CTCs in peripheral blood had significantly shorter overall survival (OS, HR: 2.58, 95% CI 1.76-3.79, P < 0.00001), progression-free survival (PFS, HR: 2.21, 95% CI 1.26-3.89, P = 0.006) and disease-free survival (DFS, HR: 2.53, 95% CI: 1.12-5.70, P = 0.03). This study provides the first meta-analysis evidence for the prognostic value of stem-like CTCs, demonstrating that these cells are associated with poor prognosis in cancer patients.Systematic review registrationCRD42022322062.
Collapse
Affiliation(s)
- Qi Zhang
- State Key Laboratory of Molecular Oncology, Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Defeng Kong
- State Key Laboratory of Molecular Oncology, Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Zhenrong Yang
- State Key Laboratory of Molecular Oncology, Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Guoliang Li
- State Key Laboratory of Molecular Oncology, Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Shujun Cheng
- State Key Laboratory of Molecular Oncology, Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Lin Feng
- State Key Laboratory of Molecular Oncology, Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Kaitai Zhang
- State Key Laboratory of Molecular Oncology, Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
| | - Wen Zhang
- Department of Immunology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
| |
Collapse
|
|
17
|
Li Z, Zhao M, Qi X, Tang Y, Cheng S. Mechanisms of portal vein tumour thrombus formation and development in patients with hepatocellular carcinoma. J Cell Mol Med 2023; 27:2103-2111. [PMID: 37349905 PMCID: PMC10399540 DOI: 10.1111/jcmm.17808] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Revised: 05/17/2023] [Accepted: 06/01/2023] [Indexed: 06/24/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common and aggressive human malignancies worldwide. Portal vein tumour thrombus (PVTT) is considered one of most fearful complications of HCC and is strongly associated with a poor prognosis. Clarification of the mechanisms underlying the formation and development of PVTT is crucial for developing novel therapeutic strategies for HCC patients. Several studies have been made to uncover that tumour microenvironment, stem cells, abnormal gene expression and non-coding RNAs deregulation are associated with PVTT in patients with HCC in the last decade. However, the exact molecular mechanisms of PVTT in patients with HCC are still largely unknown. In the present review, we briefly summarized the molecular mechanisms underlying the formation and development of PVTT in HCC.
Collapse
Affiliation(s)
- Zhenli Li
- Department of Hepatobiliary SurgeryGeneral Hospital of Northern Theater CommandShenyangChina
- Department of General SurgeryThe 963rd Hospital of the Joint Service Support Force of the PLAJiamusiChina
| | - Mingda Zhao
- Department of Hepatobiliary SurgeryGeneral Hospital of Northern Theater CommandShenyangChina
- Dalian Medical UniversityDalianChina
| | - Xingshun Qi
- Department of GastroenterologyGeneral Hospital of Northern Theater CommandShenyangChina
| | - Yufu Tang
- Department of Hepatobiliary SurgeryGeneral Hospital of Northern Theater CommandShenyangChina
| | - Shuqun Cheng
- Sixth Department of Liver Surgery, Eastern Hepatobiliary Surgery HospitalSecond Military Medical UniversityShanghaiChina
| |
Collapse
|
|
18
|
Shaik MR, Sagar PR, Shaik NA, Randhawa N. Liquid Biopsy in Hepatocellular Carcinoma: The Significance of Circulating Tumor Cells in Diagnosis, Prognosis, and Treatment Monitoring. Int J Mol Sci 2023; 24:10644. [PMID: 37445822 DOI: 10.3390/ijms241310644] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Revised: 06/17/2023] [Accepted: 06/19/2023] [Indexed: 07/15/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is an aggressive malignancy with poor outcomes when diagnosed at an advanced stage. Current curative treatments are most effective in early-stage HCC, highlighting the importance of early diagnosis and intervention. However, existing diagnostic methods, such as radiological imaging, alpha-fetoprotein (AFP) testing, and biopsy, have limitations that hinder early diagnosis. AFP elevation is absent in a significant portion of tumors, and imaging may have low sensitivity for smaller tumors or in the presence of cirrhosis. Additionally, as our understanding of the molecular pathogenesis of HCC grows, there is an increasing need for molecular information about the tumors. Biopsy, although informative, is invasive and may not always be feasible depending on tumor location. In this context, liquid biopsy technology has emerged as a promising approach for early diagnosis, enabling molecular characterization and genetic profiling of tumors. This technique involves analyzing circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), or tumor-derived exosomes. CTCs are cancer cells shed from the primary tumor or metastatic sites and circulate in the bloodstream. Their presence not only allows for early detection but also provides insights into tumor metastasis and recurrence. By detecting CTCs in peripheral blood, real-time tumor-related information at the DNA, RNA, and protein levels can be obtained. This article provides an overview of CTCs and explores their clinical significance for early detection, prognosis, treatment selection, and monitoring treatment response in HCC, citing relevant literature.
Collapse
Affiliation(s)
- Mohammed Rifat Shaik
- Department of Medicine, University of Maryland Medical Center Midtown Campus, Baltimore, MD 21201, USA
| | - Prem Raj Sagar
- Department of Medicine, University of Maryland Medical Center Midtown Campus, Baltimore, MD 21201, USA
| | - Nishat Anjum Shaik
- Department of Medicine, University of Maryland Medical Center Midtown Campus, Baltimore, MD 21201, USA
| | | |
Collapse
|
|
19
|
Kim M, Jo KW, Kim H, Han ME, Oh SO. Genetic heterogeneity of liver cancer stem cells. Anat Cell Biol 2023; 56:94-108. [PMID: 36384888 PMCID: PMC9989795 DOI: 10.5115/acb.22.161] [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: 08/22/2022] [Revised: 10/27/2022] [Accepted: 10/27/2022] [Indexed: 11/19/2022] Open
Abstract
Cancer cell heterogeneity is a serious problem in the control of tumor progression because it can cause chemoresistance and metastasis. Heterogeneity can be generated by various mechanisms, including genetic evolution of cancer cells, cancer stem cells (CSCs), and niche heterogeneity. Because the genetic heterogeneity of CSCs has been poorly characterized, the genetic mutation status of CSCs was examined using Exome-Seq and RNA-Seq data of liver cancer. Here we show that different surface markers for liver cancer stem cells (LCSCs) showed a unique propensity for genetic mutations. Cluster of differentiation 133 (CD133)-positive cells showed frequent mutations in the IRF2, BAP1, and ERBB3 genes. However, leucine-rich repeat-containing G protein-coupled receptor 5-positive cells showed frequent mutations in the CTNNB1, RELN, and ROBO1 genes. In addition, some genetic mutations were frequently observed irrespective of the surface markers for LCSCs. BAP1 mutations was frequently observed in CD133-, CD24-, CD13-, CD90-, epithelial cell adhesion molecule-, or keratin 19-positive LCSCs. ASXL2, ERBB3, IRF2, TLX3, CPS1, and NFATC2 mutations were observed in more than three types of LCSCs, suggesting that common mechanisms for the development of these LCSCs. The present study provides genetic heterogeneity depending on the surface markers for LCSCs. The genetic heterogeneity of LCSCs should be considered in the development of LCSC-targeting therapeutics.
Collapse
Affiliation(s)
- Minjeong Kim
- Department of Anatomy, School of Medicine, Pusan National University, Yangsan, Korea
| | - Kwang-Woo Jo
- Department of Anatomy, School of Medicine, Pusan National University, Yangsan, Korea
| | - Hyojin Kim
- Department of Anatomy, School of Medicine, Pusan National University, Yangsan, Korea
| | - Myoung-Eun Han
- Department of Anatomy, School of Medicine, Pusan National University, Yangsan, Korea
| | - Sae-Ock Oh
- Department of Anatomy, School of Medicine, Pusan National University, Yangsan, Korea
| |
Collapse
|
|
20
|
Yan ZJ, Chen L, Wang HY. To be or not to be: The double-edged sword roles of liver progenitor cells. Biochim Biophys Acta Rev Cancer 2023; 1878:188870. [PMID: 36842766 DOI: 10.1016/j.bbcan.2023.188870] [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: 11/23/2022] [Revised: 01/11/2023] [Accepted: 01/28/2023] [Indexed: 02/28/2023]
Abstract
Given the liver's remarkable and unique regenerative capacity, researchers have long focused on liver progenitor cells (LPCs) and liver cancer stem cells (LCSCs). LPCs can differentiate into both hepatocytes and cholangiocytes. However, the mechanism underlying cell conversion and its distinct contribution to liver homeostasis and tumorigenesis remain unclear. In this review, we discuss the complicated conversions involving LPCs and LCSCs. As the critical intermediate state in malignant transformation, LPCs play double-edged sword roles. LPCs are not only involved in hepatic wound-healing responses by supplementing liver cells and bile duct cells in the damaged liver but may transform into LCSCs under dysregulation of key signaling pathways, resulting in refractory malignant liver tumors. Because LPC lineages are temporally and spatially dynamic, we discuss crucial LPC subgroups and summarize regulatory factors correlating with the trajectories of LPCs and LCSCs in the liver tumor microenvironment. This review elaborates on the double-edged sword roles of LPCs to help understand the liver's regenerative potential and tumor heterogeneity. Understanding the sources and transformations of LPCs is essential in determining how to exploit their regenerative capacity in the future.
Collapse
Affiliation(s)
- Zi-Jun Yan
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital/National Center for Liver Cancer, Shanghai 200438, PR China; Key Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer (SMMU), Ministry of Education, Shanghai 200438, PR China; Shanghai Key Laboratory of Hepatobiliary Tumor Biology (EHBH), Shanghai 200438, PR China
| | - Lei Chen
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital/National Center for Liver Cancer, Shanghai 200438, PR China; Key Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer (SMMU), Ministry of Education, Shanghai 200438, PR China; Shanghai Key Laboratory of Hepatobiliary Tumor Biology (EHBH), Shanghai 200438, PR China.
| | - Hong-Yang Wang
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital/National Center for Liver Cancer, Shanghai 200438, PR China; Key Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer (SMMU), Ministry of Education, Shanghai 200438, PR China; Shanghai Key Laboratory of Hepatobiliary Tumor Biology (EHBH), Shanghai 200438, PR China.
| |
Collapse
|
|
21
|
Hu X, Tian T, Zhang X, Sun Q, Chen Y, Jiang W. Neutrophil-to-lymphocyte and hypopharyngeal cancer prognosis: System review and meta-analysis. Head Neck 2023; 45:492-502. [PMID: 36367335 DOI: 10.1002/hed.27246] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Revised: 10/12/2022] [Accepted: 10/28/2022] [Indexed: 11/13/2022] Open
Abstract
Several studies have reported the value of neutrophil-to-lymphocyte ratio (NLR) for the prognosis of hypopharyngeal cancer. However, contradictory findings have also been published. We aimed to clarify the effect of NLR on the prognosis of hypopharyngeal cancer through meta-analysis. Systematic search of PubMed and other database with study selection and data extraction. The combined hazard ratio (HR) and 95% confidence intervals (CI) were calculated using STATA, applying either a fixed-effects or random-effects model. Meta-regression, subgroup analysis, and sensitivity analysis were used to analyze sources of heterogeneity. Publication bias were also assessed. This meta-analysis included 2232 patients with hypopharyngeal cancer from seven studies. The combined HR (OS, HR = 1.80, 95CI%, 1.14-2.82; PFS, HR = 1.88, 95CI%, 1.26-2.79) suggested that high NLR was associated with poor overall survival (OS) and progression-free survival (PFS). Pretreatment NLR can be used as an effective serological indicator to assess the prognosis of patients with hypopharyngeal cancer.
Collapse
Affiliation(s)
- Xianyang Hu
- Department of Otolaryngology - Head and Neck Surgery, Eye Ear Nose and Throat Hospital, Fudan University, Shanghai, China.,School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, China
| | - Tengfei Tian
- Department of Otolaryngology - Head and Neck Surgery, Eye Ear Nose and Throat Hospital, Fudan University, Shanghai, China
| | - Xueyan Zhang
- The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China
| | - Qin Sun
- Department of Otolaryngology - Head and Neck Surgery, Eye Ear Nose and Throat Hospital, Fudan University, Shanghai, China
| | - Yanyang Chen
- Department of Orthopedics, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Wenxiu Jiang
- Department of Otolaryngology - Head and Neck Surgery, Eye Ear Nose and Throat Hospital, Fudan University, Shanghai, China
| |
Collapse
|
|
22
|
Pallares-Rusiñol A, Bernuz M, Moura SL, Fernández-Senac C, Rossi R, Martí M, Pividori MI. Advances in exosome analysis. Adv Clin Chem 2022; 112:69-117. [PMID: 36642486 DOI: 10.1016/bs.acc.2022.09.002] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
There is growing demand for novel biomarkers that detect early stage disease as well as monitor clinical management and therapeutic strategies. Exosome analysis could provide the next advance in attaining that goal. Exosomes are membrane encapsulated biologic nanometric-sized particles of endocytic origin which are released by all cell types. Unfortunately, exosomes are exceptionally challenging to characterize with current technologies. Exosomes are between 30 and 200nm in diameter, a size that makes them out of the sensitivity range to most cell-oriented sorting or analysis platforms, i.e., traditional flow cytometers. The most common methods for targeting exosomes to date typically involve purification followed by the characterization and the specific determination of their cargo. The whole procedure is time consuming, requiring thus skilled personnel as well as laboratory facilities and benchtop instrumentation. The most relevant methodology for exosome isolation, characterization and quantification is addressed in this chapter, including the most up-to-date approaches to explore the potential usefulness of exosomes as biomarkers in liquid biopsies and in advanced nanomedicine.
Collapse
Affiliation(s)
- Arnau Pallares-Rusiñol
- Institute of Biotechnology and Biomedicine, Universitat Autònoma de Barcelona, Bellaterra, Spain; Grup de Sensors i Biosensors, Departament de Química, Universitat Autònoma de Barcelona, Bellaterra, Spain
| | - Mireia Bernuz
- Institute of Biotechnology and Biomedicine, Universitat Autònoma de Barcelona, Bellaterra, Spain; Grup de Sensors i Biosensors, Departament de Química, Universitat Autònoma de Barcelona, Bellaterra, Spain
| | - Silio Lima Moura
- Institute of Biotechnology and Biomedicine, Universitat Autònoma de Barcelona, Bellaterra, Spain; Grup de Sensors i Biosensors, Departament de Química, Universitat Autònoma de Barcelona, Bellaterra, Spain
| | - Carolina Fernández-Senac
- Institute of Biotechnology and Biomedicine, Universitat Autònoma de Barcelona, Bellaterra, Spain; Grup de Sensors i Biosensors, Departament de Química, Universitat Autònoma de Barcelona, Bellaterra, Spain
| | - Rosanna Rossi
- Institute of Biotechnology and Biomedicine, Universitat Autònoma de Barcelona, Bellaterra, Spain; Grup de Sensors i Biosensors, Departament de Química, Universitat Autònoma de Barcelona, Bellaterra, Spain
| | - Mercè Martí
- Institute of Biotechnology and Biomedicine, Universitat Autònoma de Barcelona, Bellaterra, Spain
| | - María Isabel Pividori
- Institute of Biotechnology and Biomedicine, Universitat Autònoma de Barcelona, Bellaterra, Spain; Grup de Sensors i Biosensors, Departament de Química, Universitat Autònoma de Barcelona, Bellaterra, Spain.
| |
Collapse
|
|
23
|
Hsieh CY, Lin CC, Huang YW, Chen JH, Tsou YA, Chang LC, Fan CC, Lin CY, Chang WC. Macrophage secretory IL-1β promotes docetaxel resistance in head and neck squamous carcinoma via SOD2/CAT-ICAM1 signaling. JCI Insight 2022; 7:157285. [PMID: 36264639 PMCID: PMC9746909 DOI: 10.1172/jci.insight.157285] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Accepted: 10/18/2022] [Indexed: 01/12/2023] Open
Abstract
Docetaxel (DTX) combined with cisplatin and 5-fluorouracil has been used as induction chemotherapy for head and neck squamous cell carcinoma (HNSCC). However, the development of acquired resistance remains a major obstacle to treatment response. Tumor-associated macrophages are associated with chemotherapeutic resistance. In the present study, increased infiltration of macrophages into the tumor microenvironment (TME) was significantly associated with shorter overall survival and increased resistance to chemotherapeutic drugs, particularly DTX, in patients with HNSCC. Macrophage coculture induced expression of intercellular adhesion molecule 1 (ICAM1), which promotes stemness and the formation of polyploid giant cancer cells, thereby reducing the efficacy of DTX. Both genetic silencing and pharmacological inhibition of ICAM1 sensitized HNSCC to DTX. Macrophage secretion of IL-1β was found to induce tumor expression of ICAM1. IL-1β neutralization and IL-1 receptor blockade reversed DTX resistance induced by macrophage coculture. IL-1β activated superoxide dismutase 2 and inhibited catalase, thereby modulating intracellular levels of ROS and inducing ICAM1 expression. Arsenic trioxide (ATO) reduced macrophage infiltration into the TME and impaired IL-1β secretion by macrophages. The combinatorial use of ATO enhanced the in vivo efficacy of DTX in a mouse model, which may provide a revolutionary approach to overcoming acquired therapeutic resistance in HNSCC.
Collapse
Affiliation(s)
- Ching-Yun Hsieh
- Division of Hematology and Oncology, Department of Internal Medicine, China Medical University Hospital, China Medical University, Taichung, Taiwan
| | - Ching-Chan Lin
- Division of Hematology and Oncology, Department of Internal Medicine, China Medical University Hospital, China Medical University, Taichung, Taiwan
| | - Yu-Wen Huang
- Department of Medical Research, MacKay Memorial Hospital, Taipei, Taiwan
| | - Jong-Hang Chen
- Division of Hematology and Oncology, Department of Internal Medicine, China Medical University Hospital, China Medical University, Taichung, Taiwan
| | - Yung-An Tsou
- Department of Otolaryngology-Head and Neck Surgery and
| | - Ling-Chu Chang
- Center for Molecular Medicine, China Medical University Hospital, China Medical University, Taichung, Taiwan.,Chinese Medicinal Research and Development Center, China Medical University Hospital, and,Department of Biological Science and Technology, China Medical University, Taichung, Taiwan
| | - Chi-Chen Fan
- Department of Research and Development, Marker Exploration Corporation, Taipei, Taiwan.,Department of Medical Laboratory Science and Biotechnology, Yuanpei University of Medical Technology, Hsinchu, Taiwan
| | - Chen-Yuan Lin
- Division of Hematology and Oncology, Department of Internal Medicine, China Medical University Hospital, China Medical University, Taichung, Taiwan
| | - Wei-Chao Chang
- Center for Molecular Medicine, China Medical University Hospital, China Medical University, Taichung, Taiwan
| |
Collapse
|
|
24
|
Yang M, Zhan Y, Hou Z, Wang C, Fan W, Guo T, Li Z, Fang L, Lv S, Li S, Gu C, Ye M, Qin H, Liu Q, Cui X. VLDLR disturbs quiescence of breast cancer stem cells in a ligand-independent function. Front Oncol 2022; 12:887035. [PMID: 36568166 PMCID: PMC9767959 DOI: 10.3389/fonc.2022.887035] [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: 03/01/2022] [Accepted: 11/11/2022] [Indexed: 12/12/2022] Open
Abstract
Breast cancer stem cells are responsible for cancer initiation, progression, and drug resistance. However, effective targeting strategies against the cell subpopulation are still limited. Here, we unveil two splice variants of very-low-density lipoprotein receptor, VLDLR-I and -II, which are highly expressed in breast cancer stem cells. In breast cancer cells, VLDLR silencing suppresses sphere formation abilities in vitro and tumor growth in vivo. We find that VLDLR knockdown induces transition from self-renewal to quiescence. Surprisingly, ligand-binding activity is not involved in the cancer-promoting functions of VLDLR-I and -II. Proteomic analysis reveals that citrate cycle and ribosome biogenesis-related proteins are upregulated in VLDLR-I and -II overexpressed cells, suggesting that VLDLR dysregulation is associated with metabolic and anabolic regulation. Moreover, high expression of VLDLR in breast cancer tissues correlates with poor prognosis of patients. Collectively, these findings indicate that VLDLR may be an important therapeutic target for breast cancer treatment.
Collapse
Affiliation(s)
- Mengying Yang
- The First Affiliated Hospital, Dalian Medical University, Dalian, China,Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, Dalian, China,State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, Guangzhou, China
| | - Yajing Zhan
- Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, Dalian, China
| | - Zhijie Hou
- Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, Dalian, China
| | - Chunli Wang
- Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, Dalian, China
| | - Wenjun Fan
- Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, Dalian, China
| | - Tao Guo
- The First Affiliated Hospital, Dalian Medical University, Dalian, China
| | - Zhuoshi Li
- The First Affiliated Hospital, Dalian Medical University, Dalian, China
| | - Lei Fang
- The First Affiliated Hospital, Dalian Medical University, Dalian, China
| | - Shasha Lv
- Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, Dalian, China
| | - Sisi Li
- Department of Pathology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Chundong Gu
- The First Affiliated Hospital, Dalian Medical University, Dalian, China
| | - Mingliang Ye
- Chinese Academy of Sciences (CAS) Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Science, Dalian, China
| | - Hongqiang Qin
- Chinese Academy of Sciences (CAS) Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Science, Dalian, China,*Correspondence: Xiaonan Cui, ; Quentin Liu, ; Hongqiang Qin,
| | - Quentin Liu
- Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, Dalian, China,State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, Guangzhou, China,*Correspondence: Xiaonan Cui, ; Quentin Liu, ; Hongqiang Qin,
| | - Xiaonan Cui
- The First Affiliated Hospital, Dalian Medical University, Dalian, China,*Correspondence: Xiaonan Cui, ; Quentin Liu, ; Hongqiang Qin,
| |
Collapse
|
|
25
|
Sun R, Gao Y, Shen F. Identification of subtypes of hepatocellular carcinoma and screening of prognostic molecular diagnostic markers based on cell adhesion molecule related genes. Front Genet 2022; 13:1042540. [PMID: 36482887 PMCID: PMC9723242 DOI: 10.3389/fgene.2022.1042540] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Accepted: 11/09/2022] [Indexed: 10/03/2023] Open
Abstract
Cell adhesion molecules can predict liver hepatocellular carcinoma (LIHC) metastasis and determine prognosis, while the mechanism of the role of cell adhesion molecules in LIHC needs to be further explored. LIHC-related expression data were sourced from The Cancer Genome Atlas (TCGA) and the gene expression omnibus (GEO) databases, and genes related to cell adhesion were sourced from the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. First, the TCGA-LIHC dataset was clustered by the nonnegative matrix factorization (NMF) algorithm to find different subtypes of LIHC. Then the difference of prognosis and immune microenvironment between patients of different subtypes was evaluated. In addition, a prognostic risk model was obtained by least shrinkage and selection operator (LASSO) and Cox analysis, while a nomogram was drawn. Furthermore, functional enrichment analysis between high and low risk groups was conducted. Finally, the expressions of model genes were explored by quantitative real-time polymerase chain reaction (qRT-PCR). The 371 LIHC patients were classified into four subtypes by NMF clustering, and survival analysis revealed that disease-free survival (DFS) of these four subtypes were clearly different. Cancer-related pathways and immune microenvironment among these four subtypes were dysregulated. Moreover, 58 common differentially expressed genes (DEGs) between four subtypes were identified and were mainly associated with PPAR signaling pathway and amino acid metabolism. Furthermore, a prognostic model consisting of IGSF11, CD8A, ALCAM, CLDN6, JAM2, ITGB7, SDC3, CNTNAP1, and MPZ was built. A nomogram consisting of pathologic T and riskScore was built, and the calibration curve illustrated that the nomogram could better forecast LIHC prognosis. Gene Set Enrichment Analysis (GSEA) demonstrated that DEGs between high and low risk groups were mainly involved in cell cycle. Finally, the qRT-PCR illustrated the expressions of nine model genes between normal and LIHC tissue. A prognostic model consisting of IGSF11, CD8A, ALCAM, CLDN6, JAM2, ITGB7, SDC3, CNTNAP1, and MPZ was obtained, which provides an important reference for the molecular diagnosis of patient prognosis.
Collapse
Affiliation(s)
- Ruge Sun
- College of Medicine, Shanxi Medical University, Taiyuan, China
- Department of Gastroenterology and Hepatoloy, The First Hospital of Shanxi Medical University, Taiyuan, China
| | - Yanchao Gao
- Department of Hepatobiliary Surgery, Liaocheng People’s Hospital, Liaocheng, China
| | - Fengjun Shen
- Department of Gastroenterology and Hepatoloy, The First Hospital of Shanxi Medical University, Taiyuan, China
| |
Collapse
|
|
26
|
Xiao Y, Li Y, Shi D, Wang X, Dai S, Yang M, Kong L, Chen B, Huang X, Lin C, Liao W, Xu B, Chen X, Wang L, Chen X, Ouyang Y, Liu G, Li H, Song L. MEX3C-Mediated Decay of SOCS3 mRNA Promotes JAK2/STAT3 Signaling to Facilitate Metastasis in Hepatocellular Carcinoma. Cancer Res 2022; 82:4191-4205. [PMID: 36112698 DOI: 10.1158/0008-5472.can-22-1203] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Revised: 08/02/2022] [Accepted: 09/13/2022] [Indexed: 12/24/2022]
Abstract
Tumor metastasis is one of the major causes of high mortality in patients with hepatocellular carcinoma (HCC). Sustained activation of STAT3 signaling plays a critical role in HCC metastasis. RNA binding protein (RBP)-mediated posttranscriptional regulation is involved in the precise control of signal transduction, including STAT3 signaling. In this study, we investigated whether RBPs are important regulators of HCC metastasis. The RBP MEX3C was found to be significantly upregulated in highly metastatic HCC and correlated with poor prognosis in HCC. Mechanistically, MEX3C increased JAK2/STAT3 pathway activity by downregulating SOCS3, a major negative regulator of JAK2/STAT3 signaling. MEX3C interacted with the 3'UTR of SOCS3 and recruited CNOT7 to ubiquitinate and accelerate decay of SOCS3 mRNA. Treatment with MEX3C-specific antisense oligonucleotide significantly inhibited JAK2/STAT3 pathway activation, suppressing HCC migration in vitro and metastasis in vivo. These findings highlight a novel mRNA decay-mediated mechanism for the disruption of SOCS3-driven negative regulation of JAK2/STAT3 signaling, suggesting MEX3C may be a potential prognostic biomarker and promising therapeutic target in HCC. SIGNIFICANCE This study reveals that RNA-binding protein MEX3C induces SOCS3 mRNA decay to promote JAK2/STAT3 activation and tumor metastasis in hepatocellular carcinoma, identifying MEX3C targeting as a potential approach for treating metastatic disease.
Collapse
Affiliation(s)
- Yunyun Xiao
- Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Yue Li
- Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Dongni Shi
- Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Xiaoqing Wang
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Shuqin Dai
- Department of Medicinal Laboratory, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Muwen Yang
- Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Lingzhi Kong
- Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Boyu Chen
- Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Xinjian Huang
- Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Chuyong Lin
- Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Wenting Liao
- Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Benke Xu
- Department of Human Anatomy, School of Basic Medical Sciences, Yangtze University, Jingzhou, China
| | - Xin Chen
- Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences; Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, China
| | - Lishuai Wang
- Department of Medical Oncology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Xiangfu Chen
- Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Ying Ouyang
- Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Guozhen Liu
- School of Medicine, The Chinese University of Hong Kong, Shenzhen, China
| | - Heping Li
- Department of Medical Oncology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Libing Song
- Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.,Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences; Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, China
| |
Collapse
|
|
27
|
Mechanism of cordycepin enhancing doxorubicin against hepatocellular carcinoma in vitro and in vivo. J Funct Foods 2022. [DOI: 10.1016/j.jff.2022.105268] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
|
|
28
|
Cancer Stem Cells in Hepatocellular Carcinoma: Intrinsic and Extrinsic Molecular Mechanisms in Stemness Regulation. Int J Mol Sci 2022; 23:ijms232012327. [PMID: 36293184 PMCID: PMC9604119 DOI: 10.3390/ijms232012327] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Revised: 09/18/2022] [Accepted: 10/04/2022] [Indexed: 11/06/2022] Open
Abstract
Hepatocellular carcinoma (HCC) remains the most predominant type of liver cancer with an extremely poor prognosis due to its late diagnosis and high recurrence rate. One of the culprits for HCC recurrence and metastasis is the existence of cancer stem cells (CSCs), which are a small subset of cancer cells possessing robust stem cell properties within tumors. CSCs play crucial roles in tumor heterogeneity constitution, tumorigenesis, tumor relapse, metastasis, and resistance to anti-cancer therapies. Elucidation of how these CSCs maintain their stemness features is essential for the development of CSCs-based therapy. In this review, we summarize the present knowledge of intrinsic molecules and signaling pathways involved in hepatic CSCs, especially the CSC surface markers and associated signaling in regulating the stemness characteristics and the heterogeneous subpopulations within the CSC pool. In addition, we recapitulate the effects of crucial extrinsic cellular components in the tumor microenvironment, including stromal cells and immune cells, on the modulation of hepatic CSCs. Finally, we synopsize the currently valuable CSCs-targeted therapy strategies based on intervention in these intrinsic and extrinsic molecular mechanisms, in the hope of shedding light on better clinical management of HCC patients.
Collapse
|
|
29
|
Ding J, Zhao W. The Application of Liquid Biopsy Techniques in High-Risk Population for Hepatocellular Carcinoma. Cancer Manag Res 2022; 14:2735-2748. [PMID: 36133739 PMCID: PMC9484767 DOI: 10.2147/cmar.s373165] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Accepted: 08/27/2022] [Indexed: 12/01/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors of the digestive system and has a 5-year overall survival rate of 14.1%. Many HCC patients are diagnosed at an advanced stage, and thus early screening is essential for reducing the mortality of HCC. In addition to commonly used detection indicators such as serum alpha-fetoprotein (AFP), lens culinaris agglutinin-reactive fraction of alpha-fetoprotein (AFP-L3) and abnormal prothrombin (protein induced by vitamin K absence II, PIVKA-II), liquid biopsy techniques have been demonstrated to have diagnostic value in HCC detection. Compared with invasive procedures, liquid biopsy can detect circulatory metabolites of malignant neoplasms. Liquid biopsy techniques can detect circulating tumor cells, circulating tumor DNA, circulating RNA and exosomes and have been used in the early screening, diagnosis and prognostic evaluation of HCC. This paper reviews the molecular biological characteristics and application of different liquid biopsy techniques, and aim to highlight promising biomarkers that may be feasible options for early-stage HCC evaluation to improve early screening in populations at high risk for HCC.
Collapse
Affiliation(s)
- Jingnuo Ding
- Department of Infectious Diseases, The First Affiliated Hospital of Soochow University, Suzhou, JiangSu Province, 215000, People’s Republic of China
| | - Weifeng Zhao
- Department of Infectious Diseases, The First Affiliated Hospital of Soochow University, Suzhou, JiangSu Province, 215000, People’s Republic of China
| |
Collapse
|
|
30
|
Lin HW, Shen TJ, Chen PY, Chen TC, Yeh JH, Tsou SC, Lai CY, Chen CH, Chang YY. Particulate matter 2.5 exposure induces epithelial-mesenchymal transition via PI3K/AKT/mTOR pathway in human retinal pigment epithelial ARPE-19 cells. Biochem Biophys Res Commun 2022; 617:11-17. [PMID: 35689837 DOI: 10.1016/j.bbrc.2022.05.072] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Revised: 05/13/2022] [Accepted: 05/21/2022] [Indexed: 11/02/2022]
Abstract
Exposure to particulate matter 2.5 (PM2.5) has been linked to ocular surface diseases, yet knowledge of the molecular mechanism impacted on retina pathogenesis is limited. Therefore, the purpose of this study was to explore the effects and involved factors of PM2.5 exposure in human retinal pigment epithelial APRE-19 cells. Our data revealed a decreased cell viability and an increased migratory ability in APRE-19 cells after PM2.5 stimulation. The MMP-2 and MMP-9 protein levels were markedly increased while the MMPs regulators TIMP-1 and TIMP-2 were significantly reduced in PM2.5-exposed APRE-19 cells. PM2.5 also increased pro-MMP-2 expression in the cell culture supernatants. Additionally, PM2.5 promoted the EMT markers through the activation of PI3K/AKT/mTOR pathway. Moreover, the ICAM-1 production was also remarkably increased by PM2.5 but reduced by PI3K/AKT inhibitor LY294002 in APRE-19 cells. Taken together, these results suggest that PM2.5 promotes EMT in a PI3K/AKT/mTOR-dependent manner in the retinal pigment epithelium.
Collapse
Affiliation(s)
- Hui-Wen Lin
- Department of Optometry, Asia University, Taichung, Taiwan; Department of Medical Research, China Medical University Hospital, Taichung, Taiwan
| | - Ting-Jing Shen
- Department of Microbiology and Immunology, School of Medicine, Chung-Shan Medical University, and Clinical Laboratory, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Peng-Yu Chen
- Department of Optometry, Asia University, Taichung, Taiwan; Department of Medical Research, China Medical University Hospital, Taichung, Taiwan
| | - Tzu-Chun Chen
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - Jui-Hsuan Yeh
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - Shang-Chun Tsou
- Department of Nutrition, Chung Shan Medical University, Taichung, Taiwan
| | - Chane-Yu Lai
- Department of Occupational Safety and Health, Chung Shan Medical University, Taichung, Taiwan; Department of Occupational Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan.
| | - Chang-Han Chen
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan; Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan.
| | - Yuan-Yen Chang
- Department of Microbiology and Immunology, School of Medicine, Chung-Shan Medical University, and Clinical Laboratory, Chung Shan Medical University Hospital, Taichung, Taiwan.
| |
Collapse
|
|
31
|
Chen Q, Zou J, He Y, Pan Y, Yang G, Zhao H, Huang Y, Zhao Y, Wang A, Chen W, Lu Y. A narrative review of circulating tumor cells clusters: A key morphology of cancer cells in circulation promote hematogenous metastasis. Front Oncol 2022; 12:944487. [PMID: 36059616 PMCID: PMC9434215 DOI: 10.3389/fonc.2022.944487] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2022] [Accepted: 07/18/2022] [Indexed: 11/28/2022] Open
Abstract
Circulating tumor cells (CTCs) that survive in the blood are playing an important role in the metastasis process of tumor. In addition, they have become a tool for tumor diagnosis, prognosis and recurrence monitoring. CTCs can exist in the blood as individual cells or as clumps of aggregated cells. In recent years, more and more studies have shown that clustered CTCs have stronger metastasis ability compared to single CTCs. With the deepening of studies, scholars have found that cancer cells can combine not only with each other, but also with non-tumor cells present in the blood, such as neutrophils, platelets, etc. At the same time, it was confirmed that non-tumor cells bound to CTCs maintain the survival and proliferation of cancer cells through a variety of ways, thus promoting the occurrence and development of tumor. In this review, we collected information on tumorigenesis induced by CTC clusters to make a summary and a discussion about them. Although CTC clusters have recently been considered as a key role in the transition process, many characteristics of them remain to be deeply explored. A detailed understanding of their vulnerability can prospectively pave the way for new inhibitors for metastasis.
Collapse
Affiliation(s)
- Qiong Chen
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Jueyao Zou
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Yong He
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Yanhong Pan
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
- Department of Pharmacy, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Gejun Yang
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Han Zhao
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Ying Huang
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Yang Zhao
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
- Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine (TCM) Prevention and Treatment of Tumor, Nanjing, China
| | - Aiyun Wang
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
- Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine (TCM) Prevention and Treatment of Tumor, Nanjing, China
| | - Wenxing Chen
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
- Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine (TCM) Prevention and Treatment of Tumor, Nanjing, China
| | - Yin Lu
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
- Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine (TCM) Prevention and Treatment of Tumor, Nanjing, China
| |
Collapse
|
|
32
|
Hu X, Tian T, Sun Q, Jiang W. Prognostic value of the neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio in laryngeal cancer: What should we expect from a meta-analysis? Front Oncol 2022; 12:945820. [PMID: 36033468 PMCID: PMC9400104 DOI: 10.3389/fonc.2022.945820] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Accepted: 07/08/2022] [Indexed: 12/12/2022] Open
Abstract
Background Although many studies have shown the predictive value of the high neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) for various cancers, there are conflicting reports regarding their role in laryngeal cancer. This study aimed to evaluate the relationship between high NLR/PLR and laryngeal cancer prognosis with the help of meta-analysis. Methods PubMed, Embase and other databases were used to search relevant studies. The pooled hazard ratio (HR) and 95% confidence interval (CI) were calculated using either the random-effect-model or fixed-effect model. Sensitivity analyses and subgroups were used to explore potential sources of heterogeneity. Publication bias was also adopted. Result 5716 patients from 20 studies were involved in this meta-analysis. Pooled observed survival (OS) (HR=1.70, 95%CI, 1.41-2.04, p<0.001), progression-free survival (PFS) (HR=1.81, 95%CI, 1.47-2.23, p<0.001), and disease-free survival (DFS) (HR=1.86, 95%CI, 1.45-2.38, p<0.001) showed the prediction of high NLR for poor prognosis. It also suggested that high PLR predicted poor OS (HR=1.89, 95%CI, 1.21-2.94, p<0.001). Conclusion This study indicated that high NLR was associated with poor OS, PFS, and DFS in laryngeal cancer patients, and high PLR was related to poor OS. Both could be potential predictors of prognosis.
Collapse
Affiliation(s)
- Xianyang Hu
- School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, China
| | - Tengfei Tian
- Department of Otolaryngology-Head and Neck Surgery, Eye Ear Nose and Throat Hospital, Fudan University, Shanghai, China
| | - Qin Sun
- Department of Otolaryngology-Head and Neck Surgery, Eye Ear Nose and Throat Hospital, Fudan University, Shanghai, China
| | - Wenxiu Jiang
- Department of Otolaryngology-Head and Neck Surgery, Eye Ear Nose and Throat Hospital, Fudan University, Shanghai, China
- *Correspondence: Wenxiu Jiang,
| |
Collapse
|
|
33
|
Xue C, Gao Y, Sun Z, Li X, Zhang M, Yang Y, Han Q, Bai C, Zhao RC. Mesenchymal stem cells derived from adipose tissue accelerate the progression of colon cancer by inducing a MTCAF phenotype via ICAM1/STAT3/AKT axis. Front Oncol 2022; 12:837781. [PMID: 36016615 PMCID: PMC9398219 DOI: 10.3389/fonc.2022.837781] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Accepted: 06/28/2022] [Indexed: 11/13/2022] Open
Abstract
Previous studies have shown that the risk of colon cancer is greatly increased in people with obesity, and fat content in colorectal cancer tissue is increased in people with obesity. As an important part of tumor microenvironment, adipose-derived mesenchymal stem cells (MSCs) are also another important source of cancer-associated fibroblasts (CAFs), which may be one of the important mechanisms of affecting tumor progression. However, the mechanism is poorly defined. In the present study, CAFs were transformed from MSCs [MSC-transformed CAFs (MTCAFs)] by co-culturing with HCT116 cells. Bioinformatics and Western blotting analysis indicated a positive correlation between intercellular adhesion molecule-1(ICAM-1) and the progression of colon cancer. In clinical colon cancer specimens, we found that ICAM-1 was highly expressed and related to shorter disease-free survival, which might act as an indication for the progression of clinical colon cancer. Our data showed that ICAM-1 secreted from MTCAFs could positively promote the proliferation, migration, and invasion of colon cancer cells by activating signal transducer and activator of transcription 3 (STAT3) and Serine/threonine-protein kinase (AKT) signaling and that blocking ICAM-1 in MTCAFs reversed these effects. We further verified that ICAM-1 secreted from MTCAFs promoted tumor progression in vivo. Taken together, ICAM-1 plays a critical role in regulating tumor growth and metastasis, which could be a potential therapeutic target in colon cancer.
Collapse
Affiliation(s)
- Chunling Xue
- Beijing Key Laboratory, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Center of Excellence in Tissue Engineering Chinese Academy of Medical Sciences, Peking Union Medical College Hospital, Beijing, China
| | - Yang Gao
- Department of oncology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Zhao Sun
- Department of oncology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Xuechun Li
- Beijing Key Laboratory, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Center of Excellence in Tissue Engineering Chinese Academy of Medical Sciences, Peking Union Medical College Hospital, Beijing, China
| | - Mingjia Zhang
- Beijing Key Laboratory, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Center of Excellence in Tissue Engineering Chinese Academy of Medical Sciences, Peking Union Medical College Hospital, Beijing, China
| | - Ying Yang
- Department of oncology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Qin Han
- Beijing Key Laboratory, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Center of Excellence in Tissue Engineering Chinese Academy of Medical Sciences, Peking Union Medical College Hospital, Beijing, China
- *Correspondence: Qin Han, ; Chunmei Bai, ; Robert Chunhua Zhao,
| | - Chunmei Bai
- Department of oncology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
- *Correspondence: Qin Han, ; Chunmei Bai, ; Robert Chunhua Zhao,
| | - Robert Chunhua Zhao
- Beijing Key Laboratory, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Center of Excellence in Tissue Engineering Chinese Academy of Medical Sciences, Peking Union Medical College Hospital, Beijing, China
- *Correspondence: Qin Han, ; Chunmei Bai, ; Robert Chunhua Zhao,
| |
Collapse
|
|
34
|
Intratumoral IL-28B Gene Delivery Elicits Antitumor Effects by Remodeling of the Tumor Microenvironment in H22-Bearing Mice. J Immunol Res 2022; 2022:1345971. [PMID: 35935577 PMCID: PMC9352479 DOI: 10.1155/2022/1345971] [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: 12/15/2021] [Revised: 06/26/2022] [Accepted: 06/30/2022] [Indexed: 11/18/2022] Open
Abstract
IL-28B, belonging to type III interferons (IFN-λs), exhibits a potent antitumor activity with reduced regulated T cells (Tregs) population, yet the effect of IL-28B on the tumor microenvironment (TME) and if IL-28B can downregulate Tregs directly in vitro are still unknown. In this study, we investigated the effects of IL-28B on Tregs in the spleen and TME in H22 tumor-bearing mice and verified the downregulation of IL-28B on Tregs in vitro. We found that rAd-mIL-28B significantly inhibited tumor growth and reduced the frequency of splenic CD4+Foxp3+ T cells. The levels of CXCL13, ICAM-1, MCP-5, and IL-7 in the serum, and the levels of IL-15 and sFasL in the tumor tissue decreased significantly after rAd-mIL-28B treatment relative to rAd-EGFP. Furthermore, the percentage of CD8+ cells in the TME was significantly increased in the rAd-mIL-28B group compared with the untreated group. In vitro, splenocytes were stimulated with anti-CD3/CD28 and IL-2 in the presence of TGF-β with or without IL-28B for three days and followed by flow cytometric, RT-PCR, and IL-10 production analysis. The results showed that IL-28B significantly reduced the proportion of induced Foxp3+ cells. It demonstrated that IL-28B may be used as a promising immunotherapy strategy against cancer.
Collapse
|
|
35
|
Clinical Implication of Circulating Tumor Cells Expressing Epithelial Mesenchymal Transition (EMT) and Cancer Stem Cell (CSC) Markers and Their Perspective in HCC: A Systematic Review. Cancers (Basel) 2022; 14:cancers14143373. [PMID: 35884432 PMCID: PMC9322939 DOI: 10.3390/cancers14143373] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Revised: 06/29/2022] [Accepted: 07/07/2022] [Indexed: 12/10/2022] Open
Abstract
Simple Summary One of the major problems regarding hepatocellular carcinoma (HCC) is the development of metastasis and recurrence, even in patients with an early stage. Recently, circulating tumor cells (CTCs) enumeration has been intensively studied as a diagnostic and prognostic biomarker in HCC. Nevertheless, increasing evidence suggests the role of metastasis-associated CTC phenotypes, including epithelial–mesenchymal transition (EMT)-CTCs and circulating cancer stem cells (CCSCs). We performed a systematic review to investigate the correlation of different CTC subtypes with HCC characteristics and their prognostic relevance to clinical outcomes. A preliminary meta-analysis found that CTC subtypes had prognostic power for predicting the probability of early recurrence. This study highlights the potential of CTC subtyping analysis as a biomarker for HCC management and provides information on metastasis-associated CTCs for a deeper molecular characterization of specific CTC subtypes. Abstract Circulating tumor cells (CTCs) play a key role in hematogenous metastasis and post-surgery recurrence. In hepatocellular carcinoma (HCC), CTCs have emerged as a valuable source of therapeutically relevant information. Certain subsets or phenotypes of CTCs can survive in the bloodstream and induce metastasis. Here, we performed a systematic review on the importance of epithelial–mesenchymal transition (EMT)-CTCs and circulating cancer stem cells (CCSCs) in metastatic processes and their prognostic power in HCC management. PubMed, Scopus, and Embase databases were searched for relevant publications. PRISMA criteria were used to review all studies. Twenty publications were eligible, of which 14, 5, and 1 study reported EMT-CTCs, CCSCs, and both phenotypes, respectively. Most studies evaluated that mesenchymal CTCs and CCSCs positivity were statistically associated with extensive clinicopathological features, including larger size and multiple numbers of tumors, advanced stages, micro/macrovascular invasion, and metastatic/recurrent disease. A preliminary meta-analysis showed that the presence of mesenchymal CTCs in pre- and postoperative blood significantly increased the risk of early recurrence. Mesenchymal-CTCs positivity was the most reported association with inferior outcomes based on the prognosis of HCC recurrence. Our finding could be a step forward, conveying additional prognostic values of CTC subtypes as promising biomarkers in HCC management.
Collapse
|
|
36
|
Teng PC, Agopian VG, Lin TY, You S, Zhu Y, Tseng HR, Yang JD. Circulating tumor cells: A step toward precision medicine in hepatocellular carcinoma. J Gastroenterol Hepatol 2022; 37:1179-1190. [PMID: 35543075 PMCID: PMC9271591 DOI: 10.1111/jgh.15886] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Accepted: 05/02/2022] [Indexed: 12/09/2022]
Abstract
Serum alpha-fetoprotein and radiologic imaging are the most commonly used tests for early diagnosis and dynamic monitoring of treatment response in hepatocellular carcinoma (HCC). However, the accuracy of these tests is limited, and they may not reflect the underlying biology of the tumor. Thus, developing highly accurate novel HCC biomarkers reflecting tumor biology is a clinically unmet need. Circulating tumor cells (CTCs) have long been proposed as a noninvasive biomarker in clinical oncology. Most CTC assays utilize immunoaffinity-based, size-based, and/or enrichment-free mechanisms followed by immunocytochemical staining to characterize CTCs. The prognostic value of HCC CTC enumeration has been extensively validated. Subsets of CTCs expressing mesenchymal markers are also reported to have clinical significance. In addition, researchers have been devoting their efforts to molecular characterizations of CTCs (e.g. genetics and transcriptomics) as molecular profiling can offer a more accurate readout and provide biological insights. As new molecular profiling techniques, such as digital polymerase chain reaction, are developed to detect minimal amounts of DNA/RNA, several research groups have established HCC CTC digital scoring systems to quantify clinically relevant gene panels. Given the versatility of CTCs to provide intact molecular and functional data that reflects the underlying tumor, CTCs have great potential as a noninvasive biomarker in HCC. Large-scale, prospective studies for HCC CTCs with a standardized protocol are necessary for successful clinical translation.
Collapse
Affiliation(s)
- Pai-Chi Teng
- Department of Education and Research, Taipei City Hospital Renai Branch, Taipei, Taiwan,Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA,California NanoSystems Institute, Crump Institute for Molecular Imaging, Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA
| | - Vatche G. Agopian
- Department of Surgery, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA,Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA, USA
| | - Ting-Yi Lin
- Doctoral Degree Program of Translational Medicine, National Yang Ming Chiao Tung University and Academia Sinica, Taiwan,Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Sungyong You
- Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA,Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Yazhen Zhu
- California NanoSystems Institute, Crump Institute for Molecular Imaging, Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA
| | - Hsian-Rong Tseng
- California NanoSystems Institute, Crump Institute for Molecular Imaging, Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA,Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA, USA
| | - Ju Dong Yang
- Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA,Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, CA, USA,Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA,corresponding author (Dr. Ju Dong Yang):
| |
Collapse
|
|
37
|
Temraz S, Nasr R, Mukherji D, Kreidieh F, Shamseddine A. Liquid Biopsy Derived Circulating Tumor Cells and Circulating Tumor DNA as Novel Biomarkers in Hepatocellular Carcinoma. Expert Rev Mol Diagn 2022; 22:507-518. [PMID: 35758097 DOI: 10.1080/14737159.2022.2094706] [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] [Indexed: 12/13/2022]
Abstract
INTRODUCTION The diagnosis of hepatocellular carcinoma (HCC) is made at a relatively advanced stage resulting in poor prognosis. Alpha-fetoprotein and liver ultrasound have limited accuracy as biomarkers in HCC. Liver biopsy provides information on tumor biology; however, it is invasive and holds high threat of tumor seeding. Thus, more accurate and less invasive approaches are needed. AREAS COVERED Highly sensitive liquid biopsy assays have made possible the detection and analysis of cells or organelles such as circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), and tumor-derived exosomes. Here, we focus on CTCs and ctDNA components of liquid biopsy and their clinical application as diagnostic, prognostic and predictive biomarkers in HCC. Unlike tissue biopsy, liquid biopsy involves attaining a sample at several time frames in an easy and a non-invasive manner. They have been efficacious in detecting and classifying cancer, in predicting treatment response, in monitoring disease relapse and in identifying mechanisms of resistance to targeted therapies. EXPERT OPINION Although interesting and highly promising, liquid biopsy techniques still have many obstacles to overcome before their wide spread clinical application sees the light. It is expected that these techniques will be incorporated into traditional methodologies for better diagnostic, predictive and prognostic results.
Collapse
Affiliation(s)
- Sally Temraz
- Department of internal medicine, Hematology/Oncology division, American University of Beirut Medical Center, Riad El Solh, Beirut, Lebanon
| | - Rihab Nasr
- Department of Anatomy, Cell Biology and Physiology, American University of Beirut Medical Center, Riad El Solh, Beirut, Lebanon
| | - Deborah Mukherji
- Department of internal medicine, Hematology/Oncology division, American University of Beirut Medical Center, Riad El Solh, Beirut, Lebanon
| | - Firas Kreidieh
- Department of internal medicine, Hematology/Oncology division, American University of Beirut Medical Center, Riad El Solh, Beirut, Lebanon
| | - Ali Shamseddine
- Department of internal medicine, Hematology/Oncology division, American University of Beirut Medical Center, Riad El Solh, Beirut, Lebanon
| |
Collapse
|
|
38
|
Chen VL, Huang Q, Harouaka R, Du Y, Lok AS, Parikh ND, Garmire LX, Wicha MS. A Dual-Filtration System for Single-Cell Sequencing of Circulating Tumor Cells and Clusters in HCC. Hepatol Commun 2022; 6:1482-1491. [PMID: 35068084 PMCID: PMC9134808 DOI: 10.1002/hep4.1900] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Revised: 12/07/2021] [Accepted: 12/17/2021] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a leading cause of cancer death worldwide. Identification and sequencing of circulating tumor (CT) cells and clusters may allow for noninvasive molecular characterization of HCC, which is an unmet need, as many patients with HCC do not undergo biopsy. We evaluated CT cells and clusters, collected using a dual-filtration system in patients with HCC. We collected and filtered whole blood from patients with HCC and selected individual CT cells and clusters with a micropipette. Reverse transcription, polymerase chain reaction, and library preparation were performed using a SmartSeq2 protocol, followed by single-cell RNA sequencing (scRNAseq) on an Illumina MiSeq V3 platform. Of the 8 patients recruited, 6 had identifiable CT cells or clusters. Median age was 64 years old; 7 of 8 were male; and 7 of 8 had and Barcelona Clinic Liver Cancer stage C. We performed scRNAseq of 38 CT cells and 33 clusters from these patients. These CT cells and clusters formed two distinct groups. Group 1 had significantly higher expression than group 2 of markers associated with epithelial phenotypes (CDH1 [Cadherin 1], EPCAM [epithelial cell adhesion molecule], ASGR2 [asialoglycoprotein receptor 2], and KRT8 [Keratin 8]), epithelial-mesenchymal transition (VIM [Vimentin]), and stemness (PROM1 [CD133], POU5F1 [POU domain, class 5, transcription factor 1], NOTCH1, STAT3 [signal transducer and activator of transcription 3]) (P < 0.05 for all). Patients with identifiable group 1 cells or clusters had poorer prognosis than those without them (median overall survival 39 vs. 384 days; P = 0.048 by log-rank test). Conclusion: A simple dual-filtration system allows for isolation and sequencing of CT cells and clusters in HCC and may identify cells expressing candidate genes known to be involved in cancer biology. Presence of CT cells/clusters expressing candidate genes is associated with poorer prognosis in advanced-stage HCC.
Collapse
Affiliation(s)
- Vincent L. Chen
- Division of Gastroenterology and HepatologyDepartment of Internal MedicineUniversity of MichiganAnn ArborMIUSA
| | - Qianhui Huang
- Department of Computational Medicine and BioinformaticsUniversity of MichiganAnn ArborMIUSA
| | - Ramdane Harouaka
- Division of Hematology and OncologyDepartment of Internal MedicineUniversity of MichiganAnn ArborMIUSA
| | - Yuheng Du
- Department of Computational Medicine and BioinformaticsUniversity of MichiganAnn ArborMIUSA
| | - Anna S. Lok
- Division of Gastroenterology and HepatologyDepartment of Internal MedicineUniversity of MichiganAnn ArborMIUSA
| | - Neehar D. Parikh
- Division of Gastroenterology and HepatologyDepartment of Internal MedicineUniversity of MichiganAnn ArborMIUSA
| | - Lana X. Garmire
- Department of Computational Medicine and BioinformaticsUniversity of MichiganAnn ArborMIUSA
| | - Max S. Wicha
- Division of Hematology and OncologyDepartment of Internal MedicineUniversity of MichiganAnn ArborMIUSA
| |
Collapse
|
|
39
|
Wu H, Tang X, Wang Y, Wang N, Chen Q, Xie J, Liu S, Zhong Z, Qiu Y, Situ P, Zern MA, Wang J, Chen H, Duan Y. Dextran sulfate prevents excess aggregation of human pluripotent stem cells in 3D culture by inhibiting ICAM1 expression coupled with down-regulating E-cadherin through activating the Wnt signaling pathway. Stem Cell Res Ther 2022; 13:218. [PMID: 35619172 PMCID: PMC9137216 DOI: 10.1186/s13287-022-02890-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Accepted: 04/25/2022] [Indexed: 11/29/2022] Open
Abstract
Background Human pluripotent stem cells (hPSCs) have great potential in applications for regenerative medicine and drug development. However, 3D suspension culture systems for clinical-grade hPSC large-scale production have been a major challenge. Accumulating evidence has demonstrated that the addition of dextran sulfate (DS) could prevent excessive adhesion of hPSCs from forming larger aggregates in 3D suspension culture. However, the signaling and molecular mechanisms underlying this phenomenon remain elusive. Methods By using a cell aggregate culture assay and separating big and small aggregates in suspension culture systems, the potential mechanism and downstream target genes of DS were investigated by mRNA sequence analysis, qRT-PCR validation, colony formation assay, and interference assay. Results Since cellular adhesion molecules (CAMs) play important roles in hPSC adhesion and aggregation, we assumed that DS might prevent excess adhesion through affecting the expression of CAMs in hPSCs. As expected, after DS treatment, we found that the expression of CAMs was significantly down-regulated, especially E-cadherin (E-cad) and intercellular adhesion molecule 1 (ICAM1), two highly expressed CAMs in hPSCs. The role of E-cad in the adhesion of hPSCs has been widely investigated, but the function of ICAM1 in hPSCs is hardly understood. In the present study, we demonstrated that ICAM1 exhibited the capacity to promote the adhesion in hPSCs, and this adhesion was suppressed by the treatment with DS. Furthermore, transcriptomic analysis of RNA-seq revealed that DS treatment up-regulated genes related to Wnt signaling resulting in the activation of Wnt signaling in which SLUG, TWIST, and MMP3/7 were highly expressed, and further inhibited the expression of E-cad. Conclusion Our results demonstrated that DS played an important role in controlling the size of hPSC aggregates in 3D suspension culture by inhibiting the expression of ICAM1 coupled with the down-regulation of E-cad through the activation of the Wnt signaling pathway. These results represent a significant step toward developing the expansion of hPSCs under 3D suspension condition in large-scale cultures. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-022-02890-4.
Collapse
Affiliation(s)
- Haibin Wu
- Laboratory of Stem Cells and Translational Medicine, Institutes for Life Sciences, School of Medicine, South China University of Technology, No. 382 Waihuan East Road, Suite 406, Higher Education Mega Center, Guangzhou, 510006, People's Republic of China
| | - Xianglian Tang
- Laboratory of Stem Cells and Translational Medicine, Institutes for Life Sciences, School of Medicine, South China University of Technology, No. 382 Waihuan East Road, Suite 406, Higher Education Mega Center, Guangzhou, 510006, People's Republic of China.,School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou International Campus, Guangzhou, 510180, People's Republic of China.,Guangxi Key Laboratory of Reproductive Health and Birth Defects Prevention, Guangxi Health Commission Key Laboratory of Precise Diagnosis and Treatment of Genetic Diseases, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning, 530003, Guangxi, People's Republic of China.,Genetic and Metabolic Central Laboratory, Guangxi Birth Defects Research and Prevention Institute, Nanning, 530003, Guangxi, People's Republic of China
| | - Yiyu Wang
- Laboratory of Stem Cells and Translational Medicine, Institutes for Life Sciences, School of Medicine, South China University of Technology, No. 382 Waihuan East Road, Suite 406, Higher Education Mega Center, Guangzhou, 510006, People's Republic of China
| | - Ning Wang
- Laboratory of Stem Cells and Translational Medicine, Institutes for Life Sciences, School of Medicine, South China University of Technology, No. 382 Waihuan East Road, Suite 406, Higher Education Mega Center, Guangzhou, 510006, People's Republic of China.,School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou International Campus, Guangzhou, 510180, People's Republic of China
| | - Qicong Chen
- Laboratory of Stem Cells and Translational Medicine, Institutes for Life Sciences, School of Medicine, South China University of Technology, No. 382 Waihuan East Road, Suite 406, Higher Education Mega Center, Guangzhou, 510006, People's Republic of China.,School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou International Campus, Guangzhou, 510180, People's Republic of China
| | - Jinghe Xie
- Laboratory of Stem Cells and Translational Medicine, Institutes for Life Sciences, School of Medicine, South China University of Technology, No. 382 Waihuan East Road, Suite 406, Higher Education Mega Center, Guangzhou, 510006, People's Republic of China.,School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou International Campus, Guangzhou, 510180, People's Republic of China
| | - Shoupei Liu
- Laboratory of Stem Cells and Translational Medicine, Institutes for Life Sciences, School of Medicine, South China University of Technology, No. 382 Waihuan East Road, Suite 406, Higher Education Mega Center, Guangzhou, 510006, People's Republic of China
| | - Zhiyong Zhong
- Laboratory of Stem Cells and Translational Medicine, Institutes for Life Sciences, School of Medicine, South China University of Technology, No. 382 Waihuan East Road, Suite 406, Higher Education Mega Center, Guangzhou, 510006, People's Republic of China.,School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou International Campus, Guangzhou, 510180, People's Republic of China
| | - Yaqi Qiu
- Laboratory of Stem Cells and Translational Medicine, Institutes for Life Sciences, School of Medicine, South China University of Technology, No. 382 Waihuan East Road, Suite 406, Higher Education Mega Center, Guangzhou, 510006, People's Republic of China
| | - Ping Situ
- Laboratory of Stem Cells and Translational Medicine, Institutes for Life Sciences, School of Medicine, South China University of Technology, No. 382 Waihuan East Road, Suite 406, Higher Education Mega Center, Guangzhou, 510006, People's Republic of China.,School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou International Campus, Guangzhou, 510180, People's Republic of China
| | - Mark A Zern
- Department of Internal Medicine, University of California Davis Medical Center, Sacramento, CA, 95817, USA
| | - Jue Wang
- Laboratory of Stem Cells and Translational Medicine, Institutes for Life Sciences, School of Medicine, South China University of Technology, No. 382 Waihuan East Road, Suite 406, Higher Education Mega Center, Guangzhou, 510006, People's Republic of China.
| | - Honglin Chen
- Laboratory of Stem Cells and Translational Medicine, Institutes for Life Sciences, School of Medicine, South China University of Technology, No. 382 Waihuan East Road, Suite 406, Higher Education Mega Center, Guangzhou, 510006, People's Republic of China. .,National Engineering Research Center for Tissue Restoration and Reconstruction, South China University of Technology, Guangzhou, 510180, People's Republic of China. .,Guangdong Provincial Key Laboratory of Biomedical Engineering, South China University of Technology, Guangzhou, 510180, People's Republic of China. .,Key Laboratory of Biomedical Materials and Engineering of the Ministry of Education, South China University of Technology, Guangzhou, 510180, People's Republic of China.
| | - Yuyou Duan
- Laboratory of Stem Cells and Translational Medicine, Institutes for Life Sciences, School of Medicine, South China University of Technology, No. 382 Waihuan East Road, Suite 406, Higher Education Mega Center, Guangzhou, 510006, People's Republic of China. .,National Engineering Research Center for Tissue Restoration and Reconstruction, South China University of Technology, Guangzhou, 510180, People's Republic of China. .,Guangdong Provincial Key Laboratory of Biomedical Engineering, South China University of Technology, Guangzhou, 510180, People's Republic of China. .,Key Laboratory of Biomedical Materials and Engineering of the Ministry of Education, South China University of Technology, Guangzhou, 510180, People's Republic of China.
| |
Collapse
|
|
40
|
Zhang Y, Zhang L, Zheng S, Li M, Xu C, Jia D, Qi Y, Hou T, Wang L, Wang B, Li A, Chen S, Si J, Zhuo W. Fusobacterium nucleatum promotes colorectal cancer cells adhesion to endothelial cells and facilitates extravasation and metastasis by inducing ALPK1/NF-κB/ICAM1 axis. Gut Microbes 2022; 14:2038852. [PMID: 35220887 PMCID: PMC8890384 DOI: 10.1080/19490976.2022.2038852] [Citation(s) in RCA: 110] [Impact Index Per Article: 36.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
Metastasis is the leading cause of death for colorectal cancer (CRC) patients, and the spreading tumor cells adhesion to endothelial cells is a critical step for extravasation and further distant metastasis. Previous studies have documented the important roles of gut microbiota-host interactions in the CRC malignancy, and Fusobacterium nucleatum (F. nucleatum) was reported to increase proliferation and invasive activities of CRC cells. However, the potential functions and underlying mechanisms of F. nucleatum in the interactions between CRC cells and endothelial cells and subsequent extravasation remain unclear. Here, we uncovered that F. nucleatum enhanced the adhesion of CRC cells to endothelial cells, promoted extravasation and metastasis by inducing ICAM1 expression. Mechanistically, we identified that F. nucleatum induced a new pattern recognition receptor ALPK1 to activate NF-κB pathway, resulting in the upregulation of ICAM1. Interestingly, the abundance of F. nucleatum in tumor tissues of CRC patients was positively associated with the expression levels of ALPK1 and ICAM1. Moreover, high expression of ALPK1 or ICAM1 was significantly associated with a shorter overall survival time of CRC patients. This study provides a new insight into the role of gut microbiota in engaging into the distant metastasis of CRC cells.
Collapse
Affiliation(s)
- Ying Zhang
- Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China,Cancer Center, Zhejiang University, Hangzhou, China,Institute of Gastroenterology, Zhejiang University, Hangzhou, China
| | - Lu Zhang
- Department of Cell Biology and Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China,Cancer Center, Zhejiang University, Hangzhou, China,Institute of Gastroenterology, Zhejiang University, Hangzhou, China
| | - Sheng Zheng
- Cancer Center, Zhejiang University, Hangzhou, China,Institute of Gastroenterology, Zhejiang University, Hangzhou, China,Department of Gastroenterology, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Mengjie Li
- Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China,Cancer Center, Zhejiang University, Hangzhou, China,Institute of Gastroenterology, Zhejiang University, Hangzhou, China
| | - Chaochao Xu
- Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China,Cancer Center, Zhejiang University, Hangzhou, China,Institute of Gastroenterology, Zhejiang University, Hangzhou, China
| | - Dingjiacheng Jia
- Cancer Center, Zhejiang University, Hangzhou, China,Institute of Gastroenterology, Zhejiang University, Hangzhou, China,Department of Gastroenterology, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Yadong Qi
- Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China,Cancer Center, Zhejiang University, Hangzhou, China,Institute of Gastroenterology, Zhejiang University, Hangzhou, China
| | - Tongyao Hou
- Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China,Cancer Center, Zhejiang University, Hangzhou, China,Institute of Gastroenterology, Zhejiang University, Hangzhou, China
| | - Lan Wang
- Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China,Cancer Center, Zhejiang University, Hangzhou, China,Institute of Gastroenterology, Zhejiang University, Hangzhou, China
| | - Boya Wang
- Institute of Gastroenterology, Zhejiang University, Hangzhou, China,Department of Pharmacy, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Aiqing Li
- Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China,Cancer Center, Zhejiang University, Hangzhou, China,Institute of Gastroenterology, Zhejiang University, Hangzhou, China
| | - Shujie Chen
- Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China,Cancer Center, Zhejiang University, Hangzhou, China,Institute of Gastroenterology, Zhejiang University, Hangzhou, China,Shujie Chen Department of Gastroenterology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310016, Zhejiang, China
| | - Jianmin Si
- Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China,Cancer Center, Zhejiang University, Hangzhou, China,Institute of Gastroenterology, Zhejiang University, Hangzhou, China,Jianmin Si Department of Gastroenterology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310016, Zhejiang, China
| | - Wei Zhuo
- Department of Cell Biology and Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China,Cancer Center, Zhejiang University, Hangzhou, China,Institute of Gastroenterology, Zhejiang University, Hangzhou, China,CONTACT Wei Zhuo Department of Cell Biology and Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou310058, Zhejiang, China
| |
Collapse
|
|
41
|
Meng Y, Sang Y, Liao J, Zhao Q, Qu S, Li R, Jiang J, Wang M, Wang J, Wu D, Cheng C, Wei L. Single cell transcriptional diversity and intercellular crosstalk of human liver cancer. Cell Death Dis 2022; 13:261. [PMID: 35322024 PMCID: PMC8943132 DOI: 10.1038/s41419-022-04689-w] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Revised: 02/09/2022] [Accepted: 02/24/2022] [Indexed: 12/15/2022]
Abstract
Liver cancer arises from the evolutionary selection of the dynamic tumor microenvironment (TME), in which the tumor cell generally becomes more heterogeneous; however, the mechanisms of TME-mediated transcriptional diversity of liver cancer remain unclear. Here, we assess transcriptional diversity in 15 liver cancer patients by single-cell transcriptome analysis and observe transcriptional diversity of tumor cells is associated with stemness in liver cancer patients. Tumor-associated fibroblast (TAF), as a potential driving force behind the heterogeneity in tumor cells within and between tumors, was predicted to interact with high heterogeneous tumor cells via COL1A1-ITGA2. Moreover, COL1A1-mediated YAP-signaling activation might be the mechanistic link between TAF and tumor cells with increased transcriptional diversity. Strikingly, the levels of COL1A1, ITGA2, and YAP are associated with morphological heterogeneity and poor overall survival of liver cancer patients. Beyond providing a potential mechanistic link between the TME and heterogeneous tumor cells, this study establishes that collagen-stimulated YAP activation is associates with transcriptional diversity in tumor cells by upregulating stemness, providing a theoretical basis for individualized treatment targets.
Collapse
Affiliation(s)
- Yan Meng
- School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, 138 Xianlin Street, Nanjing, 210023, China.,Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Second Military Medical University, 225 Changhai Road, Shanghai, 200438, China
| | - Yan Sang
- Nursing Department, Affiliated Hospital of Nantong University, Nantong University, Nantong, 226001, China
| | - Jianping Liao
- Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Second Military Medical University, 225 Changhai Road, Shanghai, 200438, China.,The School of Basic Medical Sciences of Fujian Medical University, Fujian Medical University, Fuzhou, 350108, China
| | - Qiudong Zhao
- Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Second Military Medical University, 225 Changhai Road, Shanghai, 200438, China
| | - Shuping Qu
- Department of Hepatic Surgery, Third Affiliated Hospital of Second Military Medical University, 225 Changhai Road, Shanghai, 200438, China
| | - Rong Li
- Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Second Military Medical University, 225 Changhai Road, Shanghai, 200438, China
| | - Jinghua Jiang
- Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Second Military Medical University, 225 Changhai Road, Shanghai, 200438, China
| | - Meifeng Wang
- Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Second Military Medical University, 225 Changhai Road, Shanghai, 200438, China.,The School of Basic Medical Sciences of Fujian Medical University, Fujian Medical University, Fuzhou, 350108, China
| | - Jiahong Wang
- The School of Basic Medical Sciences of Fujian Medical University, Fujian Medical University, Fuzhou, 350108, China
| | - Dong Wu
- Department of Hepatic Surgery, Third Affiliated Hospital of Second Military Medical University, 225 Changhai Road, Shanghai, 200438, China.
| | - Chun Cheng
- School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, 138 Xianlin Street, Nanjing, 210023, China.
| | - Lixin Wei
- Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Second Military Medical University, 225 Changhai Road, Shanghai, 200438, China.
| |
Collapse
|
|
42
|
Wang S, Xie J, Zou X, Pan T, Yu Q, Zhuang Z, Zhong Y, Zhao X, Wang Z, Li R, Lei Y, Yin J, Yuan Y, Wei X, Liu L, Liu S, Yang H, Wu L. Establish an assessment model to characterized metastasis ability Single-cell multiomics reveals heterogeneous cell states linked to metastatic potential in liver cancer cell lines. iScience 2022; 25:103857. [PMID: 35198910 PMCID: PMC8850337 DOI: 10.1016/j.isci.2022.103857] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Revised: 01/01/2022] [Accepted: 01/28/2022] [Indexed: 11/16/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common liver cancer with a high rate of metastasis. However, the molecular mechanisms that drive metastasis remain unclear. We combined single-cell transcriptomic, proteomic, and chromatin accessibility data to investigate how heterogeneous phenotypes contribute to metastatic potential in five HCC cell lines. We confirmed that the prevalence of a mesenchymal state and levels of cell proliferation are linked to the metastatic potential. We also identified a rare hypoxic subtype that has a higher capacity for glycolysis and exhibits dormant, invasive, and malignant characteristics. This subtype has increased metastatic potential. We further identified a robust 14-gene panel representing this hypoxia signature and this hypoxia signature could serve as a prognostic index. Our data provide a valuable data resource, facilitate a deeper understanding of metastatic mechanisms, and may help diagnosis of metastatic potential in individual patients, thus supporting personalized medicine.
Provide a high-resolution single-cell triple-omics data of five liver cancer cell lines Identify a robust 14-gene set representing hypoxia signature The hypoxia signature is associated with prognosis Establish an assessment model to characterized metastasis ability
Collapse
|
|
43
|
Cancer stem cells in hepatocellular carcinoma - from origin to clinical implications. Nat Rev Gastroenterol Hepatol 2022; 19:26-44. [PMID: 34504325 DOI: 10.1038/s41575-021-00508-3] [Citation(s) in RCA: 281] [Impact Index Per Article: 93.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/26/2021] [Indexed: 02/06/2023]
Abstract
Hepatocellular carcinoma (HCC) is an aggressive disease with a poor clinical outcome. The cancer stem cell (CSC) model states that tumour growth is powered by a subset of tumour stem cells within cancers. This model explains several clinical observations in HCC (as well as in other cancers), including the almost inevitable recurrence of tumours after initial successful chemotherapy and/or radiotherapy, as well as the phenomena of tumour dormancy and treatment resistance. The past two decades have seen a marked increase in research on the identification and characterization of liver CSCs, which has encouraged the design of novel diagnostic and treatment strategies for HCC. These studies revealed novel aspects of liver CSCs, including their heterogeneity and unique immunobiology, which are suggestive of opportunities for new research directions and potential therapies. In this Review, we summarize the present knowledge of liver CSC markers and the regulators of stemness in HCC. We also comprehensively describe developments in the liver CSC field with emphasis on experiments utilizing single-cell transcriptomics to understand liver CSC heterogeneity, lineage-tracing and cell-ablation studies of liver CSCs, and the influence of the CSC niche and tumour microenvironment on liver cancer stemness, including interactions between CSCs and the immune system. We also discuss the potential application of liver CSC-based therapies for treatment of HCC.
Collapse
|
|
44
|
The Influence of ICAM1 3'UTR Gene Polymorphism on the Occurrence and Metastasis of Primary Liver Cancer. BIOMED RESEARCH INTERNATIONAL 2021; 2021:7377299. [PMID: 34869770 PMCID: PMC8642008 DOI: 10.1155/2021/7377299] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/12/2021] [Revised: 07/25/2021] [Accepted: 07/27/2021] [Indexed: 11/24/2022]
Abstract
Objective In this study, we explored the influence of single nucleotide polymorphism (SNP) in the noncoding region of intercellular adhesion molecule 1 (ICAM1) gene on the occurrence and metastasis of primary hepatocellular carcinoma (PHC). Methods Sanger sequencing was used to analyze the genotypes of rs3093032, rs923366, and rs281437 locus in the 3′untranslated region (UTR) of the ICAM1 gene. The level of plasma ICAM1 was analyzed by enzyme-linked immunosorbent assay (ELISA). Results After adjusting for risk factors such as BMI, smoking, drinking, family history of tumors, and hepatitis B virus test results, the CT genotype at rs3093032 of the ICAM1 gene (OR = 0.19, 95% CI: 0.08-0.44, P < 0.01), dominance model (OR = 0.23, 95% CI: 0.11-0.48, P < 0.01), and T allele (OR = 0.27, 95% CI: 0.14-0.53, P < 0.01) were related to the reduced risk of PHC susceptibility. rs923366 locus CT genotype (OR = 0.63, 95% CI: 0.44-0.90, P = 0.01), TT genotype (OR = 0.23, 95% CI: 0.10-0.53, P < 0.01), dominant model (OR = 0.55, 95% CI: 0.39-0.77, P < 0.01), recessive model (OR = 0.28, 95% CI: 0.12-0.62, P < 0.01), and T allele (OR = 0.55, 95% CI: 0.42-0.73, P < 0.01) were related to a reduction in the risk of PHC susceptibility. rs281437 locus CT genotype (OR = 2.08, 95% CI: 1.40-3.09, P < 0.01), TT genotype (OR = 5.20, 95% CI: 2.22-12.17, P < 0.01), dominant model (OR = 2.45, 95% CI: 1.69-3.54, P < 0.01), recessive model (OR = 4.32, 95% CI: 1.86-10.06, P < 0.01), and T allele (OR = 2.46, 95% CI: 1.79-3.38, P < 0.01) were significantly related to the increased risk of PHC susceptibility. SNPs at rs3093032, rs923366, and rs281437 of the ICAM1 gene were significantly correlated with TNM stage and tumor metastasis of PHC patients (P < 0.05). Conclusion SNPs at rs3093032, rs923366, and rs281437 in the 3′UTR region of the ICAM1 gene are related to the occurrence and metastasis of PHC.
Collapse
|
|
45
|
Espejo-Cruz ML, González-Rubio S, Zamora-Olaya J, Amado-Torres V, Alejandre R, Sánchez-Frías M, Ciria R, De la Mata M, Rodríguez-Perálvarez M, Ferrín G. Circulating Tumor Cells in Hepatocellular Carcinoma: A Comprehensive Review and Critical Appraisal. Int J Mol Sci 2021; 22:13073. [PMID: 34884878 PMCID: PMC8657934 DOI: 10.3390/ijms222313073] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Revised: 11/27/2021] [Accepted: 11/30/2021] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common neoplasm and a major cause of cancer-related death worldwide. There is no ideal biomarker allowing early diagnosis of HCC and tumor surveillance in patients receiving therapy. Liquid biopsy, and particularly circulating tumor cells (CTCs), have emerged as a useful tool for diagnosis and monitoring therapeutic responses in different tumors. In the present manuscript, we evaluate the current evidence supporting the quantitative and qualitative assessment of CTCs as potential biomarkers of HCC, as well as technical aspects related to isolation, identification, and classification of CTCs. Although the dynamic assessment of CTCs in patients with HCC may aid the decision-making process, there are still many uncertainties and technical caveats to be solved before this methodology has a true impact on clinical practice guidelines. More studies are needed to identify the optimal combination of surface markers, to increase the efficiency of ex-vivo expansion of CTCs, or even to target CTCs as a potential therapeutic strategy to prevent HCC recurrence after surgery or to hamper tumor progression and extrahepatic spreading.
Collapse
Affiliation(s)
- María Lola Espejo-Cruz
- Maimónides Institute of Biomedical Research (IMIBIC), University of Córdoba, Avda. Menéndez Pidal s/n, 14004 Córdoba, Spain; (M.L.E.-C.); (S.G.-R.); (J.Z.-O.); (V.A.-T.); (R.A.); (R.C.); (M.D.l.M.); (G.F.)
| | - Sandra González-Rubio
- Maimónides Institute of Biomedical Research (IMIBIC), University of Córdoba, Avda. Menéndez Pidal s/n, 14004 Córdoba, Spain; (M.L.E.-C.); (S.G.-R.); (J.Z.-O.); (V.A.-T.); (R.A.); (R.C.); (M.D.l.M.); (G.F.)
| | - Javier Zamora-Olaya
- Maimónides Institute of Biomedical Research (IMIBIC), University of Córdoba, Avda. Menéndez Pidal s/n, 14004 Córdoba, Spain; (M.L.E.-C.); (S.G.-R.); (J.Z.-O.); (V.A.-T.); (R.A.); (R.C.); (M.D.l.M.); (G.F.)
- Department of Hepatology and Liver Transplantation, Reina Sofía University Hospital, Avda. Menéndez Pidal s/n, 14004 Córdoba, Spain
| | - Víctor Amado-Torres
- Maimónides Institute of Biomedical Research (IMIBIC), University of Córdoba, Avda. Menéndez Pidal s/n, 14004 Córdoba, Spain; (M.L.E.-C.); (S.G.-R.); (J.Z.-O.); (V.A.-T.); (R.A.); (R.C.); (M.D.l.M.); (G.F.)
- Department of Hepatology and Liver Transplantation, Reina Sofía University Hospital, Avda. Menéndez Pidal s/n, 14004 Córdoba, Spain
| | - Rafael Alejandre
- Maimónides Institute of Biomedical Research (IMIBIC), University of Córdoba, Avda. Menéndez Pidal s/n, 14004 Córdoba, Spain; (M.L.E.-C.); (S.G.-R.); (J.Z.-O.); (V.A.-T.); (R.A.); (R.C.); (M.D.l.M.); (G.F.)
- Department of Hepatology and Liver Transplantation, Reina Sofía University Hospital, Avda. Menéndez Pidal s/n, 14004 Córdoba, Spain
| | - Marina Sánchez-Frías
- Department of Pathology, Reina Sofía University Hospital, Avda. Menéndez Pidal s/n, 14004 Córdoba, Spain;
| | - Rubén Ciria
- Maimónides Institute of Biomedical Research (IMIBIC), University of Córdoba, Avda. Menéndez Pidal s/n, 14004 Córdoba, Spain; (M.L.E.-C.); (S.G.-R.); (J.Z.-O.); (V.A.-T.); (R.A.); (R.C.); (M.D.l.M.); (G.F.)
- Department of Hepatobiliary Surgery and Liver Transplantation, Reina Sofía University Hospital, 14004 Córdoba, Spain
| | - Manuel De la Mata
- Maimónides Institute of Biomedical Research (IMIBIC), University of Córdoba, Avda. Menéndez Pidal s/n, 14004 Córdoba, Spain; (M.L.E.-C.); (S.G.-R.); (J.Z.-O.); (V.A.-T.); (R.A.); (R.C.); (M.D.l.M.); (G.F.)
- Department of Hepatology and Liver Transplantation, Reina Sofía University Hospital, Avda. Menéndez Pidal s/n, 14004 Córdoba, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 28029 Madrid, Spain
| | - Manuel Rodríguez-Perálvarez
- Maimónides Institute of Biomedical Research (IMIBIC), University of Córdoba, Avda. Menéndez Pidal s/n, 14004 Córdoba, Spain; (M.L.E.-C.); (S.G.-R.); (J.Z.-O.); (V.A.-T.); (R.A.); (R.C.); (M.D.l.M.); (G.F.)
- Department of Hepatology and Liver Transplantation, Reina Sofía University Hospital, Avda. Menéndez Pidal s/n, 14004 Córdoba, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 28029 Madrid, Spain
| | - Gustavo Ferrín
- Maimónides Institute of Biomedical Research (IMIBIC), University of Córdoba, Avda. Menéndez Pidal s/n, 14004 Córdoba, Spain; (M.L.E.-C.); (S.G.-R.); (J.Z.-O.); (V.A.-T.); (R.A.); (R.C.); (M.D.l.M.); (G.F.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 28029 Madrid, Spain
| |
Collapse
|
|
46
|
Sonntag R, Penners C, Kohlhepp M, Haas U, Lambertz D, Kroh A, Cramer T, Ticconi F, Costa IG, Tacke F, Gassler N, Trautwein C, Liedtke C. Cyclin E1 in Murine and Human Liver Cancer: A Promising Target for Therapeutic Intervention during Tumour Progression. Cancers (Basel) 2021; 13:5680. [PMID: 34830835 PMCID: PMC8616292 DOI: 10.3390/cancers13225680] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Revised: 11/03/2021] [Accepted: 11/04/2021] [Indexed: 12/24/2022] Open
Abstract
Cyclin E1 (CCNE1) is a regulatory subunit of Cyclin-dependent kinase 2 (CDK2) and is thought to control the transition of quiescent cells into cell cycle progression. Recently, we identified CCNE1 and CDK2 as key factors for the initiation of hepatocellular carcinoma (HCC). In the present study, we dissected the contributions of CCNE1 and CDK2 for HCC progression in mice and patients. Therefore, we generated genetically modified mice allowing inducible deletion of Ccne1 or Cdk2. After initiation of HCC, using the hepatocarcinogen diethylnitrosamine (DEN), we deleted Ccne1 or Cdk2 and subsequently analysed HCC progression. The relevance of CCNE1 or CDK2 for human HCC progression was investigated by in silico database analysis. Interventional deletion of Ccne1, but not of Cdk2, substantially reduced the HCC burden in mice. Ccne1-deficient HCCs were characterised by attenuated proliferation, impaired DNA damage response and downregulation of markers for stemness and microinvasion. Additionally, the tumour microenvironment of Ccne1-deficient mice showed a reduction in immune mediators, myeloid cells and cancer-associated fibroblasts. In sharp contrast, Cdk2 was dispensable for HCC progression in mice. In agreement with our mouse data, CCNE1 was overexpressed in HCC patients independent of risk factors, and associated with reduced disease-free survival, a common signature for enhanced chromosomal instability, proliferation, dedifferentiation and invasion. However, CDK2 lacked diagnostic or prognostic value in HCC patients. In summary, CCNE1 drives HCC progression in a CDK2-independent manner in mice and man. Therefore, interventional inactivation of CCNE1 represents a promising strategy the treatment of liver cancer.
Collapse
Affiliation(s)
- Roland Sonntag
- Department of Internal Medicine III, University Hospital RWTH, 52074 Aachen, Germany; (C.P.); (U.H.); (D.L.); (C.T.)
| | - Christian Penners
- Department of Internal Medicine III, University Hospital RWTH, 52074 Aachen, Germany; (C.P.); (U.H.); (D.L.); (C.T.)
| | - Marlene Kohlhepp
- Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum and Campus Charité Mitte, Charité University Medicine Berlin, 13353 Berlin, Germany; (M.K.); (F.T.)
| | - Ute Haas
- Department of Internal Medicine III, University Hospital RWTH, 52074 Aachen, Germany; (C.P.); (U.H.); (D.L.); (C.T.)
| | - Daniela Lambertz
- Department of Internal Medicine III, University Hospital RWTH, 52074 Aachen, Germany; (C.P.); (U.H.); (D.L.); (C.T.)
| | - Andreas Kroh
- Department of General, Visceral and Transplantation Surgery, University Hospital RWTH, 52074 Aachen, Germany; (A.K.); (T.C.)
| | - Thorsten Cramer
- Department of General, Visceral and Transplantation Surgery, University Hospital RWTH, 52074 Aachen, Germany; (A.K.); (T.C.)
- Department of Surgery, Maastricht University Medical Center, 6200 MD Maastricht, The Netherlands
- ESCAM—European Surgery Center Aachen Maastricht, 52074 Aachen, Germany
- ESCAM—European Surgery Center Aachen Maastricht, 6200 MD Maastricht, The Netherlands
| | - Fabio Ticconi
- IZKF Research Group Computational Biology and Bioinformatics, Helmholtz Institute for Biomedical Engineering, RWTH Aachen University, 52074 Aachen, Germany; (F.T.); (I.G.C.)
| | - Ivan G. Costa
- IZKF Research Group Computational Biology and Bioinformatics, Helmholtz Institute for Biomedical Engineering, RWTH Aachen University, 52074 Aachen, Germany; (F.T.); (I.G.C.)
| | - Frank Tacke
- Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum and Campus Charité Mitte, Charité University Medicine Berlin, 13353 Berlin, Germany; (M.K.); (F.T.)
| | - Nikolaus Gassler
- Section of Pathology, Institute of Forensic Medicine University Hospital Jena, 07747 Jena, Germany;
| | - Christian Trautwein
- Department of Internal Medicine III, University Hospital RWTH, 52074 Aachen, Germany; (C.P.); (U.H.); (D.L.); (C.T.)
| | - Christian Liedtke
- Department of Internal Medicine III, University Hospital RWTH, 52074 Aachen, Germany; (C.P.); (U.H.); (D.L.); (C.T.)
| |
Collapse
|
|
47
|
Barrera-Saldaña HA, Fernández-Garza LE, Barrera-Barrera SA. Liquid biopsy in chronic liver disease. Ann Hepatol 2021; 20:100197. [PMID: 32444248 DOI: 10.1016/j.aohep.2020.03.008] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2020] [Accepted: 03/25/2020] [Indexed: 02/04/2023]
Abstract
Chronic liver diseases account for a considerable toll of incapacities, suffering, deaths, and resources of the nation's health systems. They can be prevented, treated or even cured when the diagnosis is made on time. Traditional liver biopsy remains the gold standard to diagnose liver diseases, but it has several limitations. Liquid biopsy is emerging as a superior alternative to surgical biopsy given that it surpasses the limitations: it is more convenient, readily and repeatedly accessible, safe, cheap, and provides a more detailed molecular and cellular representation of the individual patient's disease. Progress in understanding the molecular and cellular bases of diseased tissues and organs that normally release cells and cellular components into the bloodstream is catapulting liquid biopsy as a source of biomarkers for diagnosis, prognosis, and prediction of therapeutic response, thus supporting the realization of the promises of precision medicine. The review aims to summarize the evidence of the usefulness of liquid biopsy in liver diseases, including the presence of different biomarkers as circulating epithelial cells, cell-free nucleic acids, specific species of DNA and RNA, and the content of extracellular vesicles.
Collapse
Affiliation(s)
- Hugo A Barrera-Saldaña
- Innbiogem SC at National Laboratory for Services of Research, Development, and Innovation for the Pharma and Biotech Industries (LANSEDI) of CONACyT Vitaxentrum group, Monterrey, N.L., Mexico; Center for Biotechnological Genomics of National Polytechnical Institute, Reynosa, Tamps., Mexico.
| | - Luis E Fernández-Garza
- Innbiogem SC at National Laboratory for Services of Research, Development, and Innovation for the Pharma and Biotech Industries (LANSEDI) of CONACyT Vitaxentrum group, Monterrey, N.L., Mexico
| | - Silvia A Barrera-Barrera
- Innbiogem SC at National Laboratory for Services of Research, Development, and Innovation for the Pharma and Biotech Industries (LANSEDI) of CONACyT Vitaxentrum group, Monterrey, N.L., Mexico; National Institute of Pediatrics, Mexico City, Mexico
| |
Collapse
|
|
48
|
Wan J, Zhou J, Fu L, Li Y, Zeng H, Xu X, Lv C, Jin H. Ascorbic Acid Inhibits Liver Cancer Growth and Metastasis in vitro and in vivo, Independent of Stemness Gene Regulation. Front Pharmacol 2021; 12:726015. [PMID: 34504430 PMCID: PMC8422961 DOI: 10.3389/fphar.2021.726015] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Accepted: 08/12/2021] [Indexed: 12/20/2022] Open
Abstract
Experimental and clinical evidence has indicated that the natural product ascorbic acid (AA) is effective in preventing and treating various types of cancers. However, the effect of AA on liver cancer metastasis has not yet been reported. Cancer stem cells (CSCs) play pivotal roles in cancer metastasis. Here, we demonstrated that AA selectively inhibited the viability of both liver cancer cells and CSCs, reduced the formation of cancer cell colonies and CSC spheres, and inhibited tumor growth in vivo. Additionally, AA prevented liver cancer metastasis in a xenotransplantation model without suppressing stemness gene expression in liver CSCs. Further study indicated that AA increased the concentration of H2O2 and induced apoptosis in liver CSCs. Catalase attenuated the inhibitory effects of AA on liver CSC viability. In conclusion, AA inhibited the viability of liver CSCs and the growth and metastasis of liver cancer cells in vitro and in vivo by increasing the production of H2O2 and inducing apoptosis. Our findings provide evidence that AA exerts its anti-liver cancer efficacy in vitro and in vivo, in a manner that is independent of stemness gene regulation.
Collapse
Affiliation(s)
- Jingjing Wan
- School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China
| | - Juan Zhou
- School of Pharmacy, Naval Medical University, Shanghai, China
| | - Lu Fu
- School of Pharmacy, Naval Medical University, Shanghai, China
| | - Yubin Li
- School of Pharmacy, Naval Medical University, Shanghai, China
| | - Huawu Zeng
- School of Pharmacy, Naval Medical University, Shanghai, China
| | - Xike Xu
- School of Pharmacy, Naval Medical University, Shanghai, China
| | - Chao Lv
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Huizi Jin
- School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China
| |
Collapse
|
|
49
|
Jin B, Hu W, Su S, Xu H, Lu X, Sang X, Yang H, Mao Y, Du S. The Prognostic Value of Systemic Inflammation Response Index in Cholangiocarcinoma Patients. Cancer Manag Res 2021; 13:6263-6277. [PMID: 34408489 PMCID: PMC8364361 DOI: 10.2147/cmar.s317954] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Accepted: 07/26/2021] [Indexed: 01/03/2023] Open
Abstract
Purpose We determined the prognostic value of the systemic inflammation response index (SIRI) in patients with cholangiocarcinoma after surgery and constructed a survival prediction model based on SIRI. Patients and Methods We recruited 328 patients with histopathologically confirmed cholangiocarcinoma from 2003 to 2017 and performed Kaplan–Meier survival and Cox analyses to analyze the prognostic value of the SIRI and identify other significant factors. A nomogram involving SIRI and other clinicopathological factors was established based on the training cohort. The concordance index (C-index), decision curve analysis, calibration plots, and Hosmer–Lemeshow test were used to evaluate the clinical utility of the nomogram and to compare it with the traditional TNM staging system. The results were validated using a separate validation cohort. Results The patients were randomly divided into the training (n = 232) and validation (n = 96) cohorts. In the training cohort, the independent factors derived from the Cox multivariate analysis were SIRI, platelet-to-lymphocyte ratio, jaundice, γ-glutamyl transpeptidase level, maximal tumor size, N stage, M stage, and radical surgery. Time-dependent receiver operating characteristic (ROC) curves showed higher AUC for SIRI than those for other inflammation-based biomarkers. A nomogram containing all the independent factors showed good discrimination and calibration. The C-index values for overall survival, 0.737 (95% Cl: 0.683–0.791) and 0.738 (95% Cl: 0.679–0.797) in the training and validation cohorts, respectively, were significantly better than those for the TNM staging system [0.576 (95% Cl: 0.515–0.637) and 0.523 (95% Cl: 0.465–0.581), respectively]. Conclusion SIRI was an independent prognostic factor for cholangiocarcinoma. A prognostic model based on SIRI might help clinicians to stratify patients more precisely and provide individualized treatment.
Collapse
Affiliation(s)
- Bao Jin
- Department of Liver Surgery, Peking Union Medical College Hospital (PUMCH), Peking Union Medical College (PUMC) & Chinese Academy of Medical Sciences (CAMS), Beijing, 100730, People's Republic of China
| | - Wenmo Hu
- Peking Union Medical College (PUMC) & Chinese Academy of Medical Sciences (CAMS), Beijing, 100730, People's Republic of China
| | - Si Su
- Peking Union Medical College (PUMC) & Chinese Academy of Medical Sciences (CAMS), Beijing, 100730, People's Republic of China
| | - Haifeng Xu
- Department of Liver Surgery, Peking Union Medical College Hospital (PUMCH), Peking Union Medical College (PUMC) & Chinese Academy of Medical Sciences (CAMS), Beijing, 100730, People's Republic of China
| | - Xin Lu
- Department of Liver Surgery, Peking Union Medical College Hospital (PUMCH), Peking Union Medical College (PUMC) & Chinese Academy of Medical Sciences (CAMS), Beijing, 100730, People's Republic of China
| | - Xinting Sang
- Department of Liver Surgery, Peking Union Medical College Hospital (PUMCH), Peking Union Medical College (PUMC) & Chinese Academy of Medical Sciences (CAMS), Beijing, 100730, People's Republic of China
| | - Huayu Yang
- Department of Liver Surgery, Peking Union Medical College Hospital (PUMCH), Peking Union Medical College (PUMC) & Chinese Academy of Medical Sciences (CAMS), Beijing, 100730, People's Republic of China
| | - Yilei Mao
- Department of Liver Surgery, Peking Union Medical College Hospital (PUMCH), Peking Union Medical College (PUMC) & Chinese Academy of Medical Sciences (CAMS), Beijing, 100730, People's Republic of China
| | - Shunda Du
- Department of Liver Surgery, Peking Union Medical College Hospital (PUMCH), Peking Union Medical College (PUMC) & Chinese Academy of Medical Sciences (CAMS), Beijing, 100730, People's Republic of China
| |
Collapse
|
|
50
|
Pelizzaro F, Cardin R, Penzo B, Pinto E, Vitale A, Cillo U, Russo FP, Farinati F. Liquid Biopsy in Hepatocellular Carcinoma: Where Are We Now? Cancers (Basel) 2021; 13:2274. [PMID: 34068786 PMCID: PMC8126224 DOI: 10.3390/cancers13092274] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Revised: 04/30/2021] [Accepted: 05/06/2021] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer related death worldwide. Diagnostic, prognostic, and predictive biomarkers are urgently needed in order to improve patient survival. Indeed, the most widely used biomarkers, such as alpha-fetoprotein (AFP), have limited accuracy as both diagnostic and prognostic tests. Liver biopsy provides an insight on the biology of the tumor, but it is an invasive procedure, not routinely used, and not representative of the whole neoplasia due to the demonstrated intra-tumoral heterogeneity. In recent years, liquid biopsy, defined as the molecular analysis of cancer by-products, released by the tumor in the bloodstream, emerged as an appealing source of new biomarkers. Several studies focused on evaluating extracellular vesicles, circulating tumor cells, cell-free DNA and non-coding RNA as novel reliable biomarkers. In this review, we aimed to provide a comprehensive overview on the most relevant available evidence on novel circulating biomarkers for early diagnosis, prognostic stratification, and therapeutic monitoring. Liquid biopsy seems to be a very promising instrument and, in the near future, some of these new non-invasive tools will probably change the clinical management of HCC patients.
Collapse
Affiliation(s)
- Filippo Pelizzaro
- Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, University of Padua, 35128 Padua, Italy; (F.P.); (R.C.); (B.P.); (E.P.); (F.P.R.)
| | - Romilda Cardin
- Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, University of Padua, 35128 Padua, Italy; (F.P.); (R.C.); (B.P.); (E.P.); (F.P.R.)
| | - Barbara Penzo
- Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, University of Padua, 35128 Padua, Italy; (F.P.); (R.C.); (B.P.); (E.P.); (F.P.R.)
| | - Elisa Pinto
- Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, University of Padua, 35128 Padua, Italy; (F.P.); (R.C.); (B.P.); (E.P.); (F.P.R.)
| | - Alessandro Vitale
- Hepatobiliary Surgery and Liver Transplantation Unit, Department of Surgery, Oncology and Gastroenterology, University of Padua, 35128 Padua, Italy; (A.V.); (U.C.)
| | - Umberto Cillo
- Hepatobiliary Surgery and Liver Transplantation Unit, Department of Surgery, Oncology and Gastroenterology, University of Padua, 35128 Padua, Italy; (A.V.); (U.C.)
| | - Francesco Paolo Russo
- Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, University of Padua, 35128 Padua, Italy; (F.P.); (R.C.); (B.P.); (E.P.); (F.P.R.)
| | - Fabio Farinati
- Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, University of Padua, 35128 Padua, Italy; (F.P.); (R.C.); (B.P.); (E.P.); (F.P.R.)
| |
Collapse
|