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Wang Y, Ohnuki H, Tran AD, Wang D, Ha T, Feng JX, Sim M, Barnhill R, Lugassy C, Sargen MR, Salazar-Cavazos E, Kruhlak M, Tosato G. Induced clustering of SHP2-depleted tumor cells in vascular islands restores sensitivity to MEK/ERK inhibition. J Clin Invest 2025; 135:e181609. [PMID: 40131370 PMCID: PMC12077907 DOI: 10.1172/jci181609] [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: 04/01/2024] [Accepted: 03/12/2025] [Indexed: 03/27/2025] Open
Abstract
Allosteric inhibitors of the tyrosine phosphatase Src homology 2 domain-containing protein tyrosine phosphatase 2 (SHP2) hold therapeutic promise in cancers with overactive RAS/ERK signaling, but adaptive resistance to SHP2 inhibitors may limit benefits. Here, we utilized tumor cells that proliferate similarly with or without endogenous SHP2 to explore means to overcome this growth independence from SHP2. We found that SHP2 depletion profoundly altered the output of vascular regulators, cytokines, chemokines, and other factors from SHP2 growth-resistant cancer cells. Tumors derived from inoculation of SHP2-depleted, but SHP2 growth-independent, mouse melanoma and colon carcinoma cell lines displayed a typically subverted architecture, in which proliferative tumor cells surrounding a remodeled vessel formed "vascular islands", each limited by surrounding hypoxic and dead tumor tissue, where inflammatory blood cells were limited. Although vascular islands generally reflect protected sanctuaries for tumor cells, we found that vascular island-resident, highly proliferative, SHP2-depleted tumor cells acquired an increased sensitivity to blockage of MEK/ERK signaling, resulting in reduced tumor growth. Our results show that the response to targeted therapies in resistant tumor cells was controlled by tumor cell-induced vascular changes and tumor architectural reorganization, providing a compelling approach to elicit tumor responses by exploiting tumor- and endothelium-dependent biochemical changes.
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MESH Headings
- Protein Tyrosine Phosphatase, Non-Receptor Type 11/genetics
- Protein Tyrosine Phosphatase, Non-Receptor Type 11/metabolism
- Protein Tyrosine Phosphatase, Non-Receptor Type 11/antagonists & inhibitors
- Protein Tyrosine Phosphatase, Non-Receptor Type 11/deficiency
- Animals
- Mice
- MAP Kinase Signaling System/drug effects
- Humans
- Cell Line, Tumor
- Drug Resistance, Neoplasm
- Colonic Neoplasms/pathology
- Colonic Neoplasms/drug therapy
- Melanoma, Experimental/pathology
- Melanoma, Experimental/drug therapy
- Melanoma, Experimental/enzymology
- Melanoma, Experimental/genetics
- Cell Proliferation
- Neovascularization, Pathologic/enzymology
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Affiliation(s)
- Yuyi Wang
- Laboratory of Cellular Oncology, Center for Cancer Research (CCR), National Cancer Institute (NCI), NIH, and
| | - Hidetaka Ohnuki
- Laboratory of Cellular Oncology, Center for Cancer Research (CCR), National Cancer Institute (NCI), NIH, and
| | - Andy D. Tran
- Center for Cancer Research Microscopy Core, Laboratory of Cancer Biology and Genetics, NCI, NIH, Bethesda, Maryland, USA
| | - Dunrui Wang
- Laboratory of Cellular Oncology, Center for Cancer Research (CCR), National Cancer Institute (NCI), NIH, and
| | - Taekyu Ha
- Laboratory of Cellular Oncology, Center for Cancer Research (CCR), National Cancer Institute (NCI), NIH, and
| | - Jing-Xin Feng
- Laboratory of Cellular Oncology, Center for Cancer Research (CCR), National Cancer Institute (NCI), NIH, and
| | - Minji Sim
- Laboratory of Cellular Oncology, Center for Cancer Research (CCR), National Cancer Institute (NCI), NIH, and
| | - Raymond Barnhill
- Department of Translational Research, Institut Curie, Paris, France
| | - Claire Lugassy
- Department of Translational Research, Institut Curie, Paris, France
| | - Michael R. Sargen
- Division of Cancer Epidemiology and Genetics, NCI, NIH, Rockville, Maryland, USA
| | - Emanuel Salazar-Cavazos
- Laboratory of Integrative Cancer Immunology, Center for Cancer Research, NIH, Bethesda, Maryland, USA
| | - Michael Kruhlak
- Center for Cancer Research Microscopy Core, Laboratory of Cancer Biology and Genetics, NCI, NIH, Bethesda, Maryland, USA
| | - Giovanna Tosato
- Laboratory of Cellular Oncology, Center for Cancer Research (CCR), National Cancer Institute (NCI), NIH, and
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2
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Harris AL, Kerr DJ, Pezzella F, Ribatti D. Accessing the vasculature in cancer: revising an old hallmark. Trends Cancer 2024; 10:1038-1051. [PMID: 39358088 DOI: 10.1016/j.trecan.2024.08.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Revised: 08/12/2024] [Accepted: 08/12/2024] [Indexed: 10/04/2024]
Abstract
The classic cancer hallmark, inducing angiogenesis, was born out of the long-held notion that tumours could grow only if new vessels were formed. The attempts, based on this premise, to therapeutically restrain angiogenesis in hopes of controlling tumour growth have been less effective than expected. This is partly because primary and metastatic tumours can grow without angiogenesis. The discovery of nonangiogenic cancers and the mechanisms they use to exploit normal vessels, called 'vessel co-option,' has opened a new field in cancer biology. Consequently, the cancer hallmark, 'inducing angiogenesis,' has been modified to 'inducing or accessing vasculature.'
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Affiliation(s)
| | - David J Kerr
- Radcliffe Department of Medicine, Nuffield Division of Clinical Laboratory Science, University of Oxford, Oxford, UK
| | - Francesco Pezzella
- Radcliffe Department of Medicine, Nuffield Division of Clinical Laboratory Science, University of Oxford, Oxford, UK.
| | - Domenico Ribatti
- Dipartimento di Biomedicina Traslazionale e Neuroscienze, Università degli Studi di Bari, Bari, Italy
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3
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Aziz H, Kwon YIC, Park AMG, Lai A, Lee KYC, Zhang D, Kwon Y, Pawlik TM. Recent advancements in management for noncolorectal, nonneuroendocrine hepatic metastases. J Gastrointest Surg 2024; 28:1922-1932. [PMID: 39154708 DOI: 10.1016/j.gassur.2024.08.012] [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: 07/29/2024] [Revised: 08/11/2024] [Accepted: 08/13/2024] [Indexed: 08/20/2024]
Abstract
BACKGROUND Owing to the heterogeneity of underlying primary tumors, noncolorectal, nonneuroendocrine metastases to the liver (NCNNMLs), although relatively rare, pose major challenges to treatment and long-term management. Despite being considered the gold standard for colorectal cancer liver metastases, the role of surgical resection for NCNNML remains controversial. Furthermore, advancements in locoregional treatment modalities, such as ablation and various chemotherapeutic modalities, have contributed to the treatment of patients with NCNNML. METHODS This was a comprehensive review of literature that used Medline/PubMed, Google Scholar, the Cochrane Library, and the Web of Science, which were accessed between 2014 and 2024. RESULTS NCNNMLs are rare tumor entities with varied presentation and outcomes. A multidisciplinary approach, which includes chemotherapy, surgery, and interventional radiologic techniques, can be implemented with good results. CONCLUSION Given the complex nature of NCNNML, its management should be highly individualized and multidisciplinary. Locoregional treatments, such as surgical resection and/or ablation, may be more appropriate for select patients and should be offered as a viable therapeutic option for a subset of individuals.
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Affiliation(s)
- Hassan Aziz
- Department of Surgery, University of Iowa Hospitals and Clinics, Iowa City, IA, United States
| | - Ye In Christopher Kwon
- Department of Surgery, School of Medicine, Virginia Commonwealth University, Richmond, VA, United States
| | - Andrew Min-Gi Park
- Department of Surgery, School of Medicine, Virginia Commonwealth University, Richmond, VA, United States
| | - Alan Lai
- Department of Surgery, School of Medicine, Virginia Commonwealth University, Richmond, VA, United States
| | - Kerry Yi Chen Lee
- Department of Surgery, School of Medicine, Virginia Commonwealth University, Richmond, VA, United States
| | - Dean Zhang
- Department of Surgery, School of Medicine, Virginia Commonwealth University, Richmond, VA, United States
| | - Yeseo Kwon
- Department of Surgery, School of Medicine, Tufts University, Boston, MA, United States
| | - Timothy M Pawlik
- Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH, United States.
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4
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Wu Z, Zang Y, Li C, He Z, Liu J, Du Z, Ma X, Jing L, Duan H, Feng J, Yan X. CD146, a therapeutic target involved in cell plasticity. SCIENCE CHINA. LIFE SCIENCES 2024; 67:1563-1578. [PMID: 38613742 DOI: 10.1007/s11427-023-2521-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Accepted: 12/28/2023] [Indexed: 04/15/2024]
Abstract
Since its identification as a marker for advanced melanoma in the 1980s, CD146 has been found to have multiple functions in both physiological and pathological processes, including embryonic development, tissue repair and regeneration, tumor progression, fibrosis disease, and inflammations. Subsequent research has revealed that CD146 is involved in various signaling pathways as a receptor or co-receptor in these processes. This correlation between CD146 and multiple diseases has sparked interest in its potential applications in diagnosis, prognosis, and targeted therapy. To better comprehend the versatile roles of CD146, we have summarized its research history and synthesized findings from numerous reports, proposing that cell plasticity serves as the underlying mechanism through which CD146 contributes to development, regeneration, and various diseases. Targeting CD146 would consequently halt cell state shifting during the onset and progression of these related diseases. Therefore, the development of therapy targeting CD146 holds significant practical value.
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Affiliation(s)
- Zhenzhen Wu
- CAS Engineering Laboratory for Nanozyme, Key Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
| | - Yuzhe Zang
- CAS Engineering Laboratory for Nanozyme, Key Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
- College of Life Sciences, University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Chuyi Li
- CAS Engineering Laboratory for Nanozyme, Key Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
- College of Life Sciences, University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Zhiheng He
- CAS Engineering Laboratory for Nanozyme, Key Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
- College of Life Sciences, University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Jingyu Liu
- CAS Engineering Laboratory for Nanozyme, Key Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
- College of Life Sciences, University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Zhaoqi Du
- CAS Engineering Laboratory for Nanozyme, Key Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
- College of Life Sciences, University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Xinran Ma
- CAS Engineering Laboratory for Nanozyme, Key Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
- College of Life Sciences, University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Lin Jing
- CAS Engineering Laboratory for Nanozyme, Key Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
| | - Hongxia Duan
- CAS Engineering Laboratory for Nanozyme, Key Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.
- Nanozyme Laboratory in Zhongyuan, Henan Academy of Innovations in Medical Science, Zhengzhou, 451163, China.
| | - Jing Feng
- CAS Engineering Laboratory for Nanozyme, Key Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.
| | - Xiyun Yan
- CAS Engineering Laboratory for Nanozyme, Key Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.
- College of Life Sciences, University of Chinese Academy of Sciences, Beijing, 100049, China.
- Nanozyme Laboratory in Zhongyuan, Henan Academy of Innovations in Medical Science, Zhengzhou, 451163, China.
- Joint Laboratory of Nanozymes in Zhengzhou University, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China.
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5
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Wang S, Riedstra CP, Zhang Y, Anandh S, Dudley AC. PTEN-restoration abrogates brain colonisation and perivascular niche invasion by melanoma cells. Br J Cancer 2024; 130:555-567. [PMID: 38148377 PMCID: PMC10876963 DOI: 10.1038/s41416-023-02530-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Revised: 11/23/2023] [Accepted: 11/27/2023] [Indexed: 12/28/2023] Open
Abstract
BACKGROUND Melanoma brain metastases (MBM) continue to be a significant clinical problem with limited treatment options. Highly invasive melanoma cells migrate along the vasculature and perivascular cells may contribute to residual disease and recurrence. PTEN loss and hyperactivation of AKT occur in MBM; however, a role for PTEN/AKT in perivascular invasion has not been described. METHODS We used in vivo intracranial injections of murine melanoma and bulk RNA sequencing of melanoma cells co-cultured with brain endothelial cells (brECs) to investigate brain colonisation and perivascular invasion. RESULTS We found that PTEN-null melanoma cells were highly efficient at colonising the perivascular niche relative to PTEN-expressing counterparts. PTEN re-expression (PTEN-RE) in melanoma cells significantly reduced brain colonisation and migration along the vasculature. We hypothesised this phenotype was mediated through vascular-induced TGFβ secretion, which drives AKT phosphorylation. Disabling TGFβ signalling in melanoma cells reduced colonisation and perivascular invasion; however, the introduction of constitutively active myristolated-AKT (myrAKT) restored overall tumour size but not perivascular invasion. CONCLUSIONS PTEN loss facilitates perivascular brain colonisation and invasion of melanoma. TGFβ-AKT signalling partially contributes to this phenotype, but further studies are needed to determine the complementary mechanisms that enable melanoma cells to both survive and spread along the brain vasculature.
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Affiliation(s)
- Sarah Wang
- Department of Microbiology, Immunology, and Cancer Biology, The University of Virginia, Charlottesville, VA, 22908, USA
| | - Caroline P Riedstra
- Department of Microbiology, Immunology, and Cancer Biology, The University of Virginia, Charlottesville, VA, 22908, USA
| | - Yu Zhang
- Department of Microbiology, Immunology, and Cancer Biology, The University of Virginia, Charlottesville, VA, 22908, USA
| | - Swetha Anandh
- Department of Microbiology, Immunology, and Cancer Biology, The University of Virginia, Charlottesville, VA, 22908, USA
| | - Andrew C Dudley
- Department of Microbiology, Immunology, and Cancer Biology, The University of Virginia, Charlottesville, VA, 22908, USA.
- The University of Virginia Comprehensive Cancer Center, Charlottesville, VA, USA.
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Li H, Huang H, Tan H, Jia Q, Song W, Zhang Q, Zhou B, Bai J. Key processes in tumor metastasis and therapeutic strategies with nanocarriers: a review. Mol Biol Rep 2024; 51:197. [PMID: 38270746 DOI: 10.1007/s11033-023-08910-7] [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: 10/05/2023] [Accepted: 11/14/2023] [Indexed: 01/26/2024]
Abstract
Cancer metastasis is the leading cause of cancer-related death. Metastasis occurs at all stages of tumor development, with unexplored changes occurring at the primary site and distant colonization sites. The growing understanding of the metastatic process of tumor cells has contributed to the emergence of better treatment options and strategies. This review summarizes a range of features related to tumor cell metastasis and nanobased drug delivery systems for inhibiting tumor metastasis. The mechanisms of tumor metastasis in the ideal order of metastatic progression were summarized. We focus on the prominent role of nanocarriers in the treatment of tumor metastasis, summarizing the latest applications of nanocarriers in combination with drugs to target important components and processes of tumor metastasis and providing ideas for more effective nanodrug delivery systems.
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Affiliation(s)
- Hongjie Li
- School of Clinical Medicine, Weifang Medical University, 261053, Weifang, China
| | - Haiqin Huang
- School of Bioscience and Technology, Weifang Medical University, 261053, Weifang, China
| | - Haining Tan
- National Glycoengineering Research Center, Shandong University, 250012, Jinan, China
| | - Qitao Jia
- School of Bioscience and Technology, Weifang Medical University, 261053, Weifang, China
| | - Weina Song
- Department of Pediatric Respiratory and Critical Care, Qilu Hospital of Shandong University Dezhou Hospital, 253000, Dezhou, China
| | - Qingdong Zhang
- School of Bioscience and Technology, Weifang Medical University, 261053, Weifang, China.
| | - Baolong Zhou
- School of Pharmacy, Weifang Medical University, 261053, Weifang, China.
| | - Jingkun Bai
- School of Bioscience and Technology, Weifang Medical University, 261053, Weifang, China.
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7
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Yang S, Peng LR, Yu AQ, Li J. CSNK2A2 promotes hepatocellular carcinoma progression through activation of NF-κB pathway. Ann Hepatol 2023; 28:101118. [PMID: 37268061 DOI: 10.1016/j.aohep.2023.101118] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Revised: 04/27/2023] [Accepted: 05/09/2023] [Indexed: 06/04/2023]
Abstract
INTRODUCTION AND OBJECTIVES Breast and non-small cell lung cancers harbor an upregulated CSNK2A2 oncogene that encodes the protein kinase CK2 alpha', a catalytic subunit of the highly conserved serine/threonine kinase CK2. However, its role and biological significance in hepatocellular carcinoma (HCC) remains unclear. MATERIALS AND METHODS Western-blotting and immunohistochemistry were used to measure the expression of CSNK2A2 in HCC tumor tissues and cell lines. CCK8, Hoechst staining, transwell, tube formation assay in vitro and nude mice experiments in vivo were used to measure the effects of CSNK2A2 on HCC proliferation, apoptosis, metastasis, angiogenesis and tumor formation. RESULTS In the study, we showed that CSNK2A2 was highly expressed in HCC comparison with matched control tissues, and was linked with lower survival of patients. Additional experiments indicated that silencing of CSNK2A2 promoted HCC cell apoptosis, while inhibited HCC cells migrating, proliferating, angiogenesis both in vitro and in vivo. These effects were also accompanied by reduced expression of NF-κB target genes, including CCND1, MMP9 and VEGF. Moreover, treatment with PDTC counteracted the promotional effects of CSNK2A2 on HCC cells. CONCLUSIONS Overall, our results suggested that CSNK2A2 could promote HCC progression by activating the NF-κB pathway, and this could serve as a biomarker for future prognostic and therapeutic applications.
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Affiliation(s)
- Shuang Yang
- Department of Clinical Laboratory, Hunan Provincial People's Hospital (The First-Affiliated Hospital of Hunan Normal University), Changsha 410005, PR China.
| | - Li Rong Peng
- Department of Clinical Laboratory, Hunan Provincial People's Hospital (The First-Affiliated Hospital of Hunan Normal University), Changsha 410005, PR China
| | - Ai Qing Yu
- Department of Clinical Laboratory, Hunan Provincial People's Hospital (The First-Affiliated Hospital of Hunan Normal University), Changsha 410005, PR China
| | - Jiang Li
- Department of Clinical Laboratory, Hunan Provincial People's Hospital (The First-Affiliated Hospital of Hunan Normal University), Changsha 410005, PR China
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Fernández Moro C, Geyer N, Harrizi S, Hamidi Y, Söderqvist S, Kuznyecov D, Tidholm Qvist E, Salmonson Schaad M, Hermann L, Lindberg A, Heuchel RL, Martín-Bernabé A, Dhanjal S, Navis AC, Villard C, Del Valle AC, Bozóky L, Sparrelid E, Dirix L, Strell C, Östman A, Schmierer B, Vermeulen PB, Engstrand J, Bozóky B, Gerling M. An idiosyncratic zonated stroma encapsulates desmoplastic liver metastases and originates from injured liver. Nat Commun 2023; 14:5024. [PMID: 37596278 PMCID: PMC10439160 DOI: 10.1038/s41467-023-40688-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2022] [Accepted: 07/31/2023] [Indexed: 08/20/2023] Open
Abstract
A perimetastatic capsule is a strong positive prognostic factor in liver metastases, but its origin remains unclear. Here, we systematically quantify the capsule's extent and cellular composition in 263 patients with colorectal cancer liver metastases to investigate its clinical significance and origin. We show that survival improves proportionally with increasing encapsulation and decreasing tumor-hepatocyte contact. Immunostaining reveals the gradual zonation of the capsule, transitioning from benign-like NGFRhigh stroma at the liver edge to FAPhigh stroma towards the tumor. Encapsulation correlates with decreased tumor viability and preoperative chemotherapy. In mice, chemotherapy and tumor cell ablation induce capsule formation. Our results suggest that encapsulation develops where tumor invasion into the liver plates stalls, representing a reparative process rather than tumor-induced desmoplasia. We propose a model of metastases growth, where the efficient tumor colonization of the liver parenchyma and a reparative liver injury reaction are opposing determinants of metastasis aggressiveness.
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Affiliation(s)
- Carlos Fernández Moro
- Department of Biosciences and Nutrition, Karolinska Institutet, 14183, Huddinge, Sweden
- Department of Clinical Pathology and Cancer Diagnostics, Karolinska University Hospital, Stockholm, 14186, Sweden
- Department of Laboratory Medicine, Division of Pathology, Karolinska Institutet, 14186, Stockholm, Sweden
| | - Natalie Geyer
- Department of Biosciences and Nutrition, Karolinska Institutet, 14183, Huddinge, Sweden
| | - Sara Harrizi
- Department of Biosciences and Nutrition, Karolinska Institutet, 14183, Huddinge, Sweden
| | - Yousra Hamidi
- Department of Biosciences and Nutrition, Karolinska Institutet, 14183, Huddinge, Sweden
| | - Sara Söderqvist
- Department of Biosciences and Nutrition, Karolinska Institutet, 14183, Huddinge, Sweden
| | - Danyil Kuznyecov
- Department of Clinical Genetics, Pathology and Molecular Diagnostics, Medicinsk Service, Skåne University Hospital, 22185, Lund, Sweden
| | - Evelina Tidholm Qvist
- Department of Clinical Pathology and Cancer Diagnostics, Karolinska University Hospital, Stockholm, 14186, Sweden
| | | | - Laura Hermann
- Department of Biosciences and Nutrition, Karolinska Institutet, 14183, Huddinge, Sweden
| | - Amanda Lindberg
- Department of Immunology, Genetics and Pathology, Uppsala University, 75185, Uppsala, Sweden
| | - Rainer L Heuchel
- Pancreatic Cancer Research Laboratory, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, 14183, Hudinge, Sweden
| | | | - Soniya Dhanjal
- CRISPR Functional Genomics, SciLifeLab and Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 17165, Solna, Sweden
| | - Anna C Navis
- CRISPR Functional Genomics, SciLifeLab and Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 17165, Solna, Sweden
| | - Christina Villard
- Department of Medicine Huddinge, Karolinska Institutet, 14183, Huddinge, Sweden
| | - Andrea C Del Valle
- Department of Biosciences and Nutrition, Karolinska Institutet, 14183, Huddinge, Sweden
| | - Lorand Bozóky
- Department of Biosciences and Nutrition, Karolinska Institutet, 14183, Huddinge, Sweden
| | - Ernesto Sparrelid
- Department of Clinical Science, Intervention and Technology, Division of Surgery, Karolinska Institutet, Karolinska University Hospital, 14152, Stockholm, Sweden
| | - Luc Dirix
- Translational Cancer Research Unit (GZA Hospitals and University of Antwerp), Antwerp, Belgium
| | - Carina Strell
- Department of Immunology, Genetics and Pathology, Uppsala University, 75185, Uppsala, Sweden
- Centre for Cancer Biomarkers CCBIO, Department of Clinical Medicine, University of Bergen, 5020, Bergen, Norway
| | - Arne Östman
- Department of Oncology-Pathology, Karolinska Institutet, 17176, Solna, Sweden
| | - Bernhard Schmierer
- CRISPR Functional Genomics, SciLifeLab and Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 17165, Solna, Sweden
| | - Peter B Vermeulen
- Translational Cancer Research Unit (GZA Hospitals and University of Antwerp), Antwerp, Belgium
| | - Jennie Engstrand
- Department of Clinical Science, Intervention and Technology, Division of Surgery, Karolinska Institutet, Karolinska University Hospital, 14152, Stockholm, Sweden
| | - Béla Bozóky
- Department of Clinical Pathology and Cancer Diagnostics, Karolinska University Hospital, Stockholm, 14186, Sweden
| | - Marco Gerling
- Department of Biosciences and Nutrition, Karolinska Institutet, 14183, Huddinge, Sweden.
- Theme Cancer, Karolinska University Hospital, 17 176, Solna, Sweden.
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9
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Chen X, Xia Y, Du W, Liu H, Hou R, Song Y, Xu W, Mao Y, Chen J. Contact Guidance Drives Upward Cellular Migration at the Mesoscopic Scale. Cell Mol Bioeng 2023; 16:205-218. [PMID: 37456789 PMCID: PMC10338420 DOI: 10.1007/s12195-023-00766-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Accepted: 04/05/2023] [Indexed: 07/18/2023] Open
Abstract
Introduction Cancer metastasis is associated with increased cancer incidence, recurrence, and mortality. The role of cell contact guidance behaviors in cancer metastasis has been recognized but has not been elucidated yet. Methods The contact guidance behavior of cancer cells in response to topographical constraints is identified using microgrooved substrates with varying dimensions at the mesoscopic scale. Then, the cell morphology is determined to quantitatively analyze the effects of substrate dimensions on cells contact guidance. Cell density and migrate velocity signatures within the cellular population are determined using time-lapse phase-contrast microscopy. The effect of soluble factors concentration is determined by culturing cells upside down. Then, the effect of cell-substrate interaction on cell migration is investigated using traction force microscopy. Results With increasing depth and decreasing groove width, cell elongation and alignment are enhanced, while cell spreading is inhibited. Moreover, cells display preferential distribution on the ridges, which is found to be more pronounced with increasing depth and groove width. Determinations of cell density and migration velocity signatures reveal that the preferential distribution on ridges is caused by cell upward migration. Combined with traction force measurement, we find that migration toward ridges is governed by different cell-substrate interactions between grooves and ridges caused by geometrical constraints. Interestingly, the upward migration of cells at the mesoscopic scale is driven by entropic maximization. Conclusions The mesoscopic cell contact guidance mechanism based on the entropic force driven theory provides basic support for the study of cell alignment and migration along healthy tissues with varying size, thereby aiding in the prediction of cancer metastasis. Graphical Abstract Supplementary Information The online version contains supplementary material available at 10.1007/s12195-023-00766-y.
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Affiliation(s)
- Xiaoxiao Chen
- School of Advanced Manufacturing, Nanchang University, Nanchang, 330031 Jiangxi China
- Department of Precision Machinery and Precision Instrumentation, University of Science and Technology of China, Hefei, 230027 Anhui China
| | - Youjun Xia
- Department of Precision Machinery and Precision Instrumentation, University of Science and Technology of China, Hefei, 230027 Anhui China
- Key Laboratory of Precision Scientific Instrumentation of Anhui Higher Education Institutes, University of Science and Technology of China, Hefei, 230027 Anhui China
| | - Wenqiang Du
- Biomedical Engineering Department, University of Connecticut Health Center, Farmington, CT 06030 USA
| | - Han Liu
- School of Advanced Manufacturing, Nanchang University, Nanchang, 330031 Jiangxi China
| | - Ran Hou
- School of Advanced Manufacturing, Nanchang University, Nanchang, 330031 Jiangxi China
| | - Yiyu Song
- School of Advanced Manufacturing, Nanchang University, Nanchang, 330031 Jiangxi China
| | - Wenhu Xu
- School of Advanced Manufacturing, Nanchang University, Nanchang, 330031 Jiangxi China
| | - Yuxin Mao
- School of Biomedical Engineering, Anhui Medical University, Hefei, 230032 Anhui China
| | - Jianfeng Chen
- School of Advanced Manufacturing, Nanchang University, Nanchang, 330031 Jiangxi China
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10
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do Valle IB, Oliveira SR, da Silva JM, Peterle GT, Có ACG, Sousa-Neto SS, Mendonça EF, de Arruda JAA, Gomes NA, da Silva G, Leopoldino AM, Macari S, Birbrair A, von Zeidler SV, Diniz IMA, Silva TA. The participation of tumor residing pericytes in oral squamous cell carcinoma. Sci Rep 2023; 13:5460. [PMID: 37015965 PMCID: PMC10073133 DOI: 10.1038/s41598-023-32528-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Accepted: 03/29/2023] [Indexed: 04/06/2023] Open
Abstract
Pericytes are perivascular cells related to vessel structure and angiogenesis that can interact with neoplastic cells, interfering with cancer progression and outcomes. This study focused on the characterization of pericytes in oral squamous cell carcinoma (OSCC) using clinical samples and a transgenic mouse model of oral carcinogenesis. Nestin-/NG2+ (type-1) and nestin+/NG2+ (type-2) pericytes were analyzed by direct fluorescence after induction of oral carcinogenesis (4-nitroquinoline-1-oxide). Gene expression of neuron glial antigen-2 (NG2), platelet-derived growth factor receptor beta (PDGFR-β), and cluster of differentiation 31 (CD31) was examined in human OSCC tissues. The protein expression of von Willebrand factor and NG2 was assessed in oral leukoplakia (i.e., oral potentially malignant disorders) and OSCC samples. Additionally, clinicopathological aspects and survival data were correlated and validated by bioinformatics using The Cancer Genome Atlas (TCGA). Induction of carcinogenesis in mice produced an increase in both NG2+ pericyte subsets. In human OSCC, advanced-stage tumors showed a significant reduction in CD31 mRNA and von Willebrand factor-positive vessels. Low PDGFR-β expression was related to a shorter disease-free survival time, while NG2 mRNA overexpression was associated with a reduction in overall survival, consistent with the TCGA data. Herein, oral carcinogenesis resulted in an increase in NG2+ pericytes, which negatively affected survival outcomes.
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Affiliation(s)
- Isabella Bittencourt do Valle
- Department of Oral Surgery, Pathology and Clinical Dentistry, School of Dentistry, Universidade Federal de Minas Gerais, Av. Antônio Carlos, 6627, room 3105, Belo Horizonte, Minas Gerais, CEP: 31.270-901, Brazil
| | - Sicília Rezende Oliveira
- Department of Oral Surgery, Pathology and Clinical Dentistry, School of Dentistry, Universidade Federal de Minas Gerais, Av. Antônio Carlos, 6627, room 3105, Belo Horizonte, Minas Gerais, CEP: 31.270-901, Brazil
| | - Janine Mayra da Silva
- Department of Oral Surgery, Pathology and Clinical Dentistry, School of Dentistry, Universidade Federal de Minas Gerais, Av. Antônio Carlos, 6627, room 3105, Belo Horizonte, Minas Gerais, CEP: 31.270-901, Brazil
| | - Gabriela Tonini Peterle
- Biotechnology Post-graduation Program, Centro de Ciências da Saúde, Universidade Federal do Espírito Santo, Vitória, Espírito Santo, Brazil
| | - Anna Clara Gregório Có
- Biotechnology Post-graduation Program, Centro de Ciências da Saúde, Universidade Federal do Espírito Santo, Vitória, Espírito Santo, Brazil
| | - Sebastião Silvério Sousa-Neto
- Department of Stomatology (Oral Pathology), School of Dentistry, Universidade Federal de Goiás, Goiânia, Goiás, Brazil
| | - Elismauro Francisco Mendonça
- Department of Stomatology (Oral Pathology), School of Dentistry, Universidade Federal de Goiás, Goiânia, Goiás, Brazil
| | - José Alcides Almeida de Arruda
- Department of Oral Surgery, Pathology and Clinical Dentistry, School of Dentistry, Universidade Federal de Minas Gerais, Av. Antônio Carlos, 6627, room 3105, Belo Horizonte, Minas Gerais, CEP: 31.270-901, Brazil
| | - Natália Aparecida Gomes
- Department of Restorative Dentistry, School of Dentistry, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Gabriel da Silva
- Department of Clinical Analysis, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, Universidade de São Paulo, São Paulo, Brazil
| | - Andréia Machado Leopoldino
- Department of Clinical Analysis, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, Universidade de São Paulo, São Paulo, Brazil
| | - Soraia Macari
- Department of Restorative Dentistry, School of Dentistry, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Alexander Birbrair
- Department of Pathology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Sandra Ventorin von Zeidler
- Biotechnology Post-graduation Program, Centro de Ciências da Saúde, Universidade Federal do Espírito Santo, Vitória, Espírito Santo, Brazil
| | - Ivana Márcia Alves Diniz
- Department of Restorative Dentistry, School of Dentistry, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Tarcília Aparecida Silva
- Department of Oral Surgery, Pathology and Clinical Dentistry, School of Dentistry, Universidade Federal de Minas Gerais, Av. Antônio Carlos, 6627, room 3105, Belo Horizonte, Minas Gerais, CEP: 31.270-901, Brazil.
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11
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Lezcano C, Berwick M, Luo L, Barnhill R, Duncan LM, Gerami P, Lowe L, Messina JL, Scolyer RA, Wood B, Yeh I, Zembowicz A, Busam KJ. Interobserver agreement in the histopathological classification of desmoplastic melanomas. Pathology 2023; 55:223-226. [PMID: 36653238 PMCID: PMC9974895 DOI: 10.1016/j.pathol.2022.12.347] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2022] [Revised: 12/08/2022] [Accepted: 12/13/2022] [Indexed: 01/03/2023]
Abstract
Desmoplastic melanoma is a subtype of melanoma characterised by amelanotic fusiform melanocytes dispersed in a collagenous stroma. Cell-poor and fibrous stroma-rich 'pure' variants have been distinguished from 'mixed' variants with areas of higher cell density and/or less desmoplastic stroma. This distinction is relevant because patients whose tumours display a pure phenotype have a lower risk for regional lymph node metastasis and distant recurrence. However, little is known about interobserver agreement among pathologists in the subclassification of desmoplastic melanoma. To address this issue, we conducted a study in which eleven dermatopathologists independently evaluated whole slide scanned images of excisions from 30 desmoplastic melanomas. The participating pathologists were asked to classify the tumours as pure or mixed. They were also asked to record the presence or absence of neurotropism and angiotropism. We found substantial interobserver agreement between the 11 dermatopathologists in the classification of tumours as pure versus mixed desmoplastic melanoma (kappa=0.64; p<0.0001). There was fair agreement between the 11 dermatopathologists in the evaluation of presence versus absence of neurotropism (kappa=0.26; p<0.0001), and slight agreement in the assessment of angiotropism (kappa=0.13; p<0.0001). The level of concordance in the subclassification of desmoplastic melanomas is encouraging for the acceptance of this prognostic parameter in the real-world practice of melanoma pathology.
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Affiliation(s)
- Cecilia Lezcano
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer, New York, NY, USA.
| | - Marianne Berwick
- Department of Internal Medicine, University of New Mexico Comprehensive Cancer Center, University of New Mexico, Albuquerque, NM, USA
| | - Li Luo
- Department of Internal Medicine, University of New Mexico Comprehensive Cancer Center, University of New Mexico, Albuquerque, NM, USA
| | - Raymond Barnhill
- Department of Translational Research, Institut Curie, Université de Paris UFR de Médecine, Paris, France
| | - Lyn M Duncan
- Pathology Service, Dermatopathology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Pedram Gerami
- Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Lori Lowe
- Departments of Pathology and Dermatology, University of Michigan, Ann Arbor, MI, USA
| | - Jane L Messina
- Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA
| | - Richard A Scolyer
- Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia; Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital and NSW Health Pathology, Sydney, NSW, Australia; Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia
| | - Benjamin Wood
- Department of Anatomical Pathology, PathWest Laboratory Medicine, Perth, WA, Australia
| | - Iwei Yeh
- Departments of Dermatology and Pathology, University of California San Francisco, San Francisco, CA, USA
| | - Artur Zembowicz
- Dermatopathology Consultations LLC, Lahey Clinic and Tufts Medical School, Boston, MA, USA
| | - Klaus J Busam
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer, New York, NY, USA
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12
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Diagnostic error, uncertainty, and overdiagnosis in melanoma. Pathology 2023; 55:206-213. [PMID: 36642569 PMCID: PMC10373372 DOI: 10.1016/j.pathol.2022.12.345] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Revised: 12/16/2022] [Accepted: 12/19/2022] [Indexed: 12/31/2022]
Abstract
Diagnostic error can be defined as deviation from a gold standard diagnosis, typically defined in terms of expert opinion, although sometimes in terms of unexpected events that might occur in follow-up (such as progression and death from disease). Although diagnostic error does exist for melanoma, deviations from gold standard diagnosis, certainly among appropriately trained and experienced practitioners, are likely to be the result of uncertainty and lack of specific criteria, and differences of opinion, rather than lack of diagnostic skills. In this review, the concept of diagnostic error will be considered in relation to diagnostic uncertainty, and the concept of overdiagnosis in melanoma will be presented and discussed.
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13
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Sharpe JL, Morgan J, Nisbet N, Campbell K, Casali A. Modelling Cancer Metastasis in Drosophila melanogaster. Cells 2023; 12:cells12050677. [PMID: 36899813 PMCID: PMC10000390 DOI: 10.3390/cells12050677] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Revised: 02/14/2023] [Accepted: 02/17/2023] [Indexed: 02/24/2023] Open
Abstract
Cancer metastasis, the process by which tumour cells spread throughout the body and form secondary tumours at distant sites, is the leading cause of cancer-related deaths. The metastatic cascade is a highly complex process encompassing initial dissemination from the primary tumour, travel through the blood stream or lymphatic system, and the colonisation of distant organs. However, the factors enabling cells to survive this stressful process and adapt to new microenvironments are not fully characterised. Drosophila have proven a powerful system in which to study this process, despite important caveats such as their open circulatory system and lack of adaptive immune system. Historically, larvae have been used to model cancer due to the presence of pools of proliferating cells in which tumours can be induced, and transplanting these larval tumours into adult hosts has enabled tumour growth to be monitored over longer periods. More recently, thanks largely to the discovery that there are stem cells in the adult midgut, adult models have been developed. We focus this review on the development of different Drosophila models of metastasis and how they have contributed to our understanding of important factors determining metastatic potential, including signalling pathways, the immune system and the microenvironment.
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Affiliation(s)
- Joanne L. Sharpe
- School of Biosciences, The University of Sheffield, Sheffield S10 2TN, UK
| | - Jason Morgan
- School of Biosciences, The University of Sheffield, Sheffield S10 2TN, UK
| | - Nicholas Nisbet
- School of Biosciences, The University of Sheffield, Sheffield S10 2TN, UK
| | - Kyra Campbell
- School of Biosciences, The University of Sheffield, Sheffield S10 2TN, UK
- Correspondence: (K.C.); (A.C.)
| | - Andreu Casali
- Departament de Ciències Mèdiques Bàsiques, Universitat de Lleida and IRBLleida, Av. Alcalde Rovira Roure, 80, 25198 Lleida, Spain
- Correspondence: (K.C.); (A.C.)
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14
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Kong B, Zhang Q, Zhang G. Use the term "infiltrative" instead of "replacement" when defining histopathological growth pattern in patients with liver cancer. Br J Cancer 2023; 128:489-490. [PMID: 36564564 PMCID: PMC9938117 DOI: 10.1038/s41416-022-02121-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 12/06/2022] [Accepted: 12/12/2022] [Indexed: 12/24/2022] Open
Affiliation(s)
- Bingtan Kong
- Beijing University of Chinese Medicine, 100029, Beijing, China.
| | - Qing Zhang
- Department of Oncology, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, 100010, Beijing, China.
| | - Ganlin Zhang
- Department of Oncology, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, 100010, Beijing, China.
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15
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Lugassy C, Kleinman HK, Barnhill RL. Monitoring Angiotropic Extravascular Migratory Metastasis In Vitro. Methods Mol Biol 2023; 2572:91-100. [PMID: 36161410 DOI: 10.1007/978-1-0716-2703-7_7] [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] [Indexed: 06/16/2023]
Abstract
The mechanism of cancer cell migration from the primary tumor toward secondary sites is not fully understood. In addition to intravascular cellular migration, angiotropic extravascular migratory metastasis (EVMM) has been recognized as a metastatic pathway involving tumor cells crawling along the abluminal vascular surface to distant sites. A very simple in vitro 3D assay is described here, which is based on a previous in vitro angiogenesis assay. The assay involves monitoring single fluorescence-tagged migrating cancer cells in the presence of vascular structures in real time. This coculture assay represents a quantitative approach for monitoring the migration processes of cancer cells along vessels, demonstrating phenotypic switching and migration dynamics. This protocol can be used for molecular analyses and can also be adapted for screening of therapeutic agents to block cancer metastasis.
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Affiliation(s)
- Claire Lugassy
- Department of Translational Research, Institut Curie, Paris, France.
| | - Hynda K Kleinman
- Department of Molecular Medicine and Biochemistry, The George Washington School of Medicine, Washington, DC, USA
| | - Raymond L Barnhill
- Department of Translational Research, Institut Curie, Paris, France
- Faculty of Medicine, University of Paris Réné Descartes, Paris, France
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16
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Seibel AJ, Kelly OM, Dance YW, Nelson CM, Tien J. Role of Lymphatic Endothelium in Vascular Escape of Engineered Human Breast Microtumors. Cell Mol Bioeng 2022; 15:553-569. [PMID: 36531861 PMCID: PMC9751254 DOI: 10.1007/s12195-022-00745-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Accepted: 10/06/2022] [Indexed: 11/09/2022] Open
Abstract
Introduction Lymphatic vasculature provides a route for metastasis to secondary sites in the body. The role of the lymphatic endothelium in mediating the entry of breast cancer cells into the vasculature remains unclear. Methods In this study, we formed aggregates of MDA-MB-231 human breast carcinoma cells next to human microvascular lymphatic endothelial cell (LEC)-lined cavities in type I collagen gels to model breast microtumors and lymphatic vessels, respectively. We tracked invasion and escape of breast microtumors into engineered lymphatics or empty cavities under matched flow rates for up to sixteen days. Results After coming into contact with a lymphatic vessel, tumor cells escape by moving between the endothelium and the collagen wall, between endothelial cells, and/or into the endothelial lumen. Over time, tumor cells replace the LECs within the vessel wall and create regions devoid of endothelium. The presence of lymphatic endothelium slows breast tumor invasion and escape, and addition of LEC-conditioned medium to tumors is sufficient to reproduce nearly all of these inhibitory effects. Conclusions This work sheds light on the interactions between breast cancer cells and lymphatic endothelium during vascular escape and reveals an inhibitory role for the lymphatic endothelium in breast tumor invasion and escape. Supplementary Information The online version contains supplementary material available at 10.1007/s12195-022-00745-9.
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Affiliation(s)
- Alex J. Seibel
- Department of Biomedical Engineering, Boston University, 44 Cummington Mall, Boston, MA 02215 USA
| | - Owen M. Kelly
- Department of Biomedical Engineering, Boston University, 44 Cummington Mall, Boston, MA 02215 USA
| | - Yoseph W. Dance
- Department of Biomedical Engineering, Boston University, 44 Cummington Mall, Boston, MA 02215 USA
| | - Celeste M. Nelson
- Department of Chemical and Biological Engineering, Princeton University, 303 Hoyt Laboratory, 25 William Street, Princeton, NJ 08544 USA
- Department of Molecular Biology, Princeton University, Princeton, NJ USA
| | - Joe Tien
- Department of Biomedical Engineering, Boston University, 44 Cummington Mall, Boston, MA 02215 USA
- Division of Materials Science and Engineering, Boston University, Boston, MA USA
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17
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L1CAM and laminin vascular network: Association with the high-risk replacement histopathologic growth pattern in uveal melanoma liver metastases. J Transl Med 2022; 102:1214-1224. [PMID: 36775447 DOI: 10.1038/s41374-022-00803-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Revised: 04/25/2022] [Accepted: 05/02/2022] [Indexed: 12/22/2022] Open
Abstract
The replacement histopathologic growth pattern (rHGP) in melanoma liver metastases connotes an aggressive phenotype (vascular co-option; angiotropic extravascular migratory spread) and adverse prognosis. Herein, replacement and desmoplastic HGP (dHGP) were studied in uveal melanoma liver metastases (MUM). In particular, L1CAM and a "laminin vascular network" were detected at the advancing front of 14/20 cases (p = 0.014) and 16/20 cases (p = 6.4e-05) rHGPs, respectively, but both were absent in the dHGP (8/8 cases) (p = 0.014, and p = 6.3e-05, respectively). L1CAM highlighted progressive extension of angiotropic melanoma cells along sinusoidal vessels in a pericytic location (pericytic mimicry) into the hepatic parenchyma. An inverse relationship between L1CAM expression and melanin index (p = 0.012) suggested differentiation toward an amelanotic embryonic migratory phenotype in rHGP. Laminin labeled the basement membrane zone interposed between sinusoidal vascular channels and angiotropic melanoma cells at the advancing front. Other new findings: any percentage of rHGP and pure rHGP had a significant adverse effect on metastasis-specific overall survival (p = 0.038; p = 0.0064), as well as predominant rHGP (p = 0.0058). Pure rHGP also was associated with diminished metastasis-free survival relative to dHGP (p = 0.040), possibly having important implications for mechanisms of tumor spread. In conclusion, we report for the first time that L1CAM and a laminin vascular network are directly involved in this high-risk replacement phenotype. Further, this study provides more detailed information about the adverse prognostic effect of the rHGP in MUM.
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18
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Lugassy C, Kleinman HK, Cassoux N, Barnhill R. Hematogenous metastasis and tumor dormancy as concepts or dogma? The continuum of vessel co-option and angiotropic extravascular migratory metastasis as an alternative. Front Oncol 2022; 12:996411. [PMID: 36303828 PMCID: PMC9594150 DOI: 10.3389/fonc.2022.996411] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2022] [Accepted: 09/08/2022] [Indexed: 11/15/2022] Open
Abstract
It has been accepted for many years that tumor cells spread via the circulation to distant sites. The latency period between treatment and tumor recurrence has been attributed to dormant cells in distant organs that emerge and grow as metastatic tumors. These processes are accepted with an incomplete demonstration of their existence. Challenging such a well-established accepted paradigm is not easy as history as shown. An alternative or co-existing mechanism involving tumor cell migration along the outside of the vessels and co-option of the blood vessel has been studied for over 25 years and is presented. Several lines of data support this new mechanism of tumor spread and metastatic growth and is termed angiotropic extravascular migratory metastasis or EVMM. This slow migration along the outside of the vessel wall may explain the latency period between treatment and metastatic tumor growth. The reader is asked to be open to this possible new concept in how tumors spread and grow and the reason for this latency period. A full understanding of how tumors spread and grow is fundamental for the targeting of new therapeutics.
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Affiliation(s)
- Claire Lugassy
- Department of Translational Research, Institut Curie, Paris, France
| | - Hynda K. Kleinman
- Laboratory of Cell Biology, National Institute of Dental and Craniofacial Research (NIDCR), National Institutes of Health (NIH), Bethesda, MD, United States
| | - Nathalie Cassoux
- University of Paris Réné Descartes Faculty (UFR) of Medicine, Paris, France
- Department of Ophthalmology, Institut Curie, Paris, France
| | - Raymond Barnhill
- Department of Translational Research, Institut Curie, Paris, France
- University of Paris Réné Descartes Faculty (UFR) of Medicine, Paris, France
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19
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Latacz E, Höppener D, Bohlok A, Leduc S, Tabariès S, Fernández Moro C, Lugassy C, Nyström H, Bozóky B, Floris G, Geyer N, Brodt P, Llado L, Van Mileghem L, De Schepper M, Majeed AW, Lazaris A, Dirix P, Zhang Q, Petrillo SK, Vankerckhove S, Joye I, Meyer Y, Gregorieff A, Roig NR, Vidal-Vanaclocha F, Denis L, Oliveira RC, Metrakos P, Grünhagen DJ, Nagtegaal ID, Mollevi DG, Jarnagin WR, D’Angelica MI, Reynolds AR, Doukas M, Desmedt C, Dirix L, Donckier V, Siegel PM, Barnhill R, Gerling M, Verhoef C, Vermeulen PB. Histopathological growth patterns of liver metastasis: updated consensus guidelines for pattern scoring, perspectives and recent mechanistic insights. Br J Cancer 2022; 127:988-1013. [PMID: 35650276 PMCID: PMC9470557 DOI: 10.1038/s41416-022-01859-7] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 04/19/2022] [Accepted: 05/11/2022] [Indexed: 02/08/2023] Open
Abstract
The first consensus guidelines for scoring the histopathological growth patterns (HGPs) of liver metastases were established in 2017. Since then, numerous studies have applied these guidelines, have further substantiated the potential clinical value of the HGPs in patients with liver metastases from various tumour types and are starting to shed light on the biology of the distinct HGPs. In the present guidelines, we give an overview of these studies, discuss novel strategies for predicting the HGPs of liver metastases, such as deep-learning algorithms for whole-slide histopathology images and medical imaging, and highlight liver metastasis animal models that exhibit features of the different HGPs. Based on a pooled analysis of large cohorts of patients with liver-metastatic colorectal cancer, we propose a new cut-off to categorise patients according to the HGPs. An up-to-date standard method for HGP assessment within liver metastases is also presented with the aim of incorporating HGPs into the decision-making processes surrounding the treatment of patients with liver-metastatic cancer. Finally, we propose hypotheses on the cellular and molecular mechanisms that drive the biology of the different HGPs, opening some exciting preclinical and clinical research perspectives.
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Affiliation(s)
- Emily Latacz
- grid.5284.b0000 0001 0790 3681Translational Cancer Research Unit, GZA Hospitals, Iridium Netwerk and University of Antwerp, Antwerp, Belgium
| | - Diederik Höppener
- grid.508717.c0000 0004 0637 3764Department of Surgery, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - Ali Bohlok
- grid.418119.40000 0001 0684 291XDepartment of Surgical Oncology, Institut Jules Bordet, Brussels, Belgium
| | - Sophia Leduc
- grid.5596.f0000 0001 0668 7884Laboratory for Translational Breast Cancer Research, Department of Oncology, KU Leuven, Leuven, Belgium
| | - Sébastien Tabariès
- grid.14709.3b0000 0004 1936 8649Department of Medicine, Rosalind and Morris Goodman Cancer Research Institute, McGill University, Montreal, QC Canada
| | - Carlos Fernández Moro
- grid.4714.60000 0004 1937 0626Department of Laboratory Medicine, Division of Pathology, Karolinska Institutet, Huddinge, Sweden ,grid.24381.3c0000 0000 9241 5705Department of Clinical Pathology and Cancer Diagnostics, Karolinska University Hospital, Huddinge, Sweden
| | - Claire Lugassy
- grid.418596.70000 0004 0639 6384Department of Translational Research, Institut Curie, Paris, France
| | - Hanna Nyström
- grid.12650.300000 0001 1034 3451Department of Surgical and Perioperative Sciences, Surgery, Umeå University, Umeå, Sweden ,grid.12650.300000 0001 1034 3451Wallenberg Centre for Molecular Medicine, Umeå University, Umeå, Sweden
| | - Béla Bozóky
- grid.24381.3c0000 0000 9241 5705Department of Clinical Pathology and Cancer Diagnostics, Karolinska University Hospital, Huddinge, Sweden
| | - Giuseppe Floris
- grid.5596.f0000 0001 0668 7884Department of Imaging and Pathology, Laboratory of Translational Cell & Tissue Research and University Hospitals Leuven, KU Leuven, Leuven, Belgium ,grid.410569.f0000 0004 0626 3338Department of Pathology, University Hospitals Leuven, Campus Gasthuisberg, Leuven, Belgium
| | - Natalie Geyer
- grid.4714.60000 0004 1937 0626Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden
| | - Pnina Brodt
- grid.63984.300000 0000 9064 4811Department of Surgery, Oncology and Medicine, McGill University and the Research Institute, McGill University Health Center, Montreal, QC Canada
| | - Laura Llado
- grid.418284.30000 0004 0427 2257HBP and Liver Transplantation Unit, Department of Surgery, Hospital Universitari de Bellvitge, IDIBELL, L’Hospitalet de Llobregat, Barcelona, Catalonia Spain
| | - Laura Van Mileghem
- grid.5284.b0000 0001 0790 3681Translational Cancer Research Unit, GZA Hospitals, Iridium Netwerk and University of Antwerp, Antwerp, Belgium
| | - Maxim De Schepper
- grid.5596.f0000 0001 0668 7884Laboratory for Translational Breast Cancer Research, Department of Oncology, KU Leuven, Leuven, Belgium
| | - Ali W. Majeed
- grid.31410.370000 0000 9422 8284Sheffield Teaching Hospitals NHS Trust, Sheffield, UK
| | - Anthoula Lazaris
- grid.63984.300000 0000 9064 4811Cancer Research Program, McGill University Health Centre Research Institute, Montreal, QC Canada
| | - Piet Dirix
- grid.5284.b0000 0001 0790 3681Translational Cancer Research Unit, GZA Hospitals, Iridium Netwerk and University of Antwerp, Antwerp, Belgium
| | - Qianni Zhang
- grid.4868.20000 0001 2171 1133School of Electronic Engineering and Computer Science, Queen Mary University of London, London, UK
| | - Stéphanie K. Petrillo
- grid.63984.300000 0000 9064 4811Cancer Research Program, McGill University Health Centre Research Institute, Montreal, QC Canada
| | - Sophie Vankerckhove
- grid.418119.40000 0001 0684 291XDepartment of Surgical Oncology, Institut Jules Bordet, Brussels, Belgium
| | - Ines Joye
- grid.5284.b0000 0001 0790 3681Translational Cancer Research Unit, GZA Hospitals, Iridium Netwerk and University of Antwerp, Antwerp, Belgium
| | - Yannick Meyer
- grid.508717.c0000 0004 0637 3764Department of Surgery, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - Alexander Gregorieff
- grid.63984.300000 0000 9064 4811Cancer Research Program, McGill University Health Centre Research Institute, Montreal, QC Canada ,grid.14709.3b0000 0004 1936 8649Department of Pathology, McGill University, Montreal, QC Canada ,grid.14709.3b0000 0004 1936 8649Regenerative Medicine Network, McGill University, Montreal, QC Canada
| | - Nuria Ruiz Roig
- grid.411129.e0000 0000 8836 0780Department of Pathology, Hospital Universitari de Bellvitge, L’Hospitalet de Llobregat, Barcelona, Catalonia Spain ,grid.418284.30000 0004 0427 2257Tumoral and Stromal Chemoresistance Group, Oncobell Program, IDIBELL, L’Hospitalet de Llobregat, Barcelona, Catalonia Spain ,grid.5841.80000 0004 1937 0247Human Anatomy and Embryology Unit, Department of Pathology and Experimental Therapeutics, Faculty of Medicine and Health Sciences, Universitat de Barcelona, Barcelona, Catalonia Spain
| | - Fernando Vidal-Vanaclocha
- grid.253615.60000 0004 1936 9510GWU-Cancer Center, Department of Biochemistry and Molecular Medicine, School of Medicine & Health Sciences, The George Washington University, Washington, DC, USA
| | - Larsimont Denis
- grid.418119.40000 0001 0684 291XDepartment of Pathology, Institut Jules Bordet, Brussels, Belgium
| | - Rui Caetano Oliveira
- grid.28911.330000000106861985Pathology Department, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal ,grid.8051.c0000 0000 9511 4342Clinical Academic Center of Coimbra (CACC), Coimbra, Portugal ,grid.8051.c0000 0000 9511 4342Coimbra Institute for Clinical and Biomedical Research (iCBR) area of Environment Genetics and Oncobiology (CIMAGO), Institute of Biophysics, Faculty of Medicine, University of Coimbra, Coimbra, Portugal
| | - Peter Metrakos
- grid.63984.300000 0000 9064 4811Cancer Research Program, McGill University Health Centre Research Institute, Montreal, QC Canada
| | - Dirk J. Grünhagen
- grid.508717.c0000 0004 0637 3764Department of Surgery, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - Iris D. Nagtegaal
- grid.10417.330000 0004 0444 9382Department of Pathology, Radboud University Medical Center, Nijmegen, Netherlands
| | - David G. Mollevi
- grid.418284.30000 0004 0427 2257Tumoral and Stromal Chemoresistance Group, Oncobell Program, IDIBELL, L’Hospitalet de Llobregat, Barcelona, Catalonia Spain ,grid.418701.b0000 0001 2097 8389Program Against Cancer Therapeutic Resistance (ProCURE), Institut Català d’Oncologia, L’Hospitalet de Llobregat, Barcelona, Catalonia Spain
| | - William R. Jarnagin
- grid.51462.340000 0001 2171 9952Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY USA
| | - Michael I D’Angelica
- grid.51462.340000 0001 2171 9952Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY USA
| | - Andrew R. Reynolds
- grid.417815.e0000 0004 5929 4381Oncology R&D, AstraZeneca, Cambridge, UK
| | - Michail Doukas
- grid.5645.2000000040459992XDepartment of Pathology, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Christine Desmedt
- grid.5596.f0000 0001 0668 7884Laboratory for Translational Breast Cancer Research, Department of Oncology, KU Leuven, Leuven, Belgium
| | - Luc Dirix
- grid.5284.b0000 0001 0790 3681Translational Cancer Research Unit, GZA Hospitals, Iridium Netwerk and University of Antwerp, Antwerp, Belgium
| | - Vincent Donckier
- grid.418119.40000 0001 0684 291XDepartment of Surgical Oncology, Institut Jules Bordet, Brussels, Belgium
| | - Peter M. Siegel
- grid.14709.3b0000 0004 1936 8649Department of Medicine, Rosalind and Morris Goodman Cancer Research Institute, McGill University, Montreal, QC Canada ,grid.14709.3b0000 0004 1936 8649Departments of Medicine, Biochemistry, Anatomy & Cell Biology, McGill University, Montreal, QC Canada
| | - Raymond Barnhill
- grid.418596.70000 0004 0639 6384Department of Translational Research, Institut Curie, Paris, France ,Université de Paris l’UFR de Médecine, Paris, France
| | - Marco Gerling
- grid.4714.60000 0004 1937 0626Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden ,grid.24381.3c0000 0000 9241 5705Theme Cancer, Karolinska University Hospital, Solna, Sweden
| | - Cornelis Verhoef
- grid.508717.c0000 0004 0637 3764Department of Surgery, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - Peter B. Vermeulen
- grid.5284.b0000 0001 0790 3681Translational Cancer Research Unit, GZA Hospitals, Iridium Netwerk and University of Antwerp, Antwerp, Belgium
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20
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Perivascular infiltration reflects subclinical lymph node metastasis in invasive lobular carcinoma. Virchows Arch 2022; 481:533-543. [PMID: 35947202 DOI: 10.1007/s00428-022-03391-8] [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: 04/12/2022] [Revised: 07/15/2022] [Accepted: 07/26/2022] [Indexed: 10/15/2022]
Abstract
Invasive lobular carcinoma (ILC) is characterized by discohesive cells due to irreversible loss of E-cadherin expression and multiple satellites, where individual cell migration is evident without disturbance of the stroma. Neoplastic cells sometimes infiltrate the surrounding vessel in satellites. Here, we aimed to clarify the specific role of perivascular infiltration (PVI) and ameboid migration, characterized by nondisturbance of the background stromal structure, in ILCs. A total of 139 cases with ILC and 122 cases with invasive breast carcinoma of no special type (IBC-NST) were evaluated retrospectively. PVI was significantly more common in ILC than in IBC-NST (50% [70 of 139 cases] vs. 9% [11 of 122 cases], p < 0.001). ILC cases with PVI showed a larger pathological tumour size than clinical tumour size (p < 0.01), a higher frequency of pathological node status pN2-pN3 when limited to clinically node-negative cases (p < 0.01) and lower circularity of tumour morphology on imaging (p < 0.01) than ILC cases without PVI. In the pathological evaluation, the intensity and occupancy of tumour cells expressing phospho-myosin light chain 2, which is a hallmark of ameboid migration, were significantly higher in ILC cases with PVI than in those without PVI at the tumour margins (p < 0.05). ILC with PVI is associated with irregular, poorly defined tumour margins and lymph node metastasis without adenopathy, which is difficult to assess using imaging. PVI may be caused by ameboid migration, as shown by the positive expression of phospho-myosin light chain 2. The presence of PVI may be a predictor for clinically node-negative pN2-pN3 in ILC patients.
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21
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Kong BT, Fan QS, Wang XM, Zhang Q, Zhang GL. Clinical implications and mechanism of histopathological growth pattern in colorectal cancer liver metastases. World J Gastroenterol 2022; 28:3101-3115. [PMID: 36051338 PMCID: PMC9331533 DOI: 10.3748/wjg.v28.i26.3101] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 04/21/2022] [Accepted: 06/16/2022] [Indexed: 02/06/2023] Open
Abstract
Liver is the most common site of metastases of colorectal cancer, and liver metastases present with distinct histopathological growth patterns (HGPs), including desmoplastic, pushing and replacement HGPs and two rare HGPs. HGP is a miniature of tumor-host reaction and reflects tumor biology and pathological features as well as host immune dynamics. Many studies have revealed the association of HGPs with carcinogenesis, angiogenesis, and clinical outcomes and indicates HGP functions as bond between microscopic characteristics and clinical implications. These findings make HGP a candidate marker in risk stratification and guiding treatment decision-making, and a target of imaging observation for patient screening. Of note, it is crucial to determine the underlying mechanism shaping HGP, for instance, immune infiltration and extracellular matrix remodeling in desmoplastic HGP, and aggressive characteristics and special vascularization in replacement HGP (rHGP). We highlight the importance of aggressive features, vascularization, host immune and organ structure in formation of HGP, hence propose a novel "advance under camouflage" hypothesis to explain the formation of rHGP.
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Affiliation(s)
- Bing-Tan Kong
- Department of Oncology, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing 100010, China
- School of Graduates, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Qing-Sheng Fan
- Department of Oncology, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing 100010, China
| | - Xiao-Min Wang
- Department of Oncology, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing 100010, China
| | - Qing Zhang
- Department of Oncology, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing 100010, China
| | - Gan-Lin Zhang
- Department of Oncology, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing 100010, China
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22
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Ujifuku K, Fujimoto T, Sato K, Morofuji Y, Muto H, Masumoto H, Nakagawa S, Niwa M, Matsuo T. Exploration of Pericyte-Derived Factors Implicated in Lung Cancer Brain Metastasis Protection: A Pilot Messenger RNA Sequencing Using the Blood-Brain Barrier In Vitro Model. Cell Mol Neurobiol 2022; 42:997-1004. [PMID: 33136276 PMCID: PMC11441224 DOI: 10.1007/s10571-020-00988-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Accepted: 10/23/2020] [Indexed: 01/26/2023]
Abstract
Metastatic brain tumors have poor prognoses and pose unmet clinical problems for the patients. The blood-brain barrier (BBB) implication is supposed to play a major role in brain metastasis. However, the role of pericytes remains to be elucidated in the brain metastasis. This pilot study described the expression profile of interactions between pericytes, endothelial cells, and cancer cells. We applied an in vitro BBB model with rat primary cultured BBB-related cells (endothelial cells and pericytes), and performed the gene expression analyses of pericytes under the lung cancer cells coculture conditions. Pericytes demonstrated inhibition of the cancer cell proliferation significantly (p < 0.05). RNA was extracted from the pericytes, complementary DNA library was prepared, and RNA-seq was performed. The sequence read data were analyzed on the Management and Analysis System for Enormous Reads and Tag Count Comparison-Graphical User Interface platforms. No statistically or biologically significant differentially expressed genes (DEGs) were detected in the explanatory analyses. Lot-specific DEG detection demonstrated significant decreases in the expression of two genes (Wwtr1 and Acin1), and enrichment analyses using Metascape software revealed the inhibition of apoptotic processes in fibroblasts. Our results suggest that the expression profiles of brain pericytes are partially implicated in the prevention of lung cancer metastasis to the brain. Pericytes exerted an anti-metastatic effect in the BBB model, and their neurohumoral factors remain to be elucidated.
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Affiliation(s)
- Kenta Ujifuku
- Department of Neurosurgery, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan.
| | - Takashi Fujimoto
- Department of Neurosurgery, Nagasaki University Hospital, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan
| | - Kei Sato
- Department of Neurosurgery, Nagasaki University Hospital, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan
| | - Yoichi Morofuji
- Department of Neurosurgery, Nagasaki University Hospital, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan
| | - Hideki Muto
- Biomedical Research Support Center, Nagasaki University School of Medicine, 1-12-4 Sakamoto, Nagasaki, 852-8523, Japan
| | - Hiroshi Masumoto
- Biomedical Research Support Center, Nagasaki University School of Medicine, 1-12-4 Sakamoto, Nagasaki, 852-8523, Japan
| | - Shinsuke Nakagawa
- Department of Medical Pharmacology, Nagasaki University Graduate School of Biomedical Sciences, 1-12-4 Sakamoto, Nagasaki, 852-8523, Japan
| | - Masami Niwa
- BBB Laboratory, PharmaCo-Cell Company Ltd., Dai-ichi-senshu bldg. 2nd floor, 6-19 Chitose-machi, Nagasaki, 852-8135, Japan
| | - Takayuki Matsuo
- Department of Neurosurgery, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan
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23
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Lugassy C, Vermeulen PB, Ribatti D, Pezzella F, Barnhill RL. Vessel co-option and angiotropic extravascular migratory metastasis: a continuum of tumour growth and spread? Br J Cancer 2022; 126:973-980. [PMID: 34987186 PMCID: PMC8980005 DOI: 10.1038/s41416-021-01686-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Revised: 12/07/2021] [Accepted: 12/22/2021] [Indexed: 02/08/2023] Open
Abstract
Two fields of cancer research have emerged dealing with the biology of tumour cells localised to the abluminal vascular surface: vessel co-option (VCo), a non-angiogenic mode of tumour growth and angiotropic extravascular migratory metastasis (EVMM), a non-hematogenous mode of tumour migration and metastasis. VCo is a mechanism by which tumour cells gain access to a blood supply by spreading along existing blood vessels in order to grow locally. Angiotropic EVMM involves "pericytic mimicry" (PM), which is characterised by tumour cells continuously migrating in the place of pericytes distantly along abluminal vascular surfaces. When cancer cells are engaged in PM and EVMM, they migrate along blood vessels beyond the advancing front of the tumour to secondary sites with the formation of regional and distant metastases. In the present perspective, the authors review the current scientific literature, emphasising the analogies between embryogenesis and cancer progression, the re-activation of embryonic signals by "cancer stem cells", and the important role of laminins and epithelial-mesenchymal-transition. This perspective maintains that VCo and angiotropic EVMM constitute complementary processes and represent a continuum of cancer progression from the primary tumour to metastases and of tumour growth to EVMM, analogous to the embryonic development program.
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Affiliation(s)
- Claire Lugassy
- Department of Translational Research, Institut Curie, Paris, France.
| | - Peter B Vermeulen
- Translational Cancer Research Unit, GZA Hospitals, Sint-Augustinus, Antwerp, Belgium
- Center for Oncological Research (CORE, Faculty of Medicine and Health Sciences), University of Antwerp, Wilrijk, Antwerp, Belgium
| | - Domenico Ribatti
- Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari Medical School, Bari, Italy
| | - Francesco Pezzella
- Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK
| | - Raymond L Barnhill
- Department of Translational Research, Institut Curie, Paris, France
- University of Paris UFR de Médecine, Paris, France
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24
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Carroll V. The vascular outsiders. Br J Cancer 2022; 126:1509-1510. [PMID: 35352021 PMCID: PMC9130215 DOI: 10.1038/s41416-022-01795-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Revised: 03/04/2022] [Accepted: 03/16/2022] [Indexed: 01/22/2023] Open
Abstract
A recent perspective on vessel co-option and angiotropic extravascular migratory metastasis by Lugassy et al. suggests cancers use both mechanisms sequentially during tumour growth and spread.
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Affiliation(s)
- Veronica Carroll
- Senior Lecturer in Vascular Biology, Section of Cell Biology, St George's, University of London, Cranmer Terrace, London, SW17 0RE, UK.
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25
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Chen WL, Wang Y, Zhou B, Liao JK, Chen R. Radical resection and reconstruction in patients with adenoid cystic carcinoma in the minor salivary glands of the palate. Head Face Med 2022; 18:10. [PMID: 35296329 PMCID: PMC8925237 DOI: 10.1186/s13005-022-00312-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Accepted: 02/15/2022] [Indexed: 11/25/2022] Open
Abstract
BACKGROUND This study evaluated the clinical outcomes of the patients with adenoid cystic carcinoma (ACC) of the minor salivary glands of the palate. METHODS Forty-four patients with stage I-II disease and 14 patients with stage III-IV disease underwent radical excision and reconstruction with a facial-submental artery island flap (FSAIF) and titanium mesh plus a free anterolateral thigh flap (ALTF) and radiotherapy respectively. Patients with stage III-IV disease subsequently received cobalt Co 60 adjuvant radiotherapy. Ki-67 expression was determined semiquantitatively in 52 patients with ACC by based on the cytoplasm staining intensity and percentage of positively stained tumor cells. RESULTS The median (range) follow-up was 32.9 (14-58) months. Forty-one (71.7%) patients survived without disease recurrence. Nine patients (15.5%) survived with recurrent tumors (four with local recurrence, three with regional recurrence requiring salvage surgery, and two with distant metastasis); among these patients, five had overlapping recurrence. Eight patients (13.8%) died of regional, distant, or multiorgan metastasis (range: 22-42 months). The overall median (95% CI) survival time was 32.5 (25.0-39.5) months, and the median (95% CI) progression-free survival time was 32.9 (28.5-36.9) months. Rates of survival and recurrence differed significantly between patients with low- and high-grade tumors, patients with clinical stage I-II disease and those with stage III-IV disease, patients with and without lymph node metastasis, patients who underwent radical excision with versus without radiotherapy, and patients with low and high Ki-67 expression. CONCLUSION Radical resection and reconstruction with FSAIF is suitable methods for the the treatment of stage I-II ACC of the minor salivary glands of the palate. Stage III-IV tumors require radical resection, reconstruction with titanium mesh and free ALTF, and radiotherapy.
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Affiliation(s)
- Wei-liang Chen
- Department of Oral and Maxillofacial Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, 107 Yan-jiang Road, Guangzhou, 510120 China
| | - Yan Wang
- Department of Oral and Maxillofacial Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120 China
| | - Bin Zhou
- Department of Oral and Maxillofacial Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120 China
| | - Juan-kun Liao
- Department of Oral and Maxillofacial Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120 China
| | - Rui Chen
- Department of Oral and Maxillofacial Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120 China
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26
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Senchukova MA. Issues of origin, morphology and clinical significance of tumor microvessels in gastric cancer. World J Gastroenterol 2021; 27:8262-8282. [PMID: 35068869 PMCID: PMC8717017 DOI: 10.3748/wjg.v27.i48.8262] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Revised: 07/02/2021] [Accepted: 12/07/2021] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer (GC) remains a serious oncological problem, ranking third in the structure of mortality from malignant neoplasms. Improving treatment outcomes for this pathology largely depends on understanding the pathogenesis and biological characteristics of GC, including the identification and characterization of diagnostic, prognostic, predictive, and therapeutic biomarkers. It is known that the main cause of death from malignant neoplasms and GC, in particular, is tumor metastasis. Given that angiogenesis is a critical process for tumor growth and metastasis, it is now considered an important marker of disease prognosis and sensitivity to anticancer therapy. In the presented review, modern concepts of the mechanisms of tumor vessel formation and the peculiarities of their morphology are considered; data on numerous factors influencing the formation of tumor microvessels and their role in GC progression are summarized; and various approaches to the classification of tumor vessels, as well as the methods for assessing angiogenesis activity in a tumor, are highlighted. Here, results from studies on the prognostic and predictive significance of tumor microvessels in GC are also discussed, and a new classification of tumor microvessels in GC, based on their morphology and clinical significance, is proposed for consideration.
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Affiliation(s)
- Marina A Senchukova
- Department of Oncology, Orenburg State Medical University, Orenburg 460021, Russia
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27
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Melatonin Attenuates Cardiac Ischemia-Reperfusion Injury through Modulation of IP3R-Mediated Mitochondria-ER Contact. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:1370862. [PMID: 34422206 PMCID: PMC8371645 DOI: 10.1155/2021/1370862] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Revised: 07/17/2021] [Accepted: 07/24/2021] [Indexed: 02/07/2023]
Abstract
Although the interplay between mitochondria and ER has been identified as a crucial regulator of cellular homeostasis, the pathogenic impact of alterations in mitochondria-ER contact sites (MERCS) during myocardial postischemic reperfusion (I/R) injury remains incompletely understood. Therefore, in our study, we explored the beneficial role played by melatonin in protecting cardiomyocytes against reperfusion injury via stabilizing mitochondria-ER interaction. In vitro exposure of H9C2 rat cardiomyocytes to hypoxia/reoxygenation (H/R) augmented mitochondrial ROS synthesis, suppressed both mitochondrial potential and ATP generation, and increased the mitochondrial permeability transition pore (mPTP) opening rate. Furthermore, H/R exposure upregulated the protein content of CHOP and caspase-12, two markers of ER stress, and enhanced the transcription of main MERCS tethering proteins, namely, Fis1, BAP31, Mfn2, and IP3R. Interestingly, all the above changes could be attenuated or reversed by melatonin treatment. Suggesting that melatonin-induced cardioprotection works through normalization of mitochondria-ER interaction, overexpression of IP3R abolished the protective actions offered by melatonin on mitochondria-ER fitness. These results expand our knowledge on the cardioprotective actions of melatonin during myocardial postischemic reperfusion damage and suggest that novel, more effective treatments for acute myocardial reperfusion injury might be achieved through modulation of mitochondria-ER interaction in cardiac cells.
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28
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Ji H, Wu D, Kimberlee O, Li R, Qian G. Molecular Perspectives of Mitophagy in Myocardial Stress: Pathophysiology and Therapeutic Targets. Front Physiol 2021; 12:700585. [PMID: 34276422 PMCID: PMC8279814 DOI: 10.3389/fphys.2021.700585] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Accepted: 05/27/2021] [Indexed: 01/15/2023] Open
Abstract
A variety of complex risk factors and pathological mechanisms contribute to myocardial stress, which ultimately promotes the development of cardiovascular diseases, including acute cardiac insufficiency, myocardial ischemia, myocardial infarction, high-glycemic myocardial injury, and acute alcoholic cardiotoxicity. Myocardial stress is characterized by abnormal metabolism, excessive reactive oxygen species production, an insufficient energy supply, endoplasmic reticulum stress, mitochondrial damage, and apoptosis. Mitochondria, the main organelles contributing to the energy supply of cardiomyocytes, are key determinants of cell survival and death. Mitophagy is important for cardiomyocyte function and metabolism because it removes damaged and aged mitochondria in a timely manner, thereby maintaining the proper number of normal mitochondria. In this review, we first introduce the general characteristics and regulatory mechanisms of mitophagy. We then describe the three classic mitophagy regulatory pathways and their involvement in myocardial stress. Finally, we discuss the two completely opposite effects of mitophagy on the fate of cardiomyocytes. Our summary of the molecular pathways underlying mitophagy in myocardial stress may provide therapeutic targets for myocardial protection interventions.
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Affiliation(s)
- Haizhe Ji
- Department of Cardiology, The First Medical Center, Chinese People's Liberation Army Hospital, Medical School of Chinese People's Liberation Army, Beijing, China.,Department of Cardiology, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Dan Wu
- Department of Cardiology, The First Medical Center, Chinese People's Liberation Army Hospital, Medical School of Chinese People's Liberation Army, Beijing, China
| | - O'Maley Kimberlee
- School of Public Health, University of California, Berkeley, Berkeley, CA, United States
| | - Ruibing Li
- Department of Clinical Laboratory Medicine, The First Medical Center, Medical School of Chinese People's Liberation Army, Beijing, China
| | - Geng Qian
- Department of Cardiology, The First Medical Center, Chinese People's Liberation Army Hospital, Medical School of Chinese People's Liberation Army, Beijing, China
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29
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Mo J, Zhao X, Wang W, Zhao N, Dong X, Zhang Y, Cheng R, Sun B. TFPI2 Promotes Perivascular Migration in an Angiotropism Model of Melanoma. Front Oncol 2021; 11:662434. [PMID: 34249699 PMCID: PMC8264799 DOI: 10.3389/fonc.2021.662434] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Accepted: 06/10/2021] [Indexed: 11/30/2022] Open
Abstract
Purpose Angiotropism is the process by which cancer cells attach to and migrate along blood vessels to acquire vasculature, disseminate, and metastasize. However, the molecular basis for such vessel–tumor interactions has not been fully elucidated, partly due to limited experimental models. In this study, we aimed to observe and explore the molecular mechanism underlying angiotropism in melanoma. Methods To monitor the interactions of human melanoma cells with the vasculature in vivo, a murine coxenograft model was employed by co-injecting highly and poorly invasive melanoma cells subcutaneously. To identify key pathways and genes involved in the angiotropic phenotype of melanoma, analysis of differentially expressed genes (DEGs) and gene set enrichment analysis (GSEA) were performed. The role of tissue factor pathway inhibitor 2 (TFPI2) in angiotropism was evaluated by immunostaining, adhesion assay, shRNA, and in vivo tumorigenicity. Angiotropism and TFPI2 expression were examined in surgical specimens of melanoma by immunohistochemical staining. Data from The Cancer Genome Atlas (TCGA) were analyzed to explore the expression and prognostic implications of TFPI2 in uveal and cutaneous melanoma. Results Highly invasive melanoma cells spread along the branches of intratumor blood vessels to the leading edge of invasion in the coxenograft model, resembling angiotropic migration. Mechanisms underlying angiotropism were primarily associated with molecular function regulators, regulation of cell population proliferation, developmental processes, cell differentiation, responses to cytokines and cell motility/locomotion. TFPI2 downregulation weakened the perivascular migration of highly invasive melanoma cells. High levels of TFPI2 were correlated with worse and better survival in uveal and cutaneous melanoma, respectively. Conclusion These results provide a straightforward in vivo model for the observation of angiotropism and suggest that TFPI2 could inhibit the angiotropic phenotype of melanoma.
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Affiliation(s)
- Jing Mo
- Department of Pathology, Tianjin Medical University, Tianjin, China.,Department of Pathology, General Hospital of Tianjin Medical University, Tianjin, China
| | - Xiulan Zhao
- Department of Pathology, Tianjin Medical University, Tianjin, China.,Department of Pathology, General Hospital of Tianjin Medical University, Tianjin, China
| | - Wei Wang
- Department of Pathology, Tianjin Medical University, Tianjin, China
| | - Nan Zhao
- Department of Pathology, Tianjin Medical University, Tianjin, China.,Department of Pathology, General Hospital of Tianjin Medical University, Tianjin, China
| | - Xueyi Dong
- Department of Pathology, Tianjin Medical University, Tianjin, China.,Department of Pathology, General Hospital of Tianjin Medical University, Tianjin, China
| | - Yanhui Zhang
- Department of Pathology, Cancer Hospital of Tianjin Medical University, Tianjin, China
| | - Runfen Cheng
- Department of Pathology, Cancer Hospital of Tianjin Medical University, Tianjin, China
| | - Baocun Sun
- Department of Pathology, Tianjin Medical University, Tianjin, China.,Department of Pathology, General Hospital of Tianjin Medical University, Tianjin, China.,Department of Pathology, Cancer Hospital of Tianjin Medical University, Tianjin, China
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30
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Cui C, Zhang Y, Liu G, Zhang S, Zhang J, Wang X. Advances in the study of cancer metastasis and calcium signaling as potential therapeutic targets. EXPLORATION OF TARGETED ANTI-TUMOR THERAPY 2021; 2:266-291. [PMID: 36046433 PMCID: PMC9400724 DOI: 10.37349/etat.2021.00046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Accepted: 04/21/2021] [Indexed: 11/19/2022] Open
Abstract
Metastasis is still the primary cause of cancer-related mortality. However, the underlying mechanisms of cancer metastasis are not yet fully understood. Currently, the epithelial-mesenchymal transition, metabolic remodeling, cancer cell intercommunication and the tumor microenvironment including diverse stromal cells, are reported to affect the metastatic process of cancer cells. Calcium ions (Ca2+) are ubiquitous second messengers that manipulate cancer metastasis by affecting signaling pathways. Diverse transporter/pump/channel-mediated Ca2+ currents form Ca2+ oscillations that can be decoded by Ca2+-binding proteins, which are promising prognostic biomarkers and therapeutic targets of cancer metastasis. This paper presents a review of the advances in research on the mechanisms underlying cancer metastasis and the roles of Ca2+-related signals in these events.
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Affiliation(s)
- Chaochu Cui
- Henan Key Laboratory of Medical Tissue Regeneration, College of Basic Medical Sciences, Xinxiang Medical University, Xinxiang 453003, Henan, China
| | - Yongxi Zhang
- Department of Oncology, The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang 453003, Henan, China
| | - Gang Liu
- Henan Key Laboratory of Medical Tissue Regeneration, College of Basic Medical Sciences, Xinxiang Medical University, Xinxiang 453003, Henan, China
| | - Shuhong Zhang
- Henan Key Laboratory of Medical Tissue Regeneration, College of Basic Medical Sciences, Xinxiang Medical University, Xinxiang 453003, Henan, China
| | - Jinghang Zhang
- Department of Pathology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang 453003, Henan, China
| | - Xianwei Wang
- Henan Key Laboratory of Medical Tissue Regeneration, College of Basic Medical Sciences, Xinxiang Medical University, Xinxiang 453003, Henan, China
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Wang Y, Jasper H, Toan S, Muid D, Chang X, Zhou H. Mitophagy coordinates the mitochondrial unfolded protein response to attenuate inflammation-mediated myocardial injury. Redox Biol 2021; 45:102049. [PMID: 34174558 PMCID: PMC8246635 DOI: 10.1016/j.redox.2021.102049] [Citation(s) in RCA: 156] [Impact Index Per Article: 39.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Revised: 06/04/2021] [Accepted: 06/14/2021] [Indexed: 12/17/2022] Open
Abstract
Mitochondrial dysfunction is a fundamental challenge in septic cardiomyopathy. Mitophagy and the mitochondrial unfolded protein response (UPRmt) are the predominant stress-responsive and protective mechanisms involved in repairing damaged mitochondria. Although mitochondrial homeostasis requires the coordinated actions of mitophagy and UPRmt, their molecular basis and interactive actions are poorly understood in sepsis-induced myocardial injury. Our investigations showed that lipopolysaccharide (LPS)-induced sepsis contributed to cardiac dysfunction and mitochondrial damage. Although both mitophagy and UPRmt were slightly activated by LPS in cardiomyocytes, their endogenous activation failed to prevent sepsis-mediated myocardial injury. However, administration of urolithin A, an inducer of mitophagy, obviously reduced sepsis-mediated cardiac depression by normalizing mitochondrial function. Interestingly, this beneficial action was undetectable in cardiomyocyte-specific FUNDC1 knockout (FUNDC1CKO) mice. Notably, supplementation with a mitophagy inducer had no impact on UPRmt, whereas genetic ablation of FUNDC1 significantly upregulated the expression of genes related to UPRmt in LPS-treated hearts. In contrast, enhancement of endogenous UPRmt through oligomycin administration reduced sepsis-mediated mitochondrial injury and myocardial dysfunction; this cardioprotective effect was imperceptible in FUNDC1CKO mice. Lastly, once UPRmt was inhibited, mitophagy-mediated protection of mitochondria and cardiomyocytes was partly blunted. Taken together, it is plausible that endogenous UPRmt and mitophagy are slightly activated by myocardial stress and they work together to sustain mitochondrial performance and cardiac function. Endogenous UPRmt, a downstream signal of mitophagy, played a compensatory role in maintaining mitochondrial homeostasis in the case of mitophagy inhibition. Although UPRmt activation had no negative impact on mitophagy, UPRmt inhibition compromised the partial cardioprotective actions of mitophagy. This study shows how mitophagy modulates UPRmt to attenuate inflammation-related myocardial injury and suggests the potential application of mitophagy and UPRmt targeting in the treatment of myocardial stress.
Mitochondrial dysfunction is a fundamental challenge in septic cardiomyopathy. LPS-induced sepsis contributes to cardiac dysfunction and mitochondrial damage. Endogenous UPRmt and mitophagy could be slightly activated by myocardial stress. Mitophagy modulates UPRmt to attenuate inflammation-related myocardial injury. Mitophagy and UPRmt targeting can be applied in treatment of myocardial stress.
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Affiliation(s)
- Yue Wang
- Department of Cardiology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200011, China
| | - Heinrich Jasper
- Center for Molecular Medicine, Tarrant County College, TX, 76102, USA
| | - Sam Toan
- Department of Chemical Engineering, University of Minnesota-Duluth, Duluth, MN, 55812, USA
| | - David Muid
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Xing Chang
- Guang'anmen Hospital of Chinese Academy of Traditional Chinese Medicine, Beijing, 100053, China.
| | - Hao Zhou
- Department of Cardiology, The First Medical Center, Chinese People's Liberation Army Hospital, Medical School of Chinese People's Liberation Army, Beijing, 100853, China; Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY, 82071, USA.
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32
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Roles for growth factors and mutations in metastatic dissemination. Biochem Soc Trans 2021; 49:1409-1423. [PMID: 34100888 PMCID: PMC8286841 DOI: 10.1042/bst20210048] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 05/09/2021] [Accepted: 05/14/2021] [Indexed: 12/17/2022]
Abstract
Cancer is initiated largely by specific cohorts of genetic aberrations, which are generated by mutagens and often mimic active growth factor receptors, or downstream effectors. Once initiated cells outgrow and attract blood vessels, a multi-step process, called metastasis, disseminates cancer cells primarily through vascular routes. The major steps of the metastatic cascade comprise intravasation into blood vessels, circulation as single or collectives of cells, and eventual colonization of distant organs. Herein, we consider metastasis as a multi-step process that seized principles and molecular players employed by physiological processes, such as tissue regeneration and migration of neural crest progenitors. Our discussion contrasts the irreversible nature of mutagenesis, which establishes primary tumors, and the reversible epigenetic processes (e.g. epithelial-mesenchymal transition) underlying the establishment of micro-metastases and secondary tumors. Interestingly, analyses of sequencing data from untreated metastases inferred depletion of putative driver mutations among metastases, in line with the pivotal role played by growth factors and epigenetic processes in metastasis. Conceivably, driver mutations may not confer the same advantage in the microenvironment of the primary tumor and of the colonization site, hence phenotypic plasticity rather than rigid cellular states hardwired by mutations becomes advantageous during metastasis. We review the latest reported examples of growth factors harnessed by the metastatic cascade, with the goal of identifying opportunities for anti-metastasis interventions. In summary, because the overwhelming majority of cancer-associated deaths are caused by metastatic disease, understanding the complexity of metastasis, especially the roles played by growth factors, is vital for preventing, diagnosing and treating metastasis.
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Vandyck HHLD, Hillen LM, Bosisio FM, van den Oord J, zur Hausen A, Winnepenninckx V. Rethinking the biology of metastatic melanoma: a holistic approach. Cancer Metastasis Rev 2021; 40:603-624. [PMID: 33870460 PMCID: PMC8213587 DOI: 10.1007/s10555-021-09960-8] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Accepted: 03/29/2021] [Indexed: 02/06/2023]
Abstract
Over the past decades, melanoma-related mortality has remained nearly stable. The main reason is treatment failure of metastatic disease and the inherently linked knowledge gap regarding metastasis formation. In order to elicit invasion, melanoma cells manipulate the tumor microenvironment, gain motility, and adhere to the extracellular matrix and cancer-associated fibroblasts. Melanoma cells thereby express different cell adhesion molecules like laminins, integrins, N-cadherin, and others. Epithelial-mesenchymal transition (EMT) is physiological during embryologic development, but reactivated during malignancy. Despite not being truly epithelial, neural crest-derived malignancies like melanoma share similar biological programs that enable tumorigenesis, invasion, and metastasis. This complex phenomenon is termed phenotype switching and is intertwined with oncometabolism as well as dormancy escape. Additionally, it has been shown that primary melanoma shed exosomes that create a favorable premetastatic niche in the microenvironment of secondary organs and lymph nodes. Although the growing body of literature describes the aforementioned concepts separately, an integrative holistic approach is missing. Using melanoma as a tumor model, this review will shed light on these complex biological principles in an attempt to clarify the mechanistic metastatic pathways that dictate tumor and patient fate.
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Affiliation(s)
- Hendrik HLD Vandyck
- Department of Pathology, GROW-School for Oncology & Developmental Biology, Maastricht University Medical Center, MUMC+, PO Box 5800, 6202 AZ Maastricht, The Netherlands
| | - Lisa M Hillen
- Department of Pathology, GROW-School for Oncology & Developmental Biology, Maastricht University Medical Center, MUMC+, PO Box 5800, 6202 AZ Maastricht, The Netherlands
| | - Francesca M Bosisio
- Laboratory of Translational Cell and Tissue Research (TCTR), Department of Pathology, KU Leuven and UZ Leuven, Leuven, Belgium
| | - Joost van den Oord
- Laboratory of Translational Cell and Tissue Research (TCTR), Department of Pathology, KU Leuven and UZ Leuven, Leuven, Belgium
| | - Axel zur Hausen
- Department of Pathology, GROW-School for Oncology & Developmental Biology, Maastricht University Medical Center, MUMC+, PO Box 5800, 6202 AZ Maastricht, The Netherlands
| | - Véronique Winnepenninckx
- Department of Pathology, GROW-School for Oncology & Developmental Biology, Maastricht University Medical Center, MUMC+, PO Box 5800, 6202 AZ Maastricht, The Netherlands
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Affiliation(s)
- Arjan W Griffioen
- Angiogenesis Laboratory, Department of Medical Oncology, Amsterdam University Medical Center, Vrije Universiteit Amsterdam, Cancer Center Amsterdam, Amsterdam, The Netherlands.
| | - Andrew C Dudley
- Department of Microbiology, Immunology, and Cancer Biology, The University of Virginia, & The Emily Couric Cancer Center, Charlottesville, VA, 22908, USA
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35
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Haas G, Fan S, Ghadimi M, De Oliveira T, Conradi LC. Different Forms of Tumor Vascularization and Their Clinical Implications Focusing on Vessel Co-option in Colorectal Cancer Liver Metastases. Front Cell Dev Biol 2021; 9:612774. [PMID: 33912554 PMCID: PMC8072376 DOI: 10.3389/fcell.2021.612774] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Accepted: 03/15/2021] [Indexed: 12/11/2022] Open
Abstract
In modern anti-cancer therapy of metastatic colorectal cancer (mCRC) the anti-angiogenic treatment targeting sprouting angiogenesis is firmly established for more than a decade. However, its clinical benefits still remain limited. As liver metastases (LM) represent the most common metastatic site of colorectal cancer and affect approximately one-quarter of the patients diagnosed with this malignancy, its treatment is an essential aspect for patients' prognosis. Especially in the perioperative setting, the application of anti-angiogenic drugs represents a therapeutic option that may be used in case of high-risk or borderline resectable colorectal cancer liver metastases (CRCLM) in order to achieve secondary resectability. Regarding CRCLM, one reason for the limitations of anti-angiogenic treatment may be represented by vessel co-option (VCO), which is an alternative mechanism of blood supply that differs fundamentally from the well-known sprouting angiogenesis and occurs in a significant fraction of CRCLM. In this scenario, tumor cells hijack pre-existing mature vessels of the host organ independently from stimulating new vessels formation. This represents an escape mechanism from common anti-angiogenic anti-cancer treatments, as they primarily target the main trigger of sprouting angiogenesis, the vascular endothelial growth factor A. Moreover, the mechanism of blood supply in CRCLM can be deduced from their phenotypic histopathological growth pattern (HGP). For that, a specific guideline has already been implemented. These HGP vary not only regarding their blood supply, but also concerning their tumor microenvironment (TME), as notable differences in immune cell infiltration and desmoplastic reaction surrounding the CRCLM can be observed. The latter actually serves as one of the central criteria for the classification of the HGP. Regarding the clinically relevant effects of the HGP, it is still a topic of research whether the VCO-subgroup of CRCLM results in an impaired treatment response to anti-angiogenic treatment when compared to an angiogenic subgroup. However, it is well-proved, that VCO in CRCLM generally relates to an inferior survival compared to the angiogenic subgroup. Altogether the different types of blood supply result in a relevant influence on the patients' prognosis. This reinforces the need of an extended understanding of the underlying mechanisms of VCO in CRCLM with the aim to generate more comprehensive approaches which can target tumor vessels alternatively or even other components of the TME. This review aims to augment the current state of knowledge on VCO in CRCLM and other tumor entities and its impact on anti-angiogenic anti-cancer therapy.
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Affiliation(s)
- Gwendolyn Haas
- Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Göttingen, Germany
| | - Shuang Fan
- Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Göttingen, Germany
| | - Michael Ghadimi
- Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Göttingen, Germany
| | - Tiago De Oliveira
- Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Göttingen, Germany
| | - Lena-Christin Conradi
- Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Göttingen, Germany
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Massagué J, Ganesh K. Metastasis-Initiating Cells and Ecosystems. Cancer Discov 2021; 11:971-994. [PMID: 33811127 PMCID: PMC8030695 DOI: 10.1158/2159-8290.cd-21-0010] [Citation(s) in RCA: 204] [Impact Index Per Article: 51.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Revised: 01/25/2021] [Accepted: 01/27/2021] [Indexed: 11/16/2022]
Abstract
Metastasis is initiated and sustained through therapy by cancer cells with stem-like and immune-evasive properties, termed metastasis-initiating cells (MIC). Recent progress suggests that MICs result from the adoption of a normal regenerative progenitor phenotype by malignant cells, a phenotype with intrinsic programs to survive the stresses of the metastatic process, undergo epithelial-mesenchymal transitions, enter slow-cycling states for dormancy, evade immune surveillance, establish supportive interactions with organ-specific niches, and co-opt systemic factors for growth and recurrence after therapy. Mechanistic understanding of the molecular mediators of MIC phenotypes and host tissue ecosystems could yield cancer therapeutics to improve patient outcomes. SIGNIFICANCE: Understanding the origins, traits, and vulnerabilities of progenitor cancer cells with the capacity to initiate metastasis in distant organs, and the host microenvironments that support the ability of these cells to evade immune surveillance and regenerate the tumor, is critical for developing strategies to improve the prevention and treatment of advanced cancer. Leveraging recent progress in our understanding of the metastatic process, here we review the nature of MICs and their ecosystems and offer a perspective on how this knowledge is informing innovative treatments of metastatic cancers.
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Affiliation(s)
- Joan Massagué
- Cancer Biology and Genetics Program, Sloan Kettering Institute, New York, New York.
| | - Karuna Ganesh
- Molecular Pharmacology Program, Sloan Kettering Institute, New York, New York.
- Department of Medicine, Memorial Hospital, Memorial Sloan Kettering Cancer Center, New York, New York
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Prakash R, Thareja NS, Carmichael TS, Barnhill RL, Lugassy C, Bentolila LA. Visualizing Pericyte Mimicry of Angiotropic Melanoma by Direct Labeling of the Angioarchitecture. Methods Mol Biol 2021; 2235:1-12. [PMID: 33576966 DOI: 10.1007/978-1-0716-1056-5_1] [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] [Indexed: 04/05/2023]
Abstract
In addition to intravascular dissemination, angiotropic melanoma cells have the propensity to spread along the external surface of blood vessels in a pericytic location, or pericytic mimicry. Such continuous migration without intravasation has been termed "extravascular migratory metastasis" or EVMM. In order to visualize this mechanism of tumor propagation, we used a murine brain melanoma model utilizing green fluorescent human melanoma cells and red fluorescent lectin-tagged murine vessels. This model allows the direct microscopic visualization and mapping of the interaction of melanoma cells with the brain vasculature. In this chapter, we describe the methodology of lectin perfusion to label the entire angioarchitecture in conjunction with confocal microscopy imaging to study the pericyte mimicry of the angiotropic GFP+ melanoma cells.
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Affiliation(s)
- Roshini Prakash
- Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
| | - Nikita Shivani Thareja
- Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
| | - Thomas S Carmichael
- Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
| | | | - Claire Lugassy
- Department of Translational Research, Institut Curie, Paris, France
| | - Laurent A Bentolila
- California NanoSystems Institute, University of California, Los Angeles, CA, USA.
- Department of Chemistry and Biochemistry, University of California, Los Angeles, CA, USA.
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Abstract
Despite recent therapeutic advances in cancer treatment, metastasis remains the principal cause of cancer death. Recent work has uncovered the unique biology of metastasis-initiating cells that results in tumor growth in distant organs, evasion of immune surveillance and co-option of metastatic microenvironments. Here we review recent progress that is enabling therapeutic advances in treating both micro- and macrometastases. Such insights were gained from cancer sequencing, mechanistic studies and clinical trials, including of immunotherapy. These studies reveal both the origins and nature of metastases and identify new opportunities for developing more effective strategies to target metastatic relapse and improve patient outcomes.
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Affiliation(s)
- Karuna Ganesh
- Molecular Pharmacology Program, Sloan Kettering Institute, New York, NY, USA.
- Department of Medicine, Memorial Hospital, New York, NY, USA.
| | - Joan Massagué
- Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
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Barnhill R, van Dam P, Vermeulen P, Champenois G, Nicolas A, Rawson RV, Wilmott JS, Thompson JF, Long GV, Cassoux N, Roman‐Roman S, Busam KJ, Scolyer RA, Lazar AJ, Lugassy C. Replacement and desmoplastic histopathological growth patterns in cutaneous melanoma liver metastases: frequency, characteristics, and robust prognostic value. J Pathol Clin Res 2020; 6:195-206. [PMID: 32304183 PMCID: PMC7339161 DOI: 10.1002/cjp2.161] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2019] [Revised: 02/10/2020] [Accepted: 02/14/2020] [Indexed: 12/11/2022]
Abstract
Among visceral metastatic sites, cutaneous melanoma (CM) metastasises initially to the liver in ~14-20% of cases. Liver metastases in CM patients are associated with both poor prognosis and poor response to immunotherapy. Histopathological growth patterns (HGPs) of liver metastases of the replacement and desmoplastic type, particularly from colorectal cancer and uveal melanoma (UM), may impart valuable biological and prognostic information. Here, we have studied HGP in 43 CM liver metastases resected from 42 CM patients along with other prognostic factors from three institutions. The HGPs (replacement, desmoplastic, pushing) were scored at the metastasis-liver interface with two algorithms: (1) 100% desmoplastic growth pattern (dHGP) and any (≥1%) replacement pattern (any-rHGP) and (2) >50% dHGP, >50% rHGP or mixed (<50% dHGP and/or rHGP, pushing HGP). For 1 patient with 2 metastases, an average was taken to obtain 1 final HGP yielding 42 observations from 42 patients. 22 cases (52%) had 100% dHGP whereas 20 (48%) had any replacement. Cases with rHGP demonstrated vascular co-option/angiotropism. With the development of liver metastasis, only rHGP (both algorithms), male gender and positive resection margins predicted diminished overall survival (p = 0.00099 and p = 0.0015; p = 0.034 and p = 0.024 respectively). On multivariate analysis, only HGP remained significant. 7 of 42 (17%) patients were alive with disease and 21 (50%) died with follow-up after liver metastases ranging from 1.8 to 42.2 months (mean: 20.4 months, median: 19.0 months). 14 (33%) patients with previously-treated metastatic disease had no evidence of disease at last follow up. In conclusion, we report for the first time replacement and desmoplastic HGPs in CM liver metastases and their prognostic value, as in UM and other solid cancers. Of particular importance, any rHGP significantly predicted diminished overall survival while 100% dHGP correlated with increased survival. These results contribute to a better understanding of the biology of CM liver metastases and potentially may be utilised in managing patients with these metastases.
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Affiliation(s)
- Raymond Barnhill
- Department of PathologyInstitut CurieParisFrance
- Department of Translational ResearchInstitut CurieParisFrance
- Faculty of MedicineUniversity of Paris Réné DescartesParisFrance
| | - Pieter‐Jan van Dam
- Faculty of Medicine and Health SciencesUniversity of Antwerp – MIPRO Center for Oncological Research (CORE) – TCRU, GZA Sint‐AugustinusAntwerpenBelgium
- HistoGeneXWilrijkBelgium
| | - Peter Vermeulen
- Faculty of Medicine and Health SciencesUniversity of Antwerp – MIPRO Center for Oncological Research (CORE) – TCRU, GZA Sint‐AugustinusAntwerpenBelgium
| | - Gabriel Champenois
- Experimental Pathology, Department of PathologyInstitut CurieParisFrance
| | - André Nicolas
- Experimental Pathology, Department of PathologyInstitut CurieParisFrance
| | - Robert V Rawson
- Melanoma Institute Australia, The University of SydneySydneyAustralia
- Department of Tissue Pathology and Diagnostic OncologyRoyal Prince Alfred Hospital and NSW Health PathologySydneyAustralia
- Sydney Medical School, The University of SydneySydneyAustralia
| | - James S Wilmott
- Melanoma Institute Australia, The University of SydneySydneyAustralia
- Department of Tissue Pathology and Diagnostic OncologyRoyal Prince Alfred Hospital and NSW Health PathologySydneyAustralia
- Sydney Medical School, The University of SydneySydneyAustralia
| | - John F Thompson
- Melanoma Institute Australia, The University of SydneySydneyAustralia
- Sydney Medical School, The University of SydneySydneyAustralia
- Department of SurgeryRoyal Prince Alfred Hospital and NSW Health PathologySydneyAustralia
| | - Georgina V Long
- Melanoma Institute Australia, The University of SydneySydneyAustralia
- Sydney Medical School, The University of SydneySydneyAustralia
- Department of Medical OncologyNorthern Sydney Cancer Centre, Royal North Shore HospitalSydneyAustralia
| | - Nathalie Cassoux
- Faculty of MedicineUniversity of Paris Réné DescartesParisFrance
- Department of OphthalmologyInstitut CurieParisFrance
| | | | - Klaus J Busam
- Department of PathologyMemorial Sloan Kettering Cancer CenterNew YorkNYUSA
| | - Richard A Scolyer
- Melanoma Institute Australia, The University of SydneySydneyAustralia
- Department of Tissue Pathology and Diagnostic OncologyRoyal Prince Alfred Hospital and NSW Health PathologySydneyAustralia
- Sydney Medical School, The University of SydneySydneyAustralia
| | - Alexander J Lazar
- Department of PathologyThe University of Texas MD Anderson Cancer CenterHoustonTXUSA
- Department of Genomic MedicineThe University of Texas MD Anderson Cancer CenterHoustonTXUSA
- Department of DermatologyThe University of Texas MD Anderson Cancer CenterHoustonTXUSA
- Department of Translational Molecular PathologyThe University of Texas MD Anderson Cancer CenterHoustonTXUSA
| | - Claire Lugassy
- Department of Translational ResearchInstitut CurieParisFrance
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