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Falleni M, Dal Lago M, Tosi D, Ghilardi G, De Pasquale L, Saibene AM, Felisati G, Cozzolino M, Gianelli U. Vascular mimicry and mosaic vessels in parathyroid tumours: a new diagnostic approach? J Clin Pathol 2024:jcp-2024-209703. [PMID: 39288990 DOI: 10.1136/jcp-2024-209703] [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: 06/11/2024] [Accepted: 09/05/2024] [Indexed: 09/19/2024]
Abstract
AIMS Evaluation of 'alternative' vascularisation in human cancer is considered an important prognostic parameter; the 2022 WHO classification of parathyroid tumours despite progresses in clinical triaging of patients strongly emphasises new histopathological parameters to properly stratify these lesions. 'Alternative' and 'classic' vessels were here investigated for the first time in parathyroid tumours for their possible histopathological and clinical relevance during progression. METHODS Using a double CD31/PAS staining, microvessel density (MVD, 'classic' CD31+ vessels), mosaic vessel density (MoVD, 'alternative' CD31+/-vessels) and vessel mimicry density (VMD, 'alternative' CD31-/PAS+ vessels) were evaluated in 4 normal parathyroid glands (N), 50 Adenomas (A), 35 Atypical Tumours (AT) and 10 Carcinomas (K). RESULTS Compared with N, MVD significantly increased in A (p=0.012) and decreased in K (p=0.013) with vessel counts lower than in AT and A (p<0.001). MoVs and VMs, absent in normal tissue, were documented in non-benign parathyroid lesions (AT, K) (p<0.001), with MoVs and VMs most represented in AT and K, respectively (p<0.001), in peripheral growing areas. Vessel distribution was correlated to neoplastic progression (r=-0.541 MVD; r=+0.760 MoVD, r=+0.733 VMD), with MVD decrease in AT and K inversely related to MoVD and VMD increase (r=-0.503 and r=-0.456). CONCLUSIONS 'Alternative' vessel identification in parathyroid tumours is crucial because it: (1) explains the paradox of non-angiogenic tumours, consisting in a new bloody non-endothelial vessel network and (2) helps pathologists to unmask worrisome lesions. Furthermore, detection of alternative vascular systems in human tumours might explain the limited success of antiangiogenic therapies and encourage new oncological studies.
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Affiliation(s)
- Monica Falleni
- Unit of Pathology, Department of Health Sciences, University of Milan, ASST Santi Paolo e Carlo, Milano, Italy
| | - Matteo Dal Lago
- Unit of Pathology, Department of Health Sciences, University of Milan, ASST Santi Paolo e Carlo, Milano, Italy
| | - Delfina Tosi
- Unit of Pathology, Department of Health Sciences, University of Milan, ASST Santi Paolo e Carlo, Milano, Italy
| | - Giorgio Ghilardi
- Surgical Unit, Department of Health Sciences, University of Milan, ASST Santi Paolo e Carlo, Milano, Italy
| | | | - Alberto M Saibene
- Otolaryngology Unit, Department of Health Sciences, University of Milan, ASST Santi Paolo e Carlo, Milano, Italy
| | - Giovanni Felisati
- Otolaryngology Unit, Department of Health Sciences, University of Milan, ASST Santi Paolo e Carlo, Milano, Italy
| | - Mario Cozzolino
- Renal Division, Department of Health Sciences, University of Milan, ASST Santi Paolo e Carlo, Milano, Italy
| | - Umberto Gianelli
- Unit of Pathology, Department of Health Sciences, University of Milan, ASST Santi Paolo e Carlo, Milano, Italy
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2
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Ou KL, Chen CK, Huang JJ, Chang WW, Hsieh Li SM, Jiang TX, Widelitz RB, Lansford R, Chuong CM. Adaptive patterning of vascular network during avian skin development: Mesenchymal plasticity and dermal vasculogenesis. Cells Dev 2024; 179:203922. [PMID: 38688358 PMCID: PMC11633821 DOI: 10.1016/j.cdev.2024.203922] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2023] [Revised: 04/14/2024] [Accepted: 04/15/2024] [Indexed: 05/02/2024]
Abstract
A vasculature network supplies blood to feather buds in the developing skin. Does the vasculature network during early skin development form by sequential sprouting from the central vasculature or does local vasculogenesis occur first that then connect with the central vascular tree? Using transgenic Japanese quail Tg(TIE1p.H2B-eYFP), we observe that vascular progenitor cells appear after feather primordia formation. The vasculature then radiates out from each bud and connects with primordial vessels from neighboring buds. Later they connect with the central vasculature. Epithelial-mesenchymal recombination shows local vasculature is patterned by the epithelium, which expresses FGF2 and VEGF. Perturbing noggin expression leads to abnormal vascularization. To study endothelial origin, we compare transcriptomes of TIE1p.H2B-eYFP+ cells collected from the skin and aorta. Endothelial cells from the skin more closely resemble skin dermal cells than those from the aorta. The results show developing chicken skin vasculature is assembled by (1) physiological vasculogenesis from the peripheral tissue, and (2) subsequently connects with the central vasculature. The work implies mesenchymal plasticity and convergent differentiation play significant roles in development, and such processes may be re-activated during adult regeneration. SUMMARY STATEMENT: We show the vasculature network in the chicken skin is assembled using existing feather buds as the template, and endothelia are derived from local bud dermis and central vasculature.
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Affiliation(s)
- Kuang-Ling Ou
- Department of Pathology, Keck School of Medicine of the University of Southern California, Los Angeles, CA, United States of America; Ostrow School of Dentistry of the University of Southern California, Los Angeles, CA, United States of America; Burn Center, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan; Department of Biochemistry, National Defense Medical Center, Taipei, Taiwan
| | - Chih-Kuan Chen
- Department of Pathology, Keck School of Medicine of the University of Southern California, Los Angeles, CA, United States of America
| | - Junxiang J Huang
- Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, 1501 San Pablo Street, Los Angeles, CA, United States of America; Graduate Programs in Biomedical and Biological Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States of America
| | - William Weijen Chang
- Department of Pathology, Keck School of Medicine of the University of Southern California, Los Angeles, CA, United States of America; Integrative Stem Cell Center, China Medical University, Taichung, Taiwan; Institute of Physiology, Christian-Albrechts-Universität zu Kiel, Kiel, Germany
| | - Shu-Man Hsieh Li
- Department of Pathology, Keck School of Medicine of the University of Southern California, Los Angeles, CA, United States of America; Ostrow School of Dentistry of the University of Southern California, Los Angeles, CA, United States of America
| | - Ting-Xin Jiang
- Department of Pathology, Keck School of Medicine of the University of Southern California, Los Angeles, CA, United States of America
| | - Randall B Widelitz
- Department of Pathology, Keck School of Medicine of the University of Southern California, Los Angeles, CA, United States of America
| | - Rusty Lansford
- Department of Radiology and Developmental Neuroscience Program, Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA, United States of America; Department of Radiology, Keck School of Medicine of the University of Southern California, Los Angeles, CA, United States of America
| | - Cheng-Ming Chuong
- Department of Pathology, Keck School of Medicine of the University of Southern California, Los Angeles, CA, United States of America.
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Tchurikov NA, Vartanian AA, Klushevskaya ES, Alembekov IR, Kretova AN, Lukicheva VN, Chechetkin VR, Kravatskaya GI, Kosorukov VS, Kravatsky YV. Strong Activation of ID1, ID2, and ID3 Genes Is Coupled with the Formation of Vasculogenic Mimicry Phenotype in Melanoma Cells. Int J Mol Sci 2024; 25:9291. [PMID: 39273240 PMCID: PMC11394958 DOI: 10.3390/ijms25179291] [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: 08/08/2024] [Revised: 08/22/2024] [Accepted: 08/26/2024] [Indexed: 09/15/2024] Open
Abstract
Gene expression patterns are very sensitive to external influences and are reflected in phenotypic changes. It was previously described that transferring melanoma cells from a plastic surface to Matrigel led to formation of de novo vascular networks-vasculogenic mimicry-that are characteristic to a stemness phenotype in aggressive tumors. Up to now there was no detailed data about the gene signature accompanying this process. Here, we show that this transfer shortly led to extremely strong epigenetic changes in gene expression in the melanoma cells. We observed that on Matrigel numerous genes controlling ribosome biogenesis were upregulated. However, most of the activated genes were inhibitors of the differentiation genes (ID1, ID2, and ID3). At the same time, the genes that control differentiation were downregulated. Both the upregulated and the downregulated genes are simultaneously targeted by different transcription factors shaping sets of co-expressed genes. The specific group of downregulated genes shaping contacts with rDNA genes are also associated with the H3K27me3 mark and with numerous lincRNAs and miRNAs. We conclude that the stemness phenotype of melanoma cells is due to the downregulation of developmental genes and formation of dedifferentiated cells.
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Affiliation(s)
- Nickolai A Tchurikov
- Department of Epigenetic Mechanisms of Gene Expression Regulation, Engelhardt Institute of Molecular Biology Russian Academy of Sciences, 119334 Moscow, Russia
| | - Amalia A Vartanian
- Department of Experimental Diagnosis and Therapy of Tumors, N.N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of Russia, 115478 Moscow, Russia
| | - Elena S Klushevskaya
- Department of Epigenetic Mechanisms of Gene Expression Regulation, Engelhardt Institute of Molecular Biology Russian Academy of Sciences, 119334 Moscow, Russia
| | - Ildar R Alembekov
- Department of Epigenetic Mechanisms of Gene Expression Regulation, Engelhardt Institute of Molecular Biology Russian Academy of Sciences, 119334 Moscow, Russia
| | - Antonina N Kretova
- Department of Epigenetic Mechanisms of Gene Expression Regulation, Engelhardt Institute of Molecular Biology Russian Academy of Sciences, 119334 Moscow, Russia
| | - Viktoriya N Lukicheva
- Department of Epigenetic Mechanisms of Gene Expression Regulation, Engelhardt Institute of Molecular Biology Russian Academy of Sciences, 119334 Moscow, Russia
| | - Vladimir R Chechetkin
- Department of Epigenetic Mechanisms of Gene Expression Regulation, Engelhardt Institute of Molecular Biology Russian Academy of Sciences, 119334 Moscow, Russia
| | - Galina I Kravatskaya
- Department of Epigenetic Mechanisms of Gene Expression Regulation, Engelhardt Institute of Molecular Biology Russian Academy of Sciences, 119334 Moscow, Russia
| | - Vyacheslav S Kosorukov
- Department of Experimental Diagnosis and Therapy of Tumors, N.N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of Russia, 115478 Moscow, Russia
| | - Yuri V Kravatsky
- Department of Epigenetic Mechanisms of Gene Expression Regulation, Engelhardt Institute of Molecular Biology Russian Academy of Sciences, 119334 Moscow, Russia
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Engelhardt Institute of Molecular Biology Russian Academy of Sciences, 119334 Moscow, Russia
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Lai Q, Wan Y, Zhang Y, Huang Y, Tang Q, Chen M, Li Q, Ma K, Xiao P, Luo C, Zhuang X. Hypomethylation-associated LINC00987 downregulation induced lung adenocarcinoma progression by inhibiting the phosphorylation-mediated degradation of SND1. Mol Carcinog 2024; 63:1260-1274. [PMID: 38607240 DOI: 10.1002/mc.23722] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Revised: 02/27/2024] [Accepted: 03/25/2024] [Indexed: 04/13/2024]
Abstract
DNA methylation, an epigenetic regulatory mechanism dictating gene transcription, plays a critical role in the occurrence and development of cancer. However, the molecular underpinnings of LINC00987 methylation in the regulation of lung adenocarcinoma (LUAD) remain elusive. This study investigated LINC00987 expression in LUAD patients through analysis of The Cancer Genome Atlas data sets. Quantitative real-time polymerase chain reaction (RT-qPCR) and fluorescence in situ hybridization assays were used to assess LINC00987 expression in LUAD. The bisulfite genomic sequence PCR (BSP) assay was used to determine the methylation levels of the LINC00987 promoter. The interaction between LINC00987 and SND1 was elucidated via immunoprecipitation and RNA pull-down assays. The functional significance of LINC00987 and SND1 in Calu-3 and NCI-H1688 cells was evaluated in vitro through CCK-8, EdU, Transwell, flow cytometry, and vasculogenic mimicry (VM) tube formation assays. LINC00987 expression decreased in LUAD concomitant with hypermethylation of the promoter region, while hypomethylation of the LINC00987 promoter in LUAD tissues correlated with tumor progression. Treatment with 5-Aza-CdR augmented LINC00987 expression and inhibited tumor growth. Mechanistically, LINC00987 overexpression impeded LUAD progression and VM through direct binding with SND1, thereby facilitating its phosphorylation and subsequent degradation. Additionally, overexpression of SND1 counteracted the adverse effects of LINC00987 downregulation on cell proliferation, apoptosis, cell migration, invasion, and VM in LUAD in vitro. In conclusion, this pioneering study focuses on the expression and function of LINC00987 and reveals that hypermethylation of the LINC00987 gene may contribute to LUAD progression. LINC00987 has emerged as a potential tumor suppressor gene in tumorigenesis through its binding with SND1 to facilitate its phosphorylation and subsequent degradation.
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Affiliation(s)
- Qi Lai
- Department of Thoracic Surgery, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, China
| | - Yulin Wan
- Medical Department, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, China
| | - Yingqian Zhang
- Laboratory of Nonhuman Primate Disease Modeling Research, West China Hospital, Sichuan University, Chengdu, China
| | - Yingzhao Huang
- Department of Thoracic Surgery, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, China
| | - Qiuyue Tang
- Department of Thoracic Surgery, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, China
| | - Mei Chen
- Department of Thoracic Surgery, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, China
| | - Qian Li
- Department of Thoracic Surgery, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, China
| | - Ke Ma
- Department of Thoracic Surgery, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, China
| | - Ping Xiao
- Department of Thoracic Surgery, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, China
| | - Cheng Luo
- Department of Radiation Oncology, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, China
| | - Xiang Zhuang
- Department of Thoracic Surgery, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, China
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5
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Louis EK, Abdelkawi IF, Refaiy A, Ahmed AM. N-myc downstream-regulated gene 1 can promote vasculogenic mimicry and angiogenesis in urothelial carcinoma. Virchows Arch 2024; 484:827-836. [PMID: 38561462 PMCID: PMC11106159 DOI: 10.1007/s00428-024-03793-w] [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: 01/25/2024] [Revised: 02/28/2024] [Accepted: 03/20/2024] [Indexed: 04/04/2024]
Abstract
Urothelial carcinoma (UC) of the bladder is a common cause of cancer-related death worldwide. Vasculogenic mimicry (VM) is a process by which the malignant cells can generate vascular-like structures formed of periodic acid-Schiff (PAS) positive/CD31 negative extracellular matrix independent of angiogenesis and thus promotes tumor progression. N-myc downstream-regulated gene 1 (NDRG1) is a protein that can modulate tumor angiogenesis; however, its role in regulating tumor angiogenesis and VM formation has not been previously investigated in UC. This study aims to evaluate the role of intra-tumor microvessel density (MVD) (as a surrogate measure of angiogenesis), VM, and NDRG1 in UC and their correlation with different clinicopathologic features, then assess the correlation between them in UC. Sixty specimens of UC of the bladder were included. PAS-CD31 immunohistochemical double staining method was used to evaluate the intra-tumor MVD and VM. Immunohistochemical expression of NDRG1 was also examined. VM and NDRG1 expression were detected in 41.7% and 83.3% of UC specimens respectively. The mean of intra-tumor MVD, VM area, and NDRG1 was significantly higher in tumors with higher grade, lymphovascular invasion, and higher T stage. NDRG1 expression was positively correlated with MVD and VM. We can suggest that MVD, VM, and NDRG1 may serve as poor prognostic markers for UC. The positive correlation between NDRG1 and both MVD and VM may provide the first evidence that NDRG1 can induce tumor angiogenesis and VM in UC which may offer a novel pathway for further therapeutic strategies.
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Affiliation(s)
- Ereny Kamal Louis
- Pathology Department, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Islam F Abdelkawi
- Assiut University Urology Hospital,Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Abeer Refaiy
- Pathology Department, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Asmaa M Ahmed
- Pathology Department, Faculty of Medicine, Assiut University, Assiut, Egypt.
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6
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Tang S, Chen F, Zhang J, Chang F, Lv Z, Li K, Li S, Hu Y, Yeh S. LncRNA-SERB promotes vasculogenic mimicry (VM) formation and tumor metastasis in renal cell carcinoma. J Biol Chem 2024; 300:107297. [PMID: 38641065 PMCID: PMC11126803 DOI: 10.1016/j.jbc.2024.107297] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Revised: 03/03/2024] [Accepted: 03/31/2024] [Indexed: 04/21/2024] Open
Abstract
A growing body of evidence shows that vasculogenic mimicry (VM) is closely related to the invasion and metastasis of many tumor cells. Although the estrogen receptor (ER) can promote initiation and progression of renal cell carcinoma (RCC), how the downstream biomolecules are involved, and the detailed mechanisms of how ER expression is elevated in RCC remain to be further elucidated. Here, we discovered that long noncoding RNA (LncRNA)-SERB is highly expressed in tumor cells of RCC patients. We used multiple RCC cells and an in vivo mouse model for our study, and results indicated that LncRNA-SERB could boost RCC VM formation and cell invasion in vitro and in vivo. Although a previous report showed that ERβ can affect the VM formation in RCC, it is unclear which factor could upregulate ERβ. This is the first study to show LncRNA-SERB can be the upstream regulator of ERβ to control RCC progression. Mechanistically, LncRNA-SERB may increase ERβ via binding to the promoter area, and ERβ functions through transcriptional regulation of zinc finger E-box binding homeobox 1 (ZEB1) to regulate VM formation. These results suggest that LncRNA-SERB promotes RCC cell VM formation and invasion by upregulating the ERβ/ZEB1 axis and that therapeutic targeting of this newly identified pathway may better inhibit RCC progression.
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MESH Headings
- Carcinoma, Renal Cell/genetics
- Carcinoma, Renal Cell/metabolism
- Carcinoma, Renal Cell/pathology
- RNA, Long Noncoding/genetics
- RNA, Long Noncoding/metabolism
- Humans
- Kidney Neoplasms/pathology
- Kidney Neoplasms/metabolism
- Kidney Neoplasms/genetics
- Animals
- Mice
- Neovascularization, Pathologic/metabolism
- Neovascularization, Pathologic/genetics
- Neovascularization, Pathologic/pathology
- Gene Expression Regulation, Neoplastic
- Estrogen Receptor beta/metabolism
- Estrogen Receptor beta/genetics
- Cell Line, Tumor
- Zinc Finger E-box-Binding Homeobox 1/metabolism
- Zinc Finger E-box-Binding Homeobox 1/genetics
- Neoplasm Metastasis
- Mice, Nude
- Male
- Female
- Neoplasm Invasiveness
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Affiliation(s)
- Shuai Tang
- College of Medicine, Nankai University, Tianjin, China; Department of Urology, Nankai University Affinity The Third Central Hospital, Tianjin, China; Department of Urology, The Third Central Hospital of Tianjin, Tianjin, China; Departments of Urology, Pathology, and The Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York, USA
| | - Fangmin Chen
- College of Medicine, Nankai University, Tianjin, China; Department of Urology, Nankai University Affinity The Third Central Hospital, Tianjin, China; Department of Urology, The Third Central Hospital of Tianjin, Tianjin, China.
| | - Jianghui Zhang
- Department of Urology, Nankai University Affinity The Third Central Hospital, Tianjin, China; Department of Urology, The Third Central Hospital of Tianjin, Tianjin, China
| | - Fan Chang
- Department of Urology, Nankai University Affinity The Third Central Hospital, Tianjin, China; Department of Urology, The Third Central Hospital of Tianjin, Tianjin, China
| | - Zheng Lv
- Department of Urology, Nankai University Affinity The Third Central Hospital, Tianjin, China; Department of Urology, The Third Central Hospital of Tianjin, Tianjin, China
| | - Kai Li
- Department of Urology, Nankai University Affinity The Third Central Hospital, Tianjin, China; Department of Urology, The Third Central Hospital of Tianjin, Tianjin, China
| | - Song Li
- Department of Urology, Nankai University Affinity The Third Central Hospital, Tianjin, China; Department of Urology, The Third Central Hospital of Tianjin, Tianjin, China
| | - Yixi Hu
- Departments of Urology, Pathology, and The Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York, USA
| | - Shuyuan Yeh
- Departments of Urology, Pathology, and The Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York, USA; The Sex Hormone Research Center and Department of Urology, China Medical University/Hospital, Taichung, Taiwan.
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7
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Yang Z, Zhang X, Bai X, Xi X, Liu W, Zhong W. Anti-angiogenesis in colorectal cancer therapy. Cancer Sci 2024; 115:734-751. [PMID: 38233340 PMCID: PMC10921012 DOI: 10.1111/cas.16063] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Revised: 11/16/2023] [Accepted: 12/16/2023] [Indexed: 01/19/2024] Open
Abstract
The morbidity of colorectal cancer (CRC) has risen to third place among malignant tumors worldwide. In addition, CRC is a common cancer in China whose incidence increases annually. Angiogenesis plays an important role in the development of tumors because it can bring the nutrients that cancer cells need and take away metabolic waste. Various mechanisms are involved in the formation of neovascularization, and vascular endothelial growth factor is a key mediator. Meanwhile, angiogenesis inhibitors and drug resistance (DR) are challenges to consider when formulating treatment strategies for patients with different conditions. Thus, this review will discuss the molecules, signaling pathways, microenvironment, treatment, and DR of angiogenesis in CRC.
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Affiliation(s)
- Zhenni Yang
- Department of Gastroenterology and HepatologyGeneral Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive DiseasesTianjinChina
- Department of Gastroenterology and HepatologyXing'an League People's HospitalXing'an LeagueChina
| | - Xuqian Zhang
- Department of Gastroenterology and HepatologyGeneral Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive DiseasesTianjinChina
- Department of Gastroenterology and HepatologyChina Aerospace Science and Industry CorporationBeijingChina
| | - Xiaozhe Bai
- Department of Gastroenterology and HepatologyXing'an League People's HospitalXing'an LeagueChina
| | - Xiaonan Xi
- State Key Laboratory of Medicinal Chemical Biology and College of PharmacyNankai UniversityTianjinChina
| | - Wentian Liu
- Department of Gastroenterology and HepatologyGeneral Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive DiseasesTianjinChina
| | - Weilong Zhong
- Department of Gastroenterology and HepatologyGeneral Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive DiseasesTianjinChina
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8
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Wang Y, Zou L, Song M, Zong J, Wang S, Meng L, Jia Z, Zhao L, Han X, Lu M. Establishment of skin cutaneous melanoma prognosis model based on vascular mimicry risk score. Medicine (Baltimore) 2024; 103:e36679. [PMID: 38363903 PMCID: PMC10869071 DOI: 10.1097/md.0000000000036679] [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: 07/02/2023] [Accepted: 11/24/2023] [Indexed: 02/18/2024] Open
Abstract
Studies have indicated that Vascular mimicry (VM) could contribute to the unfavorable prognosis of skin cutaneous melanoma (SKCM). Thus, the objective of this study was to identify therapeutic targets associated with VM in SKCM and develop a novel prognostic model. Gene expression data from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) were utilized to identify differentially expressed genes (DEGs). By intersecting these DEGs with VM genes, we acquired VM-related DEGs specific to SKCM, and then identified prognostic-related VM genes. A VM risk score system was established based on these prognosis-associated VM genes, and patients were then categorized into high- and low-score groups using the median score. Subsequently, differences in clinical characteristics, gene set enrichment analysis (GSEA), and other analyses were further presented between the 2 groups of patients. Finally, a novel prognostic model for SKCM was established using the VM score and clinical characteristics. 26 VM-related DEGs were identified in SKCM, among the identified DEGs associated with VM in SKCM, 5 genes were found to be prognostic-related. The VM risk score system, comprised of these genes, is an independent prognostic risk factor. There were significant differences between the 2 patient groups in terms of age, pathological stage, and T stage. VM risk scores are associated with epithelial biological processes, angiogenesis, regulation of the SKCM immune microenvironment, and sensitivity to targeted drugs. The novel prognostic model demonstrates excellent predictive ability. Our study identified VM-related prognostic markers and therapeutic targets for SKCM, providing novel insights for clinical diagnosis and treatment.
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Affiliation(s)
- Yubo Wang
- Dalian Medical University, Dalian, China
- Department of Trauma and Tissue Repair Surgery, Dalian Municipal Central Hospital, Dalian, China
| | - Linxuan Zou
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Mingzhi Song
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Junwei Zong
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Shouyu Wang
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Lei Meng
- The First Affiliated Hospital of Nanhua Medical University, Hengyang, China
| | - Zhuqiang Jia
- The First Affiliated Hospital of Dalian Medical University, Dalian, China
- Naqu People’s Hospital, Tibet, China
| | - Lin Zhao
- Department of Quality Management, Dalian Municipal Central Hospital, Dalian, China
| | - Xin Han
- Naqu People’s Hospital, Tibet, China
- Department of Orthopaedic Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Ming Lu
- Department of Trauma and Tissue Repair Surgery, Dalian Municipal Central Hospital, Dalian, China
- Department of Trauma and Tissue Repair Surgery, Dalian Municipal Central Hospital of Dalian Medical University, Dalian, China
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9
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Leone P, Malerba E, Susca N, Favoino E, Perosa F, Brunori G, Prete M, Racanelli V. Endothelial cells in tumor microenvironment: insights and perspectives. Front Immunol 2024; 15:1367875. [PMID: 38426109 PMCID: PMC10902062 DOI: 10.3389/fimmu.2024.1367875] [Citation(s) in RCA: 20] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Accepted: 02/05/2024] [Indexed: 03/02/2024] Open
Abstract
The tumor microenvironment is a highly complex and dynamic mixture of cell types, including tumor, immune and endothelial cells (ECs), soluble factors (cytokines, chemokines, and growth factors), blood vessels and extracellular matrix. Within this complex network, ECs are not only relevant for controlling blood fluidity and permeability, and orchestrating tumor angiogenesis but also for regulating the antitumor immune response. Lining the luminal side of vessels, ECs check the passage of molecules into the tumor compartment, regulate cellular transmigration, and interact with both circulating pathogens and innate and adaptive immune cells. Thus, they represent a first-line defense system that participates in immune responses. Tumor-associated ECs are involved in T cell priming, activation, and proliferation by acting as semi-professional antigen presenting cells. Thus, targeting ECs may assist in improving antitumor immune cell functions. Moreover, tumor-associated ECs contribute to the development at the tumor site of tertiary lymphoid structures, which have recently been associated with enhanced response to immune checkpoint inhibitors (ICI). When compared to normal ECs, tumor-associated ECs are abnormal in terms of phenotype, genetic expression profile, and functions. They are characterized by high proliferative potential and the ability to activate immunosuppressive mechanisms that support tumor progression and metastatic dissemination. A complete phenotypic and functional characterization of tumor-associated ECs could be helpful to clarify their complex role within the tumor microenvironment and to identify EC specific drug targets to improve cancer therapy. The emerging therapeutic strategies based on the combination of anti-angiogenic treatments with immunotherapy strategies, including ICI, CAR T cells and bispecific antibodies aim to impact both ECs and immune cells to block angiogenesis and at the same time to increase recruitment and activation of effector cells within the tumor.
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Affiliation(s)
- Patrizia Leone
- Internal Medicine Unit, Department of Interdisciplinary Medicine, Aldo Moro University of Bari, Bari, Italy
| | - Eleonora Malerba
- Department of Precision and Regenerative Medicine and Ionian Area-(DiMePRe-J), Aldo Moro University of Bari, Bari, Italy
| | - Nicola Susca
- Internal Medicine Unit, Department of Interdisciplinary Medicine, Aldo Moro University of Bari, Bari, Italy
| | - Elvira Favoino
- Rheumatic and Systemic Autoimmune Diseases Unit, Department of Interdisciplinary Medicine, Aldo Moro University of Bari, Bari, Italy
| | - Federico Perosa
- Rheumatic and Systemic Autoimmune Diseases Unit, Department of Interdisciplinary Medicine, Aldo Moro University of Bari, Bari, Italy
| | - Giuliano Brunori
- Centre for Medical Sciences, University of Trento and Nephrology and Dialysis Division, Santa Chiara Hospital, Provincial Health Care Agency (APSS), Trento, Italy
| | - Marcella Prete
- Internal Medicine Unit, Department of Interdisciplinary Medicine, Aldo Moro University of Bari, Bari, Italy
| | - Vito Racanelli
- Centre for Medical Sciences, University of Trento and Internal Medicine Division, Santa Chiara Hospital, Provincial Health Care Agency (APSS), Trento, Italy
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10
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Tadić V, Zhang W, Brozovic A. The high-grade serous ovarian cancer metastasis and chemoresistance in 3D models. Biochim Biophys Acta Rev Cancer 2024; 1879:189052. [PMID: 38097143 DOI: 10.1016/j.bbcan.2023.189052] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Revised: 12/06/2023] [Accepted: 12/06/2023] [Indexed: 12/21/2023]
Abstract
High-grade serous ovarian cancer (HGSOC) is the most frequent and aggressive type of epithelial ovarian cancer, with high recurrence rate and chemoresistance being the main issues in its clinical management. HGSOC is specifically challenging due to the metastatic dissemination via spheroids in the ascitic fluid. The HGSOC spheroids represent the invasive and chemoresistant cellular fraction, which is impossible to investigate in conventional two-dimensional (2D) monolayer cell cultures lacking critical cell-to-cell and cell-extracellular matrix interactions. Three-dimensional (3D) HGSOC cultures, where cells aggregate and exhibit relevant interactions, offer a promising in vitro model of peritoneal metastasis and multicellular drug resistance. This review summarizes recent studies of HGSOC in 3D culture conditions and highlights the role of multicellular HGSOC spheroids and ascitic environment in HGSOC metastasis and chemoresistance.
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Affiliation(s)
- Vanja Tadić
- Division of Molecular Biology, Ruđer Bošković Institute, Bijenička Str. 54, Zagreb HR-10000, Croatia
| | - Wei Zhang
- Department of Engineering Mechanics, Dalian University of Technology, Linggong Road 2, Dalian CN-116024, China
| | - Anamaria Brozovic
- Division of Molecular Biology, Ruđer Bošković Institute, Bijenička Str. 54, Zagreb HR-10000, Croatia.
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11
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Fen-Xu, Jiang LH, Chen-Fu, Feng WW, Zhou CJ. CRD-BP as a Tumor Marker of Colorectal Cancer. Anticancer Agents Med Chem 2024; 24:169-176. [PMID: 37990428 DOI: 10.2174/0118715206256546231108095912] [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: 05/09/2023] [Revised: 10/10/2023] [Accepted: 10/11/2023] [Indexed: 11/23/2023]
Abstract
The National Cancer Center published a comparative report on cancer data between China and the United States in the Chinese Medical Journal, which shows that colorectal cancer (CRC) ranks second in China and fourth in the United States. It is worth noting that since 2000, the case fatality rate of CRC in China has skyrocketed, while the United States has gradually declined. Finding tumor markers with high sensitivity and specificity is our primary goal to reduce the case fatality rate of CRC. Studies have shown that CRD-BP (Insulin-like growth factor 2 mRNA-binding protein 1) can affect a variety of signaling pathways, such as Wnt.nuclear factor KB (NF-κB), and Hedgehog, and has good biological effects as a therapeutic target for CRC. CRD-BP is expected to become a tumor marker with high sensitivity and specificity of CRC. This paper reviews the research on CRD-BP as a tumor marker of CRC.
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Affiliation(s)
- Fen-Xu
- Department of Gastroenterology, Xinhua Hospital Affiliated to Dalian University, Liaoning Command, Liaoning 116000, Liaoning Province, China
| | - Liang-Hong Jiang
- Department of Gastroenterology, Xinhua Hospital Affiliated to Dalian University, Liaoning Command, Liaoning 116000, Liaoning Province, China
| | - Chen-Fu
- Department of Gastroenterology, Xinhua Hospital Affiliated to Dalian University, Liaoning Command, Liaoning 116000, Liaoning Province, China
| | - Wei-Wei Feng
- Department of Gastroenterology, Xinhua Hospital Affiliated to Dalian University, Liaoning Command, Liaoning 116000, Liaoning Province, China
| | - Chang-Jiang Zhou
- Department of Gastroenterology, Xinhua Hospital Affiliated to Dalian University, Liaoning Command, Liaoning 116000, Liaoning Province, China
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12
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Huang J, Wang C, Hou Y, Tian Y, Li Y, Zhang H, Zhang L, Li W. Molecular mechanisms of Thrombospondin-2 modulates tumor vasculogenic mimicry by PI3K/AKT/mTOR signaling pathway. Biomed Pharmacother 2023; 167:115455. [PMID: 37696083 DOI: 10.1016/j.biopha.2023.115455] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Revised: 08/24/2023] [Accepted: 09/05/2023] [Indexed: 09/13/2023] Open
Abstract
Vasculogenic mimicry (VM) differs from the classical tumor angiogenesis model. VM does not depend on endothelial cells; instead, highly aggressive tumor cells mimic endothelial cells to form a vascular-like channel structure. VM mediated by tumor cells is significantly and positively associated with a poor prognosis and low survival rates in patients with highly aggressive cancer. In the treatment of highly aggressive malignancies, the presence of VM is considered an important reason for the unsatisfactory clinical efficacy of anti-tumor-angiogenesis therapy (e.g., therapy targeting vascular endothelial growth factor A). Many targeted therapeutic drugs based on traditional tumor blood vessels have been used clinically. Although some progress has been made in certain tumors, problems such as drug resistance have restricted the expected therapeutic effects. Thrombospondin 2 (THBS2) is one of the most important genes associated with angiogenesis, and this gene exerts angiogenesis-related functions through the PI3K/AKT signaling pathway. Although the PI3K/AKT/mTOR signaling pathway is closely related to the progression of VM, the mechanism by which the promising biomarker THBS2 participates in and regulates tumor VM by activating the PI3K/AKT/mTOR signaling pathway is unclear. In this review, we analyze the monomer structure and biological activity of THBS2, the structure and potential synthesis mechanisms of VM, and the complex mechanisms between THBS2, the PI3K/AKT/mTOR signaling pathway, and VM.
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Affiliation(s)
- Ju Huang
- The Key Laboratory of Pathobiology, Ministry of Education, The College of Basic Medical Sciences, Jilin University, Changchun, Jilin 130021, China
| | - Congcong Wang
- The Key Laboratory of Pathobiology, Ministry of Education, The College of Basic Medical Sciences, Jilin University, Changchun, Jilin 130021, China
| | - Yixuan Hou
- The Key Laboratory of Pathobiology, Ministry of Education, The College of Basic Medical Sciences, Jilin University, Changchun, Jilin 130021, China
| | - Yuanyuan Tian
- The Key Laboratory of Pathobiology, Ministry of Education, The College of Basic Medical Sciences, Jilin University, Changchun, Jilin 130021, China
| | - Yanru Li
- The Key Laboratory of Pathobiology, Ministry of Education, The College of Basic Medical Sciences, Jilin University, Changchun, Jilin 130021, China
| | - Haiying Zhang
- The Key Laboratory of Pathobiology, Ministry of Education, The College of Basic Medical Sciences, Jilin University, Changchun, Jilin 130021, China
| | - Lihong Zhang
- The Key Laboratory of Pathobiology, Ministry of Education, The College of Basic Medical Sciences, Jilin University, Changchun, Jilin 130021, China
| | - Wei Li
- The Key Laboratory of Pathobiology, Ministry of Education, The College of Basic Medical Sciences, Jilin University, Changchun, Jilin 130021, China.
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13
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Wang J, Liu Y, Zhang Y, Li X, Fang M, Qian D. Targeting exosomes enveloped EBV-miR-BART1-5p-antagomiRs for NPC therapy through both anti-vasculogenic mimicry and anti-angiogenesis. Cancer Med 2023. [PMID: 37097161 DOI: 10.1002/cam4.5941] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2022] [Revised: 03/25/2023] [Accepted: 04/01/2023] [Indexed: 04/26/2023] Open
Abstract
BACKGROUND Nasopharyngeal carcinoma (NPC) is a type of head and neck cancer with high incidence in China. The molecular mechanisms of vasculogenic mimicry (VM) and angiogenesis are not fully elucidated in NPC. More specially, it has seldomly been reported that Epstein-Barr virus-encoded miRNA can regulate VM and angiogenesis in NPC. The aim of this study was to investigate the function and molecular mechanism of a targeting exosome system (iRGD-exo-antagomiR) against VM and angiogenesis in NPC, and to provide new approaches for improving the comprehensive treatment of NPC. METHODS Exosomes were isolated by differential ultracentrifugation. Dynamic light scattering, transmission electron microscopy and western blotting were performed to characterize the exosomes. The 3D-Culture assay, tube formation assay, chicken chorioallantoic membrane assay, Matrigel plug assay, mouse xenograft tumor modeling and immunohistochemical staining were applied to evaluate the anti-VM and anti-angiogenic effects of the targeting exosome system in vitro and in vivo. Western blot was performed to detect the changes of downstream regulated networks following interference and recovery of the target gene. RESULTS In vitro or in vivo treatment with iRGD-tagged exosome containing antagomiR-BART1-5p specifically suppressed VM and angiogenesis in NPC. EBV-miR-BART1-5p promoted VM and angiogenesis in vitro and in vivo by regulating VEGF, PI3K, Akt, mTOR and HIF1-α in a Spry2-dependent manner. CONCLUSIONS Our findings demonstrated that targeting exosomes enveloped EBV-miR-BART1-5p-antagomiRs in a Spry2-dependent manner for NPC therapy through both anti-VM and anti-angiogenesis in vitro and in vivo.
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Affiliation(s)
- Jianguo Wang
- Department of Radiation Oncology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
- Core Facility Center, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
| | - Yan Liu
- Health Management center, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
| | - Yuanbin Zhang
- Shenzhen Key Laboratory of Viral Oncology, the Clinical Innovation & Research Center (CIRC), Shenzhen Hospital, Southern Medical University, Shenzhen, China
| | - Xiaoyang Li
- Department of Radiation Oncology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
- Core Facility Center, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
| | - Min Fang
- Department of Radiation Oncology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
| | - Dong Qian
- Department of Radiation Oncology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
- Core Facility Center, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
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14
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Wälchli T, Bisschop J, Carmeliet P, Zadeh G, Monnier PP, De Bock K, Radovanovic I. Shaping the brain vasculature in development and disease in the single-cell era. Nat Rev Neurosci 2023; 24:271-298. [PMID: 36941369 PMCID: PMC10026800 DOI: 10.1038/s41583-023-00684-y] [Citation(s) in RCA: 61] [Impact Index Per Article: 30.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/06/2023] [Indexed: 03/23/2023]
Abstract
The CNS critically relies on the formation and proper function of its vasculature during development, adult homeostasis and disease. Angiogenesis - the formation of new blood vessels - is highly active during brain development, enters almost complete quiescence in the healthy adult brain and is reactivated in vascular-dependent brain pathologies such as brain vascular malformations and brain tumours. Despite major advances in the understanding of the cellular and molecular mechanisms driving angiogenesis in peripheral tissues, developmental signalling pathways orchestrating angiogenic processes in the healthy and the diseased CNS remain incompletely understood. Molecular signalling pathways of the 'neurovascular link' defining common mechanisms of nerve and vessel wiring have emerged as crucial regulators of peripheral vascular growth, but their relevance for angiogenesis in brain development and disease remains largely unexplored. Here we review the current knowledge of general and CNS-specific mechanisms of angiogenesis during brain development and in brain vascular malformations and brain tumours, including how key molecular signalling pathways are reactivated in vascular-dependent diseases. We also discuss how these topics can be studied in the single-cell multi-omics era.
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Affiliation(s)
- Thomas Wälchli
- Group of CNS Angiogenesis and Neurovascular Link, Neuroscience Center Zurich, and Division of Neurosurgery, University and University Hospital Zurich, Swiss Federal Institute of Technology (ETH) Zurich, Zurich, Switzerland.
- Division of Neurosurgery, University Hospital Zurich, Zurich, Switzerland.
- Group of Brain Vasculature and Perivascular Niche, Division of Experimental and Translational Neuroscience, Krembil Brain Institute, Krembil Research Institute, Toronto Western Hospital, University Health Network, University of Toronto, Toronto, ON, Canada.
- Division of Neurosurgery, Department of Surgery, Toronto Western Hospital, Toronto, ON, Canada.
| | - Jeroen Bisschop
- Group of CNS Angiogenesis and Neurovascular Link, Neuroscience Center Zurich, and Division of Neurosurgery, University and University Hospital Zurich, Swiss Federal Institute of Technology (ETH) Zurich, Zurich, Switzerland
- Division of Neurosurgery, University Hospital Zurich, Zurich, Switzerland
- Group of Brain Vasculature and Perivascular Niche, Division of Experimental and Translational Neuroscience, Krembil Brain Institute, Krembil Research Institute, Toronto Western Hospital, University Health Network, University of Toronto, Toronto, ON, Canada
- Division of Neurosurgery, Department of Surgery, Toronto Western Hospital, Toronto, ON, Canada
- Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
| | - Peter Carmeliet
- Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, VIB & Department of Oncology, KU Leuven, Leuven, Belgium
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, People's Republic of China
- Laboratory of Angiogenesis and Vascular Heterogeneity, Department of Biomedicine, Aarhus University, Aarhus, Denmark
| | - Gelareh Zadeh
- Division of Neurosurgery, Department of Surgery, Toronto Western Hospital, Toronto, ON, Canada
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | - Philippe P Monnier
- Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
- Donald K. Johnson Research Institute, Krembil Research Institute, Krembil Discovery Tower, Toronto, ON, Canada
- Department of Ophthalmology and Vision Sciences, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
| | - Katrien De Bock
- Laboratory of Exercise and Health, Department of Health Science and Technology, Swiss Federal Institute of Technology (ETH) Zurich, Zurich, Switzerland
| | - Ivan Radovanovic
- Group of Brain Vasculature and Perivascular Niche, Division of Experimental and Translational Neuroscience, Krembil Brain Institute, Krembil Research Institute, Toronto Western Hospital, University Health Network, University of Toronto, Toronto, ON, Canada
- Division of Neurosurgery, Department of Surgery, Toronto Western Hospital, Toronto, ON, Canada
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Kicman A, Niczyporuk M, Kulesza M, Motyka J, Ławicki S. Utility of Matrix Metalloproteinases in the Diagnosis, Monitoring and Prognosis of Ovarian Cancer Patients. Cancer Manag Res 2022; 14:3359-3382. [PMID: 36474934 PMCID: PMC9719685 DOI: 10.2147/cmar.s385658] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Accepted: 11/08/2022] [Indexed: 01/14/2024] Open
Abstract
Ovarian cancer is one of the most common gynecologic malignancies. It is characterized by a high mortality rate, which is mainly due to the asymptomatic course of the disease. In light of the high mortality rate and increasing morbidity, new diagnostic methods are being explored to enable earlier detection, better monitoring, and improved prognosis. Such diagnostic methods include the assessment of tumor markers in various biological samples. Among the markers currently being investigated, extracellular matrix metalloproteinases (MMPs) are of particular interest. The objective of this article was to compile the existing knowledge of MMPs in ovarian cancer patients and to describe their potential diagnostic utility. Additionally, this article provides an overview of the symptoms, complications, and risk factors associated with ovarian cancer and the role of MMPs in physiology and pathology. Preliminary results indicate that tissue expression and blood and body fluid levels of MMPs may be different in ovarian cancer patients than in healthy women. The expression and concentration of individual MMPs have been shown to be correlated with cancer stage and disease severity. In addition, the preliminary value of some of these enzymes in predicting prognosis is discussed. However, as the amount of data is limited, more studies are needed to fully evaluate the potential function of individual MMPs in ovarian cancer patients. Based on the knowledge gathered for this article, it seems that MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-13, are tentatively the most useful. A thorough evaluation of their utility as modern biomarkers in ovarian cancer requires further investigation.
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Affiliation(s)
- Aleksandra Kicman
- Department of Aesthetic Medicine, Medical University of Bialystok, Bialystok, Poland
| | - Marek Niczyporuk
- Department of Aesthetic Medicine, Medical University of Bialystok, Bialystok, Poland
| | - Monika Kulesza
- Department of Population Medicine and Lifestyle Diseases Prevention, Medical University of Bialystok, Bialystok, Poland
| | - Joanna Motyka
- Department of Population Medicine and Lifestyle Diseases Prevention, Medical University of Bialystok, Bialystok, Poland
| | - Sławomir Ławicki
- Department of Population Medicine and Lifestyle Diseases Prevention, Medical University of Bialystok, Bialystok, Poland
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Giusti I, Poppa G, D’Ascenzo S, Esposito L, Vitale AR, Calvisi G, Dolo V. Cancer Three-Dimensional Spheroids Mimic In Vivo Tumor Features, Displaying “Inner” Extracellular Vesicles and Vasculogenic Mimicry. Int J Mol Sci 2022; 23:ijms231911782. [PMID: 36233083 PMCID: PMC9569704 DOI: 10.3390/ijms231911782] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Revised: 09/26/2022] [Accepted: 09/29/2022] [Indexed: 12/24/2022] Open
Abstract
The role of extracellular vesicles (EVs) as mediators of cell-to-cell communication in cancer progression is widely recognized. In vitro studies are routinely performed on 2D culture models, but recent studies suggest that 3D cultures could represent a more valid model. Human ovarian cancer cells CABA I were cultured by the hanging drop method to form tumor spheroids, that were moved to low adhesion supports to observe their morphology by Scanning Electron Microscopy (SEM) and to isolate the EVs. EVs release was verified by SEM and their identity confirmed by morphology (Transmission Electron Microscopy, TEM), size distribution (Nanoparticles Tracking Analysis), and markers (CD63, CD9, TSG-101, Calnexin). CABA I form spheroids with a clinically relevant size, above 400 μm; they release EVs on their external surface and also trap “inner” EVs. They also produce vasculogenic mimicry-like tubules, that bulge from the spheroid and are composed of a hollow lumen delimited by tumor cells. CABA I can be grown as multicellular spheroids to easily isolate EVs. The presence of features typical of in vivo tumors (inner entrapped EVs and vasculogenic mimicry) suggests their use as faithful experimental models to screen therapeutic drugs targeting these pro-tumorigenic processes.
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Affiliation(s)
- Ilaria Giusti
- Department of Life, Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy
| | - Giuseppina Poppa
- Department of Life, Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy
| | - Sandra D’Ascenzo
- Department of Life, Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy
| | - Letizia Esposito
- Department of Life, Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy
| | - Anna Rita Vitale
- Pathology Unit, San Salvatore Hospital, Via Lorenzo Natali, 1, Coppito, 67100 L’Aquila, Italy
| | - Giuseppe Calvisi
- Pathology Unit, San Salvatore Hospital, Via Lorenzo Natali, 1, Coppito, 67100 L’Aquila, Italy
| | - Vincenza Dolo
- Department of Life, Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy
- Correspondence: ; Tel.: +39-0862-436665
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Parvathaneni V, Chilamakuri R, Kulkarni NS, Baig NF, Agarwal S, Gupta V. Exploring Amodiaquine's Repurposing Potential in Breast Cancer Treatment-Assessment of In-Vitro Efficacy & Mechanism of Action. Int J Mol Sci 2022; 23:11455. [PMID: 36232751 PMCID: PMC9569809 DOI: 10.3390/ijms231911455] [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: 08/30/2022] [Revised: 09/18/2022] [Accepted: 09/19/2022] [Indexed: 11/24/2022] Open
Abstract
Due to the heterogeneity of breast cancer, current available treatment options are moderately effective at best. Hence, it is highly recommended to comprehend different subtypes, understand pathogenic mechanisms involved, and develop treatment modalities. The repurposing of an old FDA approved anti-malarial drug, amodiaquine (AQ) presents an outstanding opportunity to explore its efficacy in treating majority of breast cancer subtypes. Cytotoxicity, scratch assay, vasculogenic mimicry study, and clonogenic assay were employed to determine AQ's ability to inhibit cell viability, cell migration, vascular formation, and colony growth. 3D Spheroid cell culture studies were performed to identify tumor growth inhibition potential of AQ in MCF-7 and MDAMB-231 cell lines. Apoptosis assays, cell cycle analysis, RT-qPCR assays, and Western blot studies were performed to determine AQ's ability to induce apoptosis, cell cycle changes, gene expression changes, and induction of autophagy marker proteins. The results from in-vitro studies confirmed the potential of AQ as an anti-cancer drug. In different breast cancer cell lines tested, AQ significantly induces cytotoxicity, inhibit colony formation, inhibit cell migration, reduces 3D spheroid volume, induces apoptosis, blocks cell cycle progression, inhibit expression of cancer related genes, and induces LC3BII protein to inhibit autophagy. Our results demonstrate that amodiaquine is a promising drug to repurpose for breast cancer treatment, which needs numerous efforts from further studies.
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Affiliation(s)
| | | | | | | | | | - Vivek Gupta
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John’s University, 8000 Utopia Parkway, Queens, NY 11439, USA
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The Biomarker Like the Correlation between Vasculogenic Mimicry, Vascular Endothelial Cadherin, Sex-DeterminingRegion on Y-Box Transcription Factor 17, and Cyclin D1 in Oesophageal Squamous Cell Carcinoma. JOURNAL OF ONCOLOGY 2022; 2022:8915503. [PMID: 36072972 PMCID: PMC9444392 DOI: 10.1155/2022/8915503] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Accepted: 07/22/2022] [Indexed: 12/24/2022]
Abstract
Background This study aimed to explore the relationships between the sex-determining region on Y (SRY) box transcription factor 17 (SOX17), Cyclin D1, vascular endothelial cadherin (VE-cadherin), and vasculogenic mimicry (VM) in the occurrence and development of esophageal squamous cell carcinoma (ESCC). Methods The expressions of SOX17, Cyclin D1, and VE-cadherin, as well as VM, in tissues, were determined using immunohistochemistry. SOX17, Cyclin D1, and VE-cadherin mRNA in ESCC and their corresponding adjacent normal tissues were quantified using quantitative reverse transcription polymerase chain reaction analysis. Cell invasion, migration, and proliferation were determined after the silencing of VE-cadherin. SOX17, Cyclin D1, and VE-cadherin protein were quantified using Western blotting. Results The expression levels of SOX17, Cyclin D1, and VE-cadherin significantly correlated with the clinical characteristics of ESCC. After the VE-cadherin silencing, cell invasion, migration, and proliferation decreased, along with the Cyclin D1 levels, while the SOX17 levels increased. Conclusion SOX17, Cyclin D1, and VE-cadherin are involved in the development of ESCC.
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19
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Halogenated Flavonoid Derivatives Display Antiangiogenic Activity. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27154757. [PMID: 35897938 PMCID: PMC9331694 DOI: 10.3390/molecules27154757] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Revised: 07/13/2022] [Accepted: 07/14/2022] [Indexed: 11/16/2022]
Abstract
Antiangiogenic agents attenuate tumours' growth and metastases and are therefore beneficial as an adjuvant or standalone cancer regimen. Drugs with dual antiproliferative and antiangiogenic activities can achieve anticancer efficacy and overcome acquired resistance. In this study, synthetic flavones (5a,b) with reported anticancer activity, and derivatives (4b and 6a), exhibited significant inhibition of endothelial cell tube formation (40-55%, 12 h) at 1 µM, which is comparable to sunitinib (50% inhibition at 1 µM, 48 h). Flavones (4b, 5a,b and 6a) also showed 25-37% reduction in HUVECs migration at 10 µM. In a Western blotting assay, 5a and 5b subdued VEGFR2 phosphorylation by 37% and 57%, respectively, suggesting that VEGFR2 may be their main antiangiogenic target. 5b displayed the best docking fit with VEGFR2 in an in silico study, followed by 5a, emphasizing the importance of the 7-hydroxyl group accompanied by a 4-C=S for activity. Conversely, derivatives with a 4-carbonyl moiety fitted poorly into the target's binding pocket, suggesting that their antiangiogenic activity depends on a different target. This study provides valuable insight into the Structure Activity Relationships (SAR) and modes of action of halogenated flavones with VEGFR2 and highlights their therapeutic potential as antiangiogenic/anticancer lead compounds.
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m6A methylated EphA2 and VEGFA through IGF2BP2/3 regulation promotes vasculogenic mimicry in colorectal cancer via PI3K/AKT and ERK1/2 signaling. Cell Death Dis 2022; 13:483. [PMID: 35595748 PMCID: PMC9122982 DOI: 10.1038/s41419-022-04950-2] [Citation(s) in RCA: 105] [Impact Index Per Article: 35.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Revised: 05/10/2022] [Accepted: 05/12/2022] [Indexed: 02/07/2023]
Abstract
Exploring the epigenetic regulation mechanism of colorectal cancer (CRC) from the perspective of N6-methyladenosine (m6A) modification may provide a new target for tumor therapy. Analysis using high-throughput RNA-seq profile from TCGA found that the gene expression of Methyltransferase-like 3 (METTL3) was significantly upregulated among 20 m6A binding proteins in CRC, which was also validated in CRC cancer tissues and cell lines. Moreover, transcriptome sequencing in METTL3 knockdown cells using CRISPR/Cas9 editing suggested that EphA2 and VEGFA were differential expression, which were enriched in the vasculature development, PI3K/AKT and ERK1/2 signal pathway through the functional enrichment analysis. The results in vitro revealed that METTL3 as the m6A "writers" participates the methylation of EphA2 and VEGFA, which were recognized by the m6A "readers", insulin-like growth factor 2 mRNA binding protein 2/3 (IGF2BP2/3), to prevent their mRNA degradation. In addition, EphA2 and VEGFA targeted by METTL3 via different IGF2BP-dependent mechanisms were found to promote vasculogenic mimicry (VM) formation via PI3K/AKT/mTOR and ERK1/2 signaling in CRC. The study suggests that intervention with m6A-binding proteins (METTL3 and IGF2BP2/3) may provide a potential diagnostic or prognostic target of VM-based anti-metastasis drugs for CRC.
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21
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Role of Anti-Angiogenic Factors in the Pathogenesis of Breast Cancer: A Review of Therapeutic Potential. Pathol Res Pract 2022; 236:153956. [DOI: 10.1016/j.prp.2022.153956] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Revised: 05/06/2022] [Accepted: 05/25/2022] [Indexed: 11/23/2022]
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22
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Liang C, Yang L, Guo SW, Li RC. Downregulation of Astrocyte Elevated Gene-1 Expression Combined with All-Trans Retinoic Acid Inhibits Development of Vasculogenic Mimicry and Angiogenesis in Glioma. Curr Med Sci 2022; 42:397-406. [PMID: 35201552 DOI: 10.1007/s11596-022-2517-4] [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: 12/29/2020] [Accepted: 10/20/2021] [Indexed: 12/14/2022]
Abstract
OBJECTIVE This study aimed to investigate the effects of downregulating astrocyte elevated gene-1 (AEG-1) expression combined with all-trans retinoic acid (ATRA) on vasculogenic mimicry (VM) formation and angiogenesis in glioma. METHODS U87 glioma cells were transfected with AEG-1 shRNA lentiviral vectors (U87-siAEG-1) and incubated in a medium containing 20 µmol/L ATRA. Matrigel-based tube formation assay was performed to evaluate VM formation, and the cell counting kit-8 (CCK-8) assay was used to analyze the proliferation of glioma cells in vitro. Reverse transcription-quantitative polymerase chain reaction and Western blot analysis were used to investigate the mRNA and protein expression of related genes, respectively. Glioma xenograft models were generated via subcutaneous implantation of glioma cells in nude mice. Tumor-bearing mice received an intraperitoneal injection of ATRA (10 mg/kg per day). Immunohistochemistry was used to evaluate the expression of related genes and the microvessel density (MVD) in glioma xenograft models. CD34/periodic acid-Schiff double staining was performed to detect VM channels in vivo. The volume and weight of tumors were measured, and a tumor growth curve was drawn to evaluate tumor growth. RESULTS A combination of ATRA intervention and downregulation of AEG-1 expression significantly inhibited the proliferation of glioma cells in vitro and glioma VM formation in vitro and in vivo. It also significantly decreased MVD and inhibited tumor growth. Further, the expression levels of matrix metalloproteinase (MMP)-2, MMP-9, vascular endothelial-cadherin (VE-cadherin), and vascular endothelial growth factor (VEGF) in glioma significantly decreased in vivo and in vivo. CONCLUSION Hence, a combinatorial approach might be effective in treating glioma through regulating MMP-2, MMP-9, VEGF, and VE-cadherin expression.
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Affiliation(s)
- Chen Liang
- Department of Neurosurgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China.
| | - Ling Yang
- Department of Aeromedical Physical Examination, Xi'an Civil Aviation Hospital, Xi'an, 710082, China
| | - Shi-Wen Guo
- Department of Neurosurgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China
| | - Rui-Chun Li
- Department of Neurosurgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China
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23
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Sun F, Jie Q, Li Q, Wei Y, Li H, Yue X, Ma Y. TUSC3 inhibits cell proliferation and invasion in cervical squamous cell carcinoma via suppression of the AKT signalling pathway. J Cell Mol Med 2022; 26:1629-1642. [PMID: 35137520 PMCID: PMC8899155 DOI: 10.1111/jcmm.17204] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Revised: 12/28/2021] [Accepted: 01/10/2022] [Indexed: 12/24/2022] Open
Abstract
The decreased expression of tumour suppressor candidate 3 (TUSC3) is associated with proliferation in several types of cancer, leading to an unfavourable prognosis. The present study aimed to assess the cellular and molecular function of TUSC3 in patients with cervical squamous cell carcinoma (CSCC). Levels of mRNA expressions of TUSC3 were analysed in CSCC tissues and six cell lines using qRT-PCR. Immunohistochemistry(IHC) was used to evaluate the protein expression level of TUSC3 in four paired specimens, 220 paraffin-embedded CSCC specimens and 60 cases of normal cervical tissues(NCTs), respectively. Short hairpin RNA interference was employed for TUSC3 knockdown. Cell proliferation, migration and invasion were evaluated using growth curve, MTT assay, wound healing, transwell assay and xenograft tumour model, respectively. The results demonstrated that TUSC3 mRNA and protein expression levels were downregulated in CSCC samples. Multivariate and univariate analyses indicated that TUSC3 was an independent prognostic factor for patients with CSCC. Decreased TUSC3 expression levels were significantly associated with proliferation and an aggressive phenotype of cervical cancer cells both in vitro and in vivo. Moreover, the knockdown of TUSC3 promoted migration and invasion of cancer cells, while the increased expression of TUSC3 exhibited the opposite effects. The downregulation of TUSC3 facilitated proliferation and invasion of CSCC cells through the activation of the AKT signalling pathway. Our data demonstrated that the downregulation of TUSC3 promoted CSCC cell metastasis via the AKT signalling pathway. Therefore, TUSC3 may serve as a novel prognostic marker and potential target for CSCC.
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Affiliation(s)
- Fei Sun
- Hainan Provincial Key Laboratory for Human Reproductive Medicine and Genetic ResearchHainan Provincial Clinical Research Center for Thalassemiathe Key Laboratory of Tropical Translational Medicine of Ministry of EducationDepartment of Reproductive Medicinethe First Affiliated Hospital of Hainan Medical UniversityHainan Medical UniversityHaikouHainanP.R. China
- Department of Obstetrics and GynecologyNanfang HospitalSouthern Medical UniversityGuangdongChina
- Haikou Key Laboratory for Preservation of Human Genetic Resourcethe First Affiliated Hospital of Hainan Medical UniversityHaikouHainanChina
| | - Qiuling Jie
- Hainan Provincial Key Laboratory for Human Reproductive Medicine and Genetic ResearchHainan Provincial Clinical Research Center for Thalassemiathe Key Laboratory of Tropical Translational Medicine of Ministry of EducationDepartment of Reproductive Medicinethe First Affiliated Hospital of Hainan Medical UniversityHainan Medical UniversityHaikouHainanP.R. China
- Department of Obstetrics and GynecologyNanfang HospitalSouthern Medical UniversityGuangdongChina
- Haikou Key Laboratory for Preservation of Human Genetic Resourcethe First Affiliated Hospital of Hainan Medical UniversityHaikouHainanChina
| | - Qi Li
- Hainan Provincial Key Laboratory for Human Reproductive Medicine and Genetic ResearchHainan Provincial Clinical Research Center for Thalassemiathe Key Laboratory of Tropical Translational Medicine of Ministry of EducationDepartment of Reproductive Medicinethe First Affiliated Hospital of Hainan Medical UniversityHainan Medical UniversityHaikouHainanP.R. China
- Haikou Key Laboratory for Preservation of Human Genetic Resourcethe First Affiliated Hospital of Hainan Medical UniversityHaikouHainanChina
- Hainan Modern Women and Children’s HospitialReproductive MedicineHaikouHainanChina
| | - Yunjian Wei
- Hainan Provincial Key Laboratory for Human Reproductive Medicine and Genetic ResearchHainan Provincial Clinical Research Center for Thalassemiathe Key Laboratory of Tropical Translational Medicine of Ministry of EducationDepartment of Reproductive Medicinethe First Affiliated Hospital of Hainan Medical UniversityHainan Medical UniversityHaikouHainanP.R. China
- Department of Obstetrics and GynecologyNanfang HospitalSouthern Medical UniversityGuangdongChina
- Haikou Key Laboratory for Preservation of Human Genetic Resourcethe First Affiliated Hospital of Hainan Medical UniversityHaikouHainanChina
| | - Hong Li
- Department of Obstetrics and GynecologyNanfang HospitalSouthern Medical UniversityGuangdongChina
| | - Xiaojing Yue
- Department of Obstetrics and GynecologyNanfang HospitalSouthern Medical UniversityGuangdongChina
| | - Yanlin Ma
- Hainan Provincial Key Laboratory for Human Reproductive Medicine and Genetic ResearchHainan Provincial Clinical Research Center for Thalassemiathe Key Laboratory of Tropical Translational Medicine of Ministry of EducationDepartment of Reproductive Medicinethe First Affiliated Hospital of Hainan Medical UniversityHainan Medical UniversityHaikouHainanP.R. China
- Department of Obstetrics and GynecologyNanfang HospitalSouthern Medical UniversityGuangdongChina
- Haikou Key Laboratory for Preservation of Human Genetic Resourcethe First Affiliated Hospital of Hainan Medical UniversityHaikouHainanChina
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24
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Souza JCD, Bastos VC, Pereira NB, Dias AAM, Avelar GFD, Gomez RS, Gomes CC. Angiogenesis in patient-derived xenografts of odontogenic myxoma. Int J Exp Pathol 2022; 103:65-69. [PMID: 35225401 PMCID: PMC8961500 DOI: 10.1111/iep.12431] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2021] [Revised: 01/26/2022] [Accepted: 02/05/2022] [Indexed: 12/01/2022] Open
Abstract
Previously, by employing 3D organotypic tissue culture and patient-derived xenograft (PDX) model, oral myxoma response to a MAPK/MEK inhibitor was observed. Gross examination of the tumour fragments obtained after 55 days of PDX grafting revealed increased capsule vascularization. Microscopic analyses showed blood capillaries intermixed with myxoma cells, but the origin of these capillaries, from mice or humans, was not established. This study aimed to investigate whether the endothelial cells observed in the myxoma PDX model are derived from the mouse or from the primary human tumour. Immunohistochemistry was performed on five tumour fragments from the PDX of myxoma after 55 days of implantation in mice. Immunopositivity for antibodies against human (HLA-ABC) and mouse (H2 Db/H2-D1) major histocompatibility complex class I (MHCI) was assessed in the endothelial cells. The endothelial cells in the PDX fragments revealed a membrane staining for the human MHCI protein in the PDX tumour and adjacent connective tissue capsule, indicating that capillaries were derived from the human tumour fragment. Considering the probable human origin of the endothelial cells from capillary blood vessels in the myxoma PDX, we conclude that this PDX model is an interesting model to study myxoma angiogenesis.
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Affiliation(s)
- Juliana Cristina de Souza
- Department of Pathology, Biological Science Institute (ICB), Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil
| | - Victor Coutinho Bastos
- Department of Pathology, Biological Science Institute (ICB), Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil
| | - Núbia Braga Pereira
- Department of Pathology, Biological Science Institute (ICB), Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil
| | - Adriana Abalen Martins Dias
- Department of General Biology, Biological Science Institute (ICB), Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil
| | - Gleide Fernandes de Avelar
- Department of Morphology, Biological Science Institute (ICB), Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil
| | - Ricardo Santiago Gomez
- Department of Oral Surgery and Pathology, School of Dentistry, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil
| | - Carolina Cavaliéri Gomes
- Department of Pathology, Biological Science Institute (ICB), Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil
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25
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Han DS, Lee EO. Sp1 Plays a Key Role in Vasculogenic Mimicry of Human Prostate Cancer Cells. Int J Mol Sci 2022; 23:1321. [PMID: 35163245 PMCID: PMC8835864 DOI: 10.3390/ijms23031321] [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] [Revised: 01/20/2022] [Accepted: 01/20/2022] [Indexed: 12/16/2022] Open
Abstract
Sp1 transcription factor regulates genes involved in various phenomena of tumor progression. Vasculogenic mimicry (VM) is the alternative neovascularization by aggressive tumor cells. However, there is no evidence of the relationship between Sp1 and VM. This study investigated whether and how Sp1 plays a crucial role in the process of VM in human prostate cancer (PCa) cell lines, PC-3 and DU145. A cell viability assay and three-dimensional culture VM tube formation assay were performed. Protein and mRNA expression levels were detected by Western blot and reverse transcriptase-polymerase chain reaction, respectively. The nuclear twist expression was observed by immunofluorescence assay. A co-immunoprecipitation assay was performed. Mithramycin A (MiA) and Sp1 siRNA significantly decreased serum-induced VM, whereas Sp1 overexpression caused a significant induction of VM. Serum-upregulated vascular endothelial cadherin (VE-cadherin) protein and mRNA expression levels were decreased after MiA treatment or Sp1 silencing. The protein expression and the nuclear localization of twist were increased by serum, which was effectively inhibited after MiA treatment or Sp1 silencing. The interaction between Sp1 and twist was reduced by MiA. On the contrary, Sp1 overexpression enhanced VE-cadherin and twist expressions. Serum phosphorylated AKT and raised matrix metalloproteinase-2 (MMP-2) and laminin subunit 5 gamma-2 (LAMC2) expressions. MiA or Sp1 silencing impaired these effects. However, Sp1 overexpression upregulated phosphor-AKT, MMP-2 and LAMC2 expressions. Serum-upregulated Sp1 was significantly reduced by an AKT inhibitor, wortmannin. These results demonstrate that Sp1 mediates VM formation through interacting with the twist/VE-cadherin/AKT pathway in human PCa cells.
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Affiliation(s)
- Deok-Soo Han
- Department of Science in Korean Medicine, Graduate School, College of Korean Medicine, Kyung Hee University, 26, Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Korea;
| | - Eun-Ok Lee
- Department of Science in Korean Medicine, Graduate School, College of Korean Medicine, Kyung Hee University, 26, Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Korea;
- Department of Cancer Preventive Material Development, Graduate School, College of Korean Medicine, Kyung Hee University, 26, Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Korea
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26
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Manarang JC, McDermott A. Evaluation of Pharmaceutical Inhibition of Vasculogenic Mimicry In Vitro. Methods Mol Biol 2022; 2514:129-139. [PMID: 35771425 DOI: 10.1007/978-1-0716-2403-6_13] [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: 06/15/2023]
Abstract
Vasculogenic mimicry formation is generally assessed using three-dimensional (3D) cultures of aggressive tumor cells grown over an extended incubation period. Test agents can be introduced during growth of the 3D cultures to determine their effect on vasculogenic mimicry formation. Here, we describe the protocol for evaluation of the inhibitory effect of drugs on vasculogenic mimicry in vitro using bright-field and fluorescence microscopy on 3D cultures of tumor cells grown in Matrigel.
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27
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de Andrade Peixoto M, Marques Dos Reis E, Marques Porto L. Cancer Cell Spheroids as a 3D Model for Exploring the Pathobiology of Vasculogenic Mimicry. Methods Mol Biol 2022; 2514:45-51. [PMID: 35771417 DOI: 10.1007/978-1-0716-2403-6_5] [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: 06/15/2023]
Abstract
Spheroids are 3D spherical cell aggregates, which, cultivated in vitro, behave differently than regular monolayer cellular cultures. Cancer spheroids share many characteristics with in vivo solid tumors, making them a powerful tool in cancer research. The use of cancer spheroids makes it possible to identify the potential of new anticancer pharmacological targets, leading them to be widely used in preclinical oncology research. 3D in vitro models allow the study in detail of many important aspects of the cellular transformation process, such as cell morphology, gene expression, cell-cell and cell-ECM interactions, angiogenesis, and vasculogenic mimicry.In this chapter, the importance of studies using spheroids for current cancer research is described, focusing on vasculogenic mimicry, its morphological structure, and the different methods used in the formation of spheroids. The main method uses agarose to produce the molds for the cancer spheroids, is known as the non-adherent hydrogel micro-mold method, and is being covered in more detail below.
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Affiliation(s)
- Maíra de Andrade Peixoto
- Chemical and Food Engineering Department, Federal University of Santa Catarina, Florianópolis, SC, Brazil.
| | - Emily Marques Dos Reis
- Chemical and Food Engineering Department, Federal University of Santa Catarina, Florianópolis, SC, Brazil
| | - Luismar Marques Porto
- Chemical and Food Engineering Department, Federal University of Santa Catarina, Florianópolis, SC, Brazil
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28
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Biagioni A, Andreucci E. Immunohistochemistry for VM Markers. Methods Mol Biol 2022; 2514:141-152. [PMID: 35771426 DOI: 10.1007/978-1-0716-2403-6_14] [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: 06/15/2023]
Abstract
Vasculogenic mimicry (VM) is the biological process by which aggressive cancer cells are able to organize themselves-independently from endothelial cells-into new vessel-like structures to sustain fast tumor perfusion and thus an efficient supply of oxygen and nutrients, required for rapid cancer growth and dissemination. In the last two decades, the molecular mechanisms and key regulators of VM have been identified. Several methods are currently available to detect VM both in vitro and in vivo, but the gold standard is still the immunohistochemical staining of specific antigens. Even though many markers are debated if belong to the angiogenic process or VM exclusively, the immunohistochemistry of CD31 and the PAS reaction often clarify in frozen or paraffin sections the pathologic status and the vasculature grade of a tumor mass.
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Affiliation(s)
- Alessio Biagioni
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Florence, Italy.
| | - Elena Andreucci
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Florence, Italy.
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29
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Harry JA, Ormiston ML. Novel Pathways for Targeting Tumor Angiogenesis in Metastatic Breast Cancer. Front Oncol 2021; 11:772305. [PMID: 34926282 PMCID: PMC8678517 DOI: 10.3389/fonc.2021.772305] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Accepted: 11/12/2021] [Indexed: 12/29/2022] Open
Abstract
Breast cancer is the most common cancer affecting women and is the second leading cause of cancer related death worldwide. Angiogenesis, the process of new blood vessel development from pre-existing vasculature, has been implicated in the growth, progression, and metastasis of cancer. Tumor angiogenesis has been explored as a key therapeutic target for decades, as the blockade of this process holds the potential to reduce the oxygen and nutrient supplies that are required for tumor growth. However, many existing anti-angiogenic approaches, such as those targeting Vascular Endothelial Growth Factor, Notch, and Angiopoietin signaling, have been associated with severe side-effects, limited survival advantage, and enhanced cancer regrowth rates. To address these setbacks, alternative pathways involved in the regulation of tumor angiogenesis are being explored, including those involving Bone Morphogenetic Protein-9 signaling, the Sonic Hedgehog pathway, Cyclooxygenase-2, p38-mitogen-activated protein kinase, and Chemokine Ligand 18. This review article will introduce the concept of tumor angiogenesis in the context of breast cancer, followed by an overview of current anti-angiogenic therapies, associated resistance mechanisms and novel therapeutic targets.
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Affiliation(s)
- Jordan A Harry
- Department of Medicine, Queen's University, Kingston, ON, Canada
| | - Mark L Ormiston
- Department of Medicine, Queen's University, Kingston, ON, Canada.,Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON, Canada.,Department of Surgery, Queen's University, Kingston, ON, Canada
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30
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Cocola C, Magnaghi V, Abeni E, Pelucchi P, Martino V, Vilardo L, Piscitelli E, Consiglio A, Grillo G, Mosca E, Gualtierotti R, Mazzaccaro D, La Sala G, Di Pietro C, Palizban M, Liuni S, DePedro G, Morara S, Nano G, Kehler J, Greve B, Noghero A, Marazziti D, Bussolino F, Bellipanni G, D'Agnano I, Götte M, Zucchi I, Reinbold R. Transmembrane Protein TMEM230, a Target of Glioblastoma Therapy. Front Cell Neurosci 2021; 15:703431. [PMID: 34867197 PMCID: PMC8636015 DOI: 10.3389/fncel.2021.703431] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Accepted: 10/12/2021] [Indexed: 11/13/2022] Open
Abstract
Glioblastomas (GBM) are the most aggressive tumors originating in the brain. Histopathologic features include circuitous, disorganized, and highly permeable blood vessels with intermittent blood flow. These features contribute to the inability to direct therapeutic agents to tumor cells. Known targets for anti-angiogenic therapies provide minimal or no effect in overall survival of 12–15 months following diagnosis. Identification of novel targets therefore remains an important goal for effective treatment of highly vascularized tumors such as GBM. We previously demonstrated in zebrafish that a balanced level of expression of the transmembrane protein TMEM230/C20ORF30 was required to maintain normal blood vessel structural integrity and promote proper vessel network formation. To investigate whether TMEM230 has a role in the pathogenesis of GBM, we analyzed its prognostic value in patient tumor gene expression datasets and performed cell functional analysis. TMEM230 was found necessary for growth of U87-MG cells, a model of human GBM. Downregulation of TMEM230 resulted in loss of U87 migration, substratum adhesion, and re-passaging capacity. Conditioned media from U87 expressing endogenous TMEM230 induced sprouting and tubule-like structure formation of HUVECs. Moreover, TMEM230 promoted vascular mimicry-like behavior of U87 cells. Gene expression analysis of 702 patients identified that TMEM230 expression levels distinguished high from low grade gliomas. Transcriptomic analysis of patients with gliomas revealed molecular pathways consistent with properties observed in U87 cell assays. Within low grade gliomas, elevated TMEM230 expression levels correlated with reduced overall survival independent from tumor subtype. Highest level of TMEM230 correlated with glioblastoma and ATP-dependent microtubule kinesin motor activity, providing a direction for future therapeutic intervention. Our studies support that TMEM230 has both glial tumor and endothelial cell intracellular and extracellular functions. Elevated levels of TMEM230 promote glial tumor cell migration, extracellular scaffold remodeling, and hypervascularization and abnormal formation of blood vessels. Downregulation of TMEM230 expression may inhibit both low grade glioma and glioblastoma tumor progression and promote normalization of abnormally formed blood vessels. TMEM230 therefore is both a promising anticancer and antiangiogenic therapeutic target for inhibiting GBM tumor cells and tumor-driven angiogenesis.
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Affiliation(s)
- Cinzia Cocola
- Institute for Biomedical Technologies, National Research Council, Milan, Italy.,Consorzio Italbiotec, Milan, Italy
| | - Valerio Magnaghi
- Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy
| | - Edoardo Abeni
- Institute for Biomedical Technologies, National Research Council, Milan, Italy
| | - Paride Pelucchi
- Institute for Biomedical Technologies, National Research Council, Milan, Italy
| | - Valentina Martino
- Institute for Biomedical Technologies, National Research Council, Milan, Italy
| | - Laura Vilardo
- Institute for Biomedical Technologies, National Research Council, Milan, Italy
| | - Eleonora Piscitelli
- Institute for Biomedical Technologies, National Research Council, Milan, Italy
| | - Arianna Consiglio
- Institute for Biomedical Technologies, National Research Council, Milan, Italy
| | - Giorgio Grillo
- Institute for Biomedical Technologies, National Research Council, Milan, Italy
| | - Ettore Mosca
- Institute for Biomedical Technologies, National Research Council, Milan, Italy
| | - Roberta Gualtierotti
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Daniela Mazzaccaro
- Operative Unit of Vascular Surgery, IRCCS Policlinico San Donato, San Donato Milanese, Italy
| | - Gina La Sala
- Institute of Biochemistry and Cell Biology, Italian National Research Council, Rome, Italy
| | - Chiara Di Pietro
- Institute of Biochemistry and Cell Biology, Italian National Research Council, Rome, Italy
| | - Mira Palizban
- Department of Gynecology and Obstetrics, University Hospital of Münster, Münster, Germany
| | - Sabino Liuni
- Institute for Biomedical Technologies, National Research Council, Milan, Italy
| | - Giuseppina DePedro
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | | | - Giovanni Nano
- Operative Unit of Vascular Surgery, IRCCS Policlinico San Donato, San Donato Milanese, Italy.,Department of Biomedical Sciences for Health, Università degli Studi di Milano, Milan, Italy
| | - James Kehler
- National Institutes of Health, NIDDK, Laboratory of Cell and Molecular Biology, Bethesda, MD, United States
| | - Burkhard Greve
- Department of Radiation Therapy and Radiation Oncology, University Hospital of Münster, Münster, Germany
| | - Alessio Noghero
- Lovelace Biomedical Research Institute, Albuquerque, NM, United States.,Department of Oncology, University of Turin, Orbassano, Italy
| | - Daniela Marazziti
- Institute of Biochemistry and Cell Biology, Italian National Research Council, Rome, Italy
| | - Federico Bussolino
- Department of Oncology, University of Turin, Orbassano, Italy.,Laboratory of Vascular Oncology Candiolo Cancer Institute - IRCCS, Candiolo, Italy
| | - Gianfranco Bellipanni
- Department of Biology, Center for Biotechnology, Sbarro Institute for Cancer Research and Molecular Medicine, Temple University, Philadelphia, PA, United States
| | - Igea D'Agnano
- Institute for Biomedical Technologies, National Research Council, Milan, Italy
| | - Martin Götte
- Department of Gynecology and Obstetrics, University Hospital of Münster, Münster, Germany
| | - Ileana Zucchi
- Institute for Biomedical Technologies, National Research Council, Milan, Italy
| | - Rolland Reinbold
- Institute for Biomedical Technologies, National Research Council, Milan, Italy
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31
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Herrera-Vargas AK, García-Rodríguez E, Olea-Flores M, Mendoza-Catalán MA, Flores-Alfaro E, Navarro-Tito N. Pro-angiogenic activity and vasculogenic mimicry in the tumor microenvironment by leptin in cancer. Cytokine Growth Factor Rev 2021; 62:23-41. [PMID: 34736827 DOI: 10.1016/j.cytogfr.2021.10.006] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Revised: 10/18/2021] [Accepted: 10/18/2021] [Indexed: 12/11/2022]
Abstract
The acquired ability to induce the formation of a functional vasculature is a hallmark of cancer. Blood vessels in tumors are formed through various mechanisms, among the most important in cancer biology, angiogenesis, and vasculogenic mimicry have been described. Leptin is one of the main adipokines secreted by adipocytes in normal breast tissue and the tumor microenvironment. Here, we provide information on the relationship between leptin and the development of angiogenesis and vasculogenic mimicry in different types of cancer. Here, we report that leptin activates different pathways such as JAK-STAT3, MAPK/ERK, PKC, JNK, p38, and PI3K-Akt to induce the expression of various angiogenic factors and vasculogenic mimicry. In vivo models, leptin induces blood vessel formation through the PI3K-Akt-mTOR pathway. Interestingly, the relationship between leptin and vasculogenic mimicry was more significant in breast cancer. The information obtained suggests that leptin could be playing an essential role in tumor survival and metastasis through the induction of vascular mechanisms such as angiogenesis and vasculogenic mimicry; thus, leptin-induced pathways could be suggested as a promising therapeutic target.
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Affiliation(s)
- Ana K Herrera-Vargas
- Laboratorio de Biología Celular del Cáncer, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Av. Lázaro Cárdenas s/n, Chilpancingo, GRO 39090, Mexico.
| | - Eduardo García-Rodríguez
- Laboratorio de Biología Celular del Cáncer, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Av. Lázaro Cárdenas s/n, Chilpancingo, GRO 39090, Mexico.
| | - Monserrat Olea-Flores
- Laboratorio de Biología Celular del Cáncer, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Av. Lázaro Cárdenas s/n, Chilpancingo, GRO 39090, Mexico.
| | - Miguel A Mendoza-Catalán
- Laboratorio de Biomedicina Molecular, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Chilpancingo, GRO, 39090, Mexico.
| | - Eugenia Flores-Alfaro
- Laboratorio de Epidemiología Clínica y Molecular, Facultad de Ciencias Químico-Biológicas, Universidad Autónoma de Guerrero, Chilpancingo, GRO 39087, Mexico.
| | - Napoleón Navarro-Tito
- Laboratorio de Biología Celular del Cáncer, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Av. Lázaro Cárdenas s/n, Chilpancingo, GRO 39090, Mexico.
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Xu Y, Fu L, Pan D, Wei J, Xia H, Wang S, Sun G. Folic Acid Inhibited Vasculogenic Mimicry in Esophageal Cancer Cell Line Eca-109, the One Target Was EphA2. Nutr Cancer 2021; 74:2235-2242. [PMID: 34678082 DOI: 10.1080/01635581.2021.1988992] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2021] [Revised: 09/24/2021] [Accepted: 09/26/2021] [Indexed: 10/20/2022]
Abstract
The degree of vasculogenic mimicry(VM) is correlated with the prognosis of esophageal cancer, and folic acid supplementation could decrease esophagus cancer deaths among populations. This study aimed to explore the effect of folic acid on VM formation of esophageal cancer cell, and the target. Human esophageal squamous cancer cell lines(Eca-109) were cultured with different concentrations of folic acid (0,1,10,100,200,400, 600,800 μg/ml). A cell counting kit-8 (CCK-8) assay was used to measure the cell proliferation. Then, the amount of VM under the effect of different concentrations of folic acid was observed. Target genes were screened out from several possible targets genes including MMP2, MMP9, EphA2, VE-cad or Ln-5γ2 by employing reverse transcription-quantitative polymerase chain reaction(RT-qPCR). Finally, western blot analysis was used to verify the target proteins. In conclusion, this study found that folic acid inhibited the formation of VM in Eca-109 cells, and the one target protein was EphA2.
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Affiliation(s)
- YuLing Xu
- Key Laboratory of Environmental Medicine and Engineering of Ministry of Education, and Department of Nutrition and Food Hygiene, School of Public Health, Southeast University, Nanjing, China
| | - LingMeng Fu
- Key Laboratory of Environmental Medicine and Engineering of Ministry of Education, and Department of Nutrition and Food Hygiene, School of Public Health, Southeast University, Nanjing, China
| | - Da Pan
- Key Laboratory of Environmental Medicine and Engineering of Ministry of Education, and Department of Nutrition and Food Hygiene, School of Public Health, Southeast University, Nanjing, China
| | - Jie Wei
- Key Laboratory of Environmental Medicine and Engineering of Ministry of Education, and Department of Nutrition and Food Hygiene, School of Public Health, Southeast University, Nanjing, China
| | - Hui Xia
- Key Laboratory of Environmental Medicine and Engineering of Ministry of Education, and Department of Nutrition and Food Hygiene, School of Public Health, Southeast University, Nanjing, China
| | - ShaoKang Wang
- Key Laboratory of Environmental Medicine and Engineering of Ministry of Education, and Department of Nutrition and Food Hygiene, School of Public Health, Southeast University, Nanjing, China
| | - GuiJu Sun
- Key Laboratory of Environmental Medicine and Engineering of Ministry of Education, and Department of Nutrition and Food Hygiene, School of Public Health, Southeast University, Nanjing, China
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Charfi C, Demeule M, Currie JC, Larocque A, Zgheib A, Danalache BA, Ouanouki A, Béliveau R, Marsolais C, Annabi B. New Peptide-Drug Conjugates for Precise Targeting of SORT1-Mediated Vasculogenic Mimicry in the Tumor Microenvironment of TNBC-Derived MDA-MB-231 Breast and Ovarian ES-2 Clear Cell Carcinoma Cells. Front Oncol 2021; 11:760787. [PMID: 34751242 PMCID: PMC8571021 DOI: 10.3389/fonc.2021.760787] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Accepted: 10/06/2021] [Indexed: 01/17/2023] Open
Abstract
Vasculogenic mimicry (VM) is defined as the formation of microvascular channels by genetically deregulated cancer cells and is often associated with high tumor grade and cancer therapy resistance. This microcirculation system, independent of endothelial cells, provides oxygen and nutrients to tumors, and contributes also in part to metastasis. VM has been observed in ovarian cancer and in triple negative breast cancer (TNBC) and shown to correlate with decreased overall cancer patient survival. Thus, strategies designed to inhibit VM may improve cancer patient treatments. In this study, sortilin (SORT1) receptor was detected in in vitro 3D capillary-like structures formed by ES-2 ovarian cancer and MDA-MB-231 TNBC-derived cells when grown on Matrigel. SORT1 gene silencing or antibodies directed against its extracellular domain inhibited capillary-like structure formation. In vitro, VM also correlated with increased gene expression of matrix metalloproteinase-9 (MMP-9) and of the cancer stem cell marker CD133. In vivo ES-2 xenograft model showed PAS+/CD31- VM structures (staining positive for both SORT1 and CD133). TH1904, a Doxorubicin-peptide conjugate that is internalized by SORT1, significantly decreased in vitro VM at low nM concentrations. In contrast, VM was unaffected by unconjugated Doxorubicin or Doxil (liposomal Doxorubicin) up to μM concentrations. TH1902, a Docetaxel-peptide conjugate, altered even more efficiently in vitro VM at pM concentrations. Overall, current data evidence for the first time that 1) SORT1 itself exerts a crucial role in both ES-2 and MDA-MB-231 VM, and that 2) VM in these cancer cell models can be efficiently inhibited by the peptide-drug conjugates TH1902/TH1904. These new findings also indicate that both peptide-drug conjugates, in addition to their reported cytotoxicity, could possibly inhibit VM in SORT1-positive TNBC and ovarian cancer patients.
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Affiliation(s)
| | | | | | | | - Alain Zgheib
- Laboratoire d’Oncologie Moléculaire, Département de chimie, Université du Québec à Montréal, Montréal, QC, Canada
| | - Bogdan Alexandru Danalache
- Laboratoire d’Oncologie Moléculaire, Département de chimie, Université du Québec à Montréal, Montréal, QC, Canada
| | - Amira Ouanouki
- Laboratoire d’Oncologie Moléculaire, Département de chimie, Université du Québec à Montréal, Montréal, QC, Canada
| | - Richard Béliveau
- Laboratoire d’Oncologie Moléculaire, Département de chimie, Université du Québec à Montréal, Montréal, QC, Canada
| | | | - Borhane Annabi
- Laboratoire d’Oncologie Moléculaire, Département de chimie, Université du Québec à Montréal, Montréal, QC, Canada
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The emerging roles of circular RNAs in vessel co-option and vasculogenic mimicry: clinical insights for anti-angiogenic therapy in cancers. Cancer Metastasis Rev 2021; 41:173-191. [PMID: 34664157 DOI: 10.1007/s10555-021-10000-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Accepted: 10/12/2021] [Indexed: 12/20/2022]
Abstract
Unexpected resistance to anti-angiogenic treatment prompted the investigation of non-angiogenic tumor processes. Vessel co-option (VC) and vasculogenic mimicry (VM) are recognized as primary non-angiogenic mechanisms. In VC, cancer cells utilize pre-existing blood vessels for support, whereas in VM, cancer cells channel and provide blood flow to rapidly growing tumors. Both processes have been implicated in the development of tumor and resistance to anti-angiogenic drugs in many tumor types. The morphology, but rare molecular alterations have been investigated in VC and VM. There is a pressing need to better understand the underlying cellular and molecular mechanisms. Here, we review the emerging circular RNA (circRNA)-mediated regulation of non-angiogenic processes, VC and VM.
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Massimini M, Romanucci M, De Maria R, Della Salda L. An Update on Molecular Pathways Regulating Vasculogenic Mimicry in Human Osteosarcoma and Their Role in Canine Oncology. Front Vet Sci 2021; 8:722432. [PMID: 34631854 PMCID: PMC8494780 DOI: 10.3389/fvets.2021.722432] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Accepted: 08/23/2021] [Indexed: 01/16/2023] Open
Abstract
Canine tumors are valuable comparative models for human counterparts, especially to explore novel biomarkers and to understand pathways and processes involved in metastasis. Vasculogenic mimicry (VM) is a unique property of malignant cancer cells which promote metastasis. Thus, it represents an opportunity to investigate both the molecular mechanisms and the therapeutic targets of a crucial phenotypic malignant switch. Although this biological process has been largely investigated in different human cancer types, including osteosarcoma, it is still largely unknown in veterinary pathology, where it has been mainly explored in canine mammary tumors. The presence of VM in human osteosarcoma is associated with poor clinical outcome, reduced patient survival, and increased risk of metastasis and it shares the main pathways involved in other type of human tumors. This review illustrates the main findings concerning the VM process in human osteosarcoma, search for the related current knowledge in canine pathology and oncology, and potential involvement of multiple pathways in VM formation, in order to provide a basis for future investigations on VM in canine tumors.
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Abstract
The growth of solid tumours relies on an ever-increasing supply of oxygen and nutrients that are delivered via vascular networks. Tumour vasculature includes endothelial cell lined angiogenesis and the less common cancer cell lined vasculogenic mimicry (VM). To study and compare the development of vascular networks formed during angiogenesis and VM (represented here by breast cancer and pancreatic cancer cell lines) a number of in vitro assays were utilised. From live cell imaging, we performed a large-scale automated extraction of network parameters and identified properties not previously reported. We show that for both angiogenesis and VM, the characteristic network path length reduces over time; however, only endothelial cells increase network clustering coefficients thus maintaining small-world network properties as they develop. When compared to angiogenesis, the VM network efficiency is improved by decreasing the number of edges and vertices, and also by increasing edge length. Furthermore, our results demonstrate that angiogenic and VM networks appear to display similar properties to road traffic networks and are also subject to the well-known Braess paradox. This quantitative measurement framework opens up new avenues to potentially evaluate the impact of anti-cancer drugs and anti-vascular therapies. Fouladzadeh, Dorraki and colleagues investigate the development of angiogenic networks for in vitro cancer cell lines. They demonstrate that during the growth stages of vasculogenic mimicry, the number of edges and vertices decreases but the edge length increases resulting in improved network efficiency.
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37
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Aspriţoiu VM, Stoica I, Bleotu C, Diaconu CC. Epigenetic Regulation of Angiogenesis in Development and Tumors Progression: Potential Implications for Cancer Treatment. Front Cell Dev Biol 2021; 9:689962. [PMID: 34552922 PMCID: PMC8451900 DOI: 10.3389/fcell.2021.689962] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Accepted: 08/16/2021] [Indexed: 12/15/2022] Open
Abstract
Angiogenesis is a multi-stage process of new blood vessel development from pre-existing vessels toward an angiogenic stimulus. The process is essential for tissue maintenance and homeostasis during embryonic development and adult life as well as tumor growth. Under normal conditions, angiogenesis is involved in physiological processes, such as wound healing, cyclic regeneration of the endometrium, placental development and repairing certain cardiac damage, in pathological conditions, it is frequently associated with cancer development and metastasis. The control mechanisms of angiogenesis in carcinogenesis are tightly regulated at the genetic and epigenetic level. While genetic alterations are the critical part of gene silencing in cancer cells, epigenetic dysregulation can lead to repression of tumor suppressor genes or oncogene activation, becoming an important event in early development and the late stages of tumor development, as well. The global alteration of the epigenetic spectrum, which includes DNA methylation, histone modification, chromatin remodeling, microRNAs, and other chromatin components, is considered one of the hallmarks of cancer, and the efforts are concentrated on the discovery of molecular epigenetic markers that identify cancerous precursor lesions or early stage cancer. This review aims to highlight recent findings on the genetic and epigenetic changes that can occur in physiological and pathological angiogenesis and analyze current knowledge on how deregulation of epigenetic modifiers contributes to tumorigenesis and tumor maintenance. Also, we will evaluate the clinical relevance of epigenetic markers of angiogenesis and the potential use of "epi-drugs" in modulating the responsiveness of cancer cells to anticancer therapy through chemotherapy, radiotherapy, immunotherapy and hormone therapy as anti-angiogenic strategies in cancer.
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Affiliation(s)
| | - Ileana Stoica
- Faculty of Biology, University of Bucharest, Bucharest, Romania
| | - Coralia Bleotu
- Faculty of Biology, University of Bucharest, Bucharest, Romania
- Romanian Academy, Stefan S. Nicolau Institute of Virology, Bucharest, Romania
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38
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Thankamony AP, Subbalakshmi AR, Jolly MK, Nair R. Lineage Plasticity in Cancer: The Tale of a Skin-Walker. Cancers (Basel) 2021; 13:3602. [PMID: 34298815 PMCID: PMC8306016 DOI: 10.3390/cancers13143602] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2021] [Revised: 07/04/2021] [Accepted: 07/14/2021] [Indexed: 12/11/2022] Open
Abstract
Lineage plasticity, the switching of cells from one lineage to another, has been recognized as a cardinal property essential for embryonic development, tissue repair and homeostasis. However, such a highly regulated process goes awry when cancer cells exploit this inherent ability to their advantage, resulting in tumorigenesis, relapse, metastasis and therapy resistance. In this review, we summarize our current understanding on the role of lineage plasticity in tumor progression and therapeutic resistance in multiple cancers. Lineage plasticity can be triggered by treatment itself and is reported across various solid as well as liquid tumors. Here, we focus on the importance of lineage switching in tumor progression and therapeutic resistance of solid tumors such as the prostate, lung, hepatocellular and colorectal carcinoma and the myeloid and lymphoid lineage switch observed in leukemias. Besides this, we also discuss the role of epithelial-mesenchymal transition (EMT) in facilitating the lineage switch in biphasic cancers such as aggressive carcinosarcomas. We also discuss the mechanisms involved, current therapeutic approaches and challenges that lie ahead in taming the scourge of lineage plasticity in cancer.
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Affiliation(s)
- Archana P. Thankamony
- Cancer Research Program, Rajiv Gandhi Centre for Biotechnology, Kerala 695014, India;
- Manipal Academy of Higher Education (MAHE), Manipal 576104, India
| | - Ayalur Raghu Subbalakshmi
- Centre for BioSystems Science and Engineering, Indian Institute of Science, Bangalore 560012, India;
| | - Mohit Kumar Jolly
- Centre for BioSystems Science and Engineering, Indian Institute of Science, Bangalore 560012, India;
| | - Radhika Nair
- Cancer Research Program, Rajiv Gandhi Centre for Biotechnology, Kerala 695014, India;
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Braun A, Anders HJ, Gudermann T, Mammadova-Bach E. Platelet-Cancer Interplay: Molecular Mechanisms and New Therapeutic Avenues. Front Oncol 2021; 11:665534. [PMID: 34322381 PMCID: PMC8311658 DOI: 10.3389/fonc.2021.665534] [Citation(s) in RCA: 55] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Accepted: 06/17/2021] [Indexed: 12/18/2022] Open
Abstract
Although platelets are critically involved in thrombosis and hemostasis, experimental and clinical evidence indicate that platelets promote tumor progression and metastasis through a wide range of physical and functional interactions between platelets and cancer cells. Thrombotic and thromboembolic events are frequent complications in patients with solid tumors. Hence, cancer modulates platelet function by directly inducing platelet-tumor aggregates and triggering platelet granule release and altering platelet turnover. Also, platelets enhance tumor cell dissemination by activating endothelial cell function and recruiting immune cells to primary and metastatic tumor sites. In this review, we summarize current knowledge on the complex interactions between platelets and tumor cells and the host microenvironment. We also critically discuss the potential of anti-platelet agents for cancer prevention and treatment.
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Affiliation(s)
- Attila Braun
- Walther-Straub-Institute for Pharmacology and Toxicology, Ludwig-Maximilian-University, Member of the German Center for Lung Research (DZL), Munich, Germany
| | - Hans-Joachim Anders
- Division of Nephrology, Department of Medicine IV, Ludwig-Maximilians-University Hospital, Munich, Germany
| | - Thomas Gudermann
- Walther-Straub-Institute for Pharmacology and Toxicology, Ludwig-Maximilian-University, Member of the German Center for Lung Research (DZL), Munich, Germany
| | - Elmina Mammadova-Bach
- Walther-Straub-Institute for Pharmacology and Toxicology, Ludwig-Maximilian-University, Member of the German Center for Lung Research (DZL), Munich, Germany.,Division of Nephrology, Department of Medicine IV, Ludwig-Maximilians-University Hospital, Munich, Germany
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40
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Upcin B, Henke E, Kleefeldt F, Hoffmann H, Rosenwald A, Irmak-Sav S, Aktas HB, Rückschloß U, Ergün S. Contribution of Adventitia-Derived Stem and Progenitor Cells to New Vessel Formation in Tumors. Cells 2021; 10:cells10071719. [PMID: 34359889 PMCID: PMC8304670 DOI: 10.3390/cells10071719] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Revised: 07/01/2021] [Accepted: 07/03/2021] [Indexed: 11/22/2022] Open
Abstract
Blocking tumor vascularization has not yet come to fruition to the extent it was hoped for, as angiogenesis inhibitors have shown only partial success in the clinic. We hypothesized that under-appreciated vascular wall-resident stem and progenitor cells (VW-SPCs) might be involved in tumor vascularization and influence effectiveness of anti-angiogenic therapy. Indeed, in patient samples, we observed that vascular adventitia-resident CD34+ VW-SPCs are recruited to tumors in situ from co-opted vessels. To elucidate this in detail, we established an ex vivo model using concomitant embedding of multi-cellular tumor spheroids (MCTS) and mouse aortic rings (ARs) into collagen gels, similar to the so-called aortic ring assay (ARA). Moreover, ARA was modified by removing the ARs’ adventitia that harbors VW-SPCs. Thus, this model enabled distinguishing the contribution of VW-SPCs from that of mature endothelial cells (ECs) to new vessel formation. Our results show that the formation of capillary-like sprouts is considerably delayed, and their number and network formation were significantly reduced by removing the adventitia. Substituting iPSC-derived neural spheroids for MCTS resulted in distinct sprouting patterns that were also strongly influenced by the presence or absence of VW-SPCs, also underlying the involvement of these cells in non-pathological vascularization. Our data suggest that more comprehensive approaches are needed in order to block all of the mechanisms contributing to tumor vascularization.
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Affiliation(s)
- Berin Upcin
- Institute of Anatomy and Cell Biology, Julius-Maximilians-University, 97070 Würzburg, Germany; (B.U.); (E.H.); (F.K.); (H.H.); (U.R.)
| | - Erik Henke
- Institute of Anatomy and Cell Biology, Julius-Maximilians-University, 97070 Würzburg, Germany; (B.U.); (E.H.); (F.K.); (H.H.); (U.R.)
| | - Florian Kleefeldt
- Institute of Anatomy and Cell Biology, Julius-Maximilians-University, 97070 Würzburg, Germany; (B.U.); (E.H.); (F.K.); (H.H.); (U.R.)
| | - Helene Hoffmann
- Institute of Anatomy and Cell Biology, Julius-Maximilians-University, 97070 Würzburg, Germany; (B.U.); (E.H.); (F.K.); (H.H.); (U.R.)
| | - Andreas Rosenwald
- Institute of Pathology, Julius-Maximilians-University, 97070 Würzburg, Germany;
| | - Ster Irmak-Sav
- Faculty of Health Sciences, İstanbul Bilgi University, 34060 Istanbul, Turkey;
| | - Huseyin Bertal Aktas
- Department of Medicine, Hematology, Brigham and Women’s Hospital, Boston, MA 02115, USA;
| | - Uwe Rückschloß
- Institute of Anatomy and Cell Biology, Julius-Maximilians-University, 97070 Würzburg, Germany; (B.U.); (E.H.); (F.K.); (H.H.); (U.R.)
| | - Süleyman Ergün
- Institute of Anatomy and Cell Biology, Julius-Maximilians-University, 97070 Würzburg, Germany; (B.U.); (E.H.); (F.K.); (H.H.); (U.R.)
- Correspondence: ; Tel.: +49-931-31-82701
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41
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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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Almahmoudi R, Salem A, Hadler-Olsen E, Svineng G, Salo T, Al-Samadi A. The effect of interleukin-17F on vasculogenic mimicry in oral tongue squamous cell carcinoma. Cancer Sci 2021; 112:2223-2232. [PMID: 33743555 PMCID: PMC8177764 DOI: 10.1111/cas.14894] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Revised: 03/06/2021] [Accepted: 03/17/2021] [Indexed: 01/06/2023] Open
Abstract
Oral tongue squamous cell carcinoma (OTSCC) is one of the most common cancers worldwide and is characterized by early metastasis and poor prognosis. Recently, we reported that extracellular interleukin-17F (IL-17F) correlates with better disease-specific survival in OTSCC patients and has promising anticancer effects in vitro. Vasculogenic mimicry (VM) is the formation of an alternative vasculogenic system by aggressive tumor cells, which is implicated in treatment failure and poor survival of cancer patients. We sought to confirm the formation of VM in OTSCC and to investigate the effect of IL-17F on VM formation. Here, we showed that highly invasive OTSCC cells (HSC-3 and SAS) form tube-like VM on Matrigel similar to those formed by human umbilical vein endothelial cells. Interestingly, the less invasive cells (SCC-25) did not form any VM structures. Droplet-digital PCR, FACS, and immunofluorescence staining revealed the presence of CD31 mRNA and protein in OTSCC cells. Additionally, in a mouse orthotopic model, HSC-3 cells expressed VE-cadherin (CD144) but lacked Von Willebrand Factor. We identified different patterns of VM structures in patient samples and in an orthotopic OTSCC mouse model. Similar to the effect produced by the antiangiogenic drug sorafenib, IL-17F inhibited the formation of VM structures in vitro by HSC-3 and reduced almost all VM-related parameters. In conclusion, our findings indicate the presence of VM in OTSCC and the antitumorigenic effect of IL-17F through its effect on the VM. Therefore, targeting IL-17F or its regulatory pathways may lead to promising therapeutic strategies in patients with OTSCC.
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Affiliation(s)
- Rabeia Almahmoudi
- Department of Oral and Maxillofacial Diseases, University of Helsinki, Helsinki, Finland.,Translational Immunology Research Program (TRIMM), University of Helsinki, Helsinki, Finland
| | - Abdelhakim Salem
- Department of Oral and Maxillofacial Diseases, University of Helsinki, Helsinki, Finland.,Translational Immunology Research Program (TRIMM), University of Helsinki, Helsinki, Finland
| | - Elin Hadler-Olsen
- Department of Medical Biology, Faculty of Health Sciences, UiT The Arctic University of Norway, Tromsø, Norway.,The Public Dental Health Service Competence Center of Northern Norway, Tromsø, Norway
| | - Gunbjørg Svineng
- Department of Medical Biology, Faculty of Health Sciences, UiT The Arctic University of Norway, Tromsø, Norway
| | - Tuula Salo
- Department of Oral and Maxillofacial Diseases, University of Helsinki, Helsinki, Finland.,Translational Immunology Research Program (TRIMM), University of Helsinki, Helsinki, Finland.,Cancer and Translational Medicine Research Unit, University of Oulu, Oulu, Finland.,Medical Research Centre, Oulu University Hospital, Oulu, Finland.,Helsinki University Hospital, Helsinki, Finland
| | - Ahmed Al-Samadi
- Department of Oral and Maxillofacial Diseases, University of Helsinki, Helsinki, Finland.,Translational Immunology Research Program (TRIMM), University of Helsinki, Helsinki, Finland
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Angiogenesis in the Normal Adrenal Fetal Cortex and Adrenocortical Tumors. Cancers (Basel) 2021; 13:cancers13051030. [PMID: 33804534 PMCID: PMC7957756 DOI: 10.3390/cancers13051030] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 02/18/2021] [Accepted: 02/24/2021] [Indexed: 01/10/2023] Open
Abstract
Angiogenesis plays an important role in several physiological and pathological processes. Pharmacological angiogenesis modulation has been robustly demonstrated to achieve clinical benefits in several cancers. Adrenocortical carcinomas (ACC) are rare tumors that often have a poor prognosis. In addition, therapeutic options for ACC are limited. Understanding the mechanisms that regulate adrenocortical angiogenesis along the embryonic development and in ACC could provide important clues on how these processes could be pharmacologically modulated for ACC treatment. In this report, we performed an integrative review on adrenal cortex angiogenesis regulation in physiological conditions and ACC. During embryonic development, adrenal angiogenesis is regulated by both VEGF and Ang-Tie signaling pathways. In ACC, early research efforts were focused on VEGF signaling and this pathway was identified as a good prognostic factor and thus a promising therapeutic target. However, every clinical trial so far conducted in ACC using VEGF pathway- targeting drugs, alone or in combination, yielded disappointing results. In contrast, although the Ang-Tie pathway has been pointed out as an important regulator of fetal adrenocortical angiogenesis, its role is yet to be explored in ACC. In the future, further research on the role and efficacy of modulating both Ang-Tie and VEGF pathways in ACC is needed.
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Wei X, Chen Y, Jiang X, Peng M, Liu Y, Mo Y, Ren D, Hua Y, Yu B, Zhou Y, Liao Q, Wang H, Xiang B, Zhou M, Li X, Li G, Li Y, Xiong W, Zeng Z. Mechanisms of vasculogenic mimicry in hypoxic tumor microenvironments. Mol Cancer 2021; 20:7. [PMID: 33397409 PMCID: PMC7784348 DOI: 10.1186/s12943-020-01288-1] [Citation(s) in RCA: 258] [Impact Index Per Article: 64.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Accepted: 11/24/2020] [Indexed: 02/08/2023] Open
Abstract
Background Vasculogenic mimicry (VM) is a recently discovered angiogenetic process found in many malignant tumors, and is different from the traditional angiogenetic process involving vascular endothelium. It involves the formation of microvascular channels composed of tumor cells; therefore, VM is considered a new model for the formation of new blood vessels in aggressive tumors, and can provide blood supply for tumor growth. Many studies have pointed out that in recent years, some clinical treatments against angiogenesis have not been satisfactory possibly due to the activation of VM. Although the mechanisms underlying VM have not been fully elucidated, increasing research on the soil “microenvironment” for tumor growth suggests that the initial hypoxic environment in solid tumors is inseparable from VM. Main body In this review, we describe that the stemness and differentiation potential of cancer stem cells are enhanced under hypoxic microenvironments, through hypoxia-induced epithelial-endothelial transition (EET) and extracellular matrix (ECM) remodeling to form the specific mechanism of vasculogenic mimicry; we also summarized some of the current drugs targeting VM through these processes, suggesting a new reference for the clinical treatment of tumor angiogenesis. Conclusion Overall, the use of VM inhibitors in combination with conventional anti-angiogenesis treatments is a promising strategy for improving the effectiveness of targeted angiogenesis treatments; further, considering the importance of hypoxia in tumor invasion and metastasis, drugs targeting the hypoxia signaling pathway seem to achieve good results.
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Affiliation(s)
- Xiaoxu Wei
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital, Xiangya School of Medicine, Central South University, Changsha, Hunan, China.,Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, China.,Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Disease Genome Research Center, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yunhua Chen
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital, Xiangya School of Medicine, Central South University, Changsha, Hunan, China.,Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, China.,Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Disease Genome Research Center, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Xianjie Jiang
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, China
| | - Miao Peng
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, China
| | - Yiduo Liu
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, China
| | - Yongzhen Mo
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, China
| | - Daixi Ren
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, China
| | - Yuze Hua
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, China
| | - Boyao Yu
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, China
| | - Yujuan Zhou
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital, Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Qianjin Liao
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital, Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Hui Wang
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital, Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Bo Xiang
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital, Xiangya School of Medicine, Central South University, Changsha, Hunan, China.,Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, China.,Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Disease Genome Research Center, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Ming Zhou
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital, Xiangya School of Medicine, Central South University, Changsha, Hunan, China.,Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, China.,Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Disease Genome Research Center, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Xiaoling Li
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital, Xiangya School of Medicine, Central South University, Changsha, Hunan, China.,Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, China.,Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Disease Genome Research Center, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Guiyuan Li
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital, Xiangya School of Medicine, Central South University, Changsha, Hunan, China.,Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, China.,Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Disease Genome Research Center, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yong Li
- Department of Medicine, Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA
| | - Wei Xiong
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital, Xiangya School of Medicine, Central South University, Changsha, Hunan, China.,Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, China.,Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Disease Genome Research Center, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Zhaoyang Zeng
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital, Xiangya School of Medicine, Central South University, Changsha, Hunan, China. .,Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, China. .,Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Disease Genome Research Center, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China.
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Stucker S, Chen J, Watt FE, Kusumbe AP. Bone Angiogenesis and Vascular Niche Remodeling in Stress, Aging, and Diseases. Front Cell Dev Biol 2020; 8:602269. [PMID: 33324652 PMCID: PMC7726257 DOI: 10.3389/fcell.2020.602269] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Accepted: 11/05/2020] [Indexed: 02/05/2023] Open
Abstract
The bone marrow (BM) vascular niche microenvironments harbor stem and progenitor cells of various lineages. Bone angiogenesis is distinct and involves tissue-specific signals. The nurturing vascular niches in the BM are complex and heterogenous consisting of distinct vascular and perivascular cell types that provide crucial signals for the maintenance of stem and progenitor cells. Growing evidence suggests that the BM niche is highly sensitive to stress. Aging, inflammation and other stress factors induce changes in BM niche cells and their crosstalk with tissue cells leading to perturbed hematopoiesis, bone angiogenesis and bone formation. Defining vascular niche remodeling under stress conditions will improve our understanding of the BM vascular niche and its role in homeostasis and disease. Therefore, this review provides an overview of the current understanding of the BM vascular niches for hematopoietic stem cells and their malfunction during aging, bone loss diseases, arthritis and metastasis.
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Affiliation(s)
- Sina Stucker
- Tissue and Tumor Microenvironments Group, Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford, United Kingdom
| | - Junyu Chen
- Tissue and Tumor Microenvironments Group, Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford, United Kingdom
- Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Fiona E. Watt
- Centre for Osteoarthritis Pathogenesis Versus Arthritis, Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford, United Kingdom
| | - Anjali P. Kusumbe
- Tissue and Tumor Microenvironments Group, Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford, United Kingdom
- Centre for Osteoarthritis Pathogenesis Versus Arthritis, Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford, United Kingdom
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46
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Liang C, Shangguan J, Yang L, Guo S. Downregulation of astrocyte elevated gene-1 expression inhibits the development of vasculogenic mimicry in gliomas. Exp Ther Med 2020; 21:22. [PMID: 33235631 PMCID: PMC7678608 DOI: 10.3892/etm.2020.9454] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2019] [Accepted: 10/14/2020] [Indexed: 12/18/2022] Open
Abstract
Vasculogenic mimicry (VM) contributes to the resistance of anti-angiogenic therapies in glioma. Certain genes, including MMP-2 and VEGF may be associated with the development of VM. Astrocyte elevated gene-1 (AEG-1) is considered to be an oncogene that promotes autophagy, invasion, metastasis, angiogenesis and drug resistance; however, the association between AEG-1 and VM formation is still unknown. The present study investigated the effects of AEG-1 downregulation on VM formation in the U87 glioma cell line in vitro and in xenograft models of glioma, and the potential underlying mechanisms of action. In the present study, U87 glioma cells were infected with the AEG-1 short hairpin RNA lentivirus. A Matrigel-based tube formation assay was performed to evaluate VM formation in vitro. Reverse transcription-quantitative PCR and western blot analysis were conducted to investigate the mRNA and protein expression levels of MMP-2 and VEGF. Glioma xenograft models were generated through the intracerebral implantation of U87 glioma cells into nude rats; CD34/Periodic Acid-Schiff double-staining was performed to detect VM channels in vivo. Following AEG-1 downregulation in U87 cells, the development of VM was significantly decreased in vitro and in vivo. In addition, the expression levels of MMP-2 and VEGF in glioma cells were decreased compared with the control group. These results suggested that downregulation of AEG-1 expression could significantly inhibit the development of VM in gliomas, both in vitro and in vivo, and may be partially related to the regulation of VEGF and MMP-2 expression.
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Affiliation(s)
- Chen Liang
- Department of Neurosurgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Jian Shangguan
- Department of Neurosurgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Ling Yang
- Department of Aeromedical Physical Examination, Xi'an Civil Aviation Hospital, Xi'an, Shaanxi 710082, P.R. China
| | - Shiwen Guo
- Department of Neurosurgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
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de Faria Lainetti P, Brandi A, Leis Filho AF, Prado MCM, Kobayashi PE, Laufer-Amorim R, Fonseca-Alves CE. Establishment and Characterization of Canine Mammary Gland Carcinoma Cell Lines With Vasculogenic Mimicry Ability in vitro and in vivo. Front Vet Sci 2020; 7:583874. [PMID: 33195606 PMCID: PMC7655132 DOI: 10.3389/fvets.2020.583874] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Accepted: 09/15/2020] [Indexed: 12/11/2022] Open
Abstract
Mammary tumors affect intact and elderly female dogs, and almost 50% of these cases are malignant. Cell culture offers a promising preclinical model to study this disease and creates the opportunity to deposit cell lines at a cell bank to allow greater assay reproducibility and more reliable validation of the results. Another important aspect is the possibility of establishing models and improving our understanding of tumor characteristics, such as vasculogenic mimicry. Because of the importance of cancer cell lines in preclinical models, the present study established and characterized primary cell lines from canine mammary gland tumors. Cell cultures were evaluated for morphology, phenotype, vasculogenic mimicry (VM), and tumorigenicity abilities. We collected 17 primary mammary carcinoma and three metastases and obtained satisfactory results from 10 samples. The cells were transplanted to a xenograft model. All cell lines exhibited a spindle-shaped or polygonal morphology and expressed concomitant pancytokeratin and cytokeratin 8/18. Four cell lines had vasculogenic mimicry ability in vitro, and two cell lines showed in vivo tumorigenicity and VM in the xenotransplanted tumor. Cellular characterization will help create a database to increase our knowledge of mammary carcinomas in dogs, including studies of tumor behavior and the identification of new therapeutic targets.
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Affiliation(s)
| | - Andressa Brandi
- School of Veterinary Medicine and Animal Science, São Paulo State University—UNESP, Botucatu, Brazil
| | | | | | - Priscila Emiko Kobayashi
- School of Veterinary Medicine and Animal Science, São Paulo State University—UNESP, Botucatu, Brazil
| | - Renée Laufer-Amorim
- School of Veterinary Medicine and Animal Science, São Paulo State University—UNESP, Botucatu, Brazil
| | - Carlos Eduardo Fonseca-Alves
- School of Veterinary Medicine and Animal Science, São Paulo State University—UNESP, Botucatu, Brazil
- Institute of Health Sciences, Universidade Paulista-UNIP, Bauru, Brazil
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48
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Aggarwal V, Miranda O, Johnston PA, Sant S. Three dimensional engineered models to study hypoxia biology in breast cancer. Cancer Lett 2020; 490:124-142. [PMID: 32569616 PMCID: PMC7442747 DOI: 10.1016/j.canlet.2020.05.030] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2020] [Revised: 05/13/2020] [Accepted: 05/22/2020] [Indexed: 12/14/2022]
Abstract
Breast cancer is the second leading cause of mortality among women worldwide. Despite the available therapeutic regimes, variable treatment response is reported among different breast cancer subtypes. Recently, the effects of the tumor microenvironment on tumor progression as well as treatment responses have been widely recognized. Hypoxia and hypoxia inducible factors in the tumor microenvironment have long been known as major players in tumor progression and survival. However, the majority of our understanding of hypoxia biology has been derived from two dimensional (2D) models. Although many hypoxia-targeted therapies have elicited promising results in vitro and in vivo, these results have not been successfully translated into clinical trials. These limitations of 2D models underscore the need to develop and integrate three dimensional (3D) models that recapitulate the complex tumor-stroma interactions in vivo. This review summarizes role of hypoxia in various hallmarks of cancer progression. We then compare traditional 2D experimental systems with novel 3D tissue-engineered models giving accounts of different bioengineering platforms available to develop 3D models and how these 3D models are being exploited to understand the role of hypoxia in breast cancer progression.
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Affiliation(s)
- Vaishali Aggarwal
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, 15261, USA
| | - Oshin Miranda
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, 15261, USA
| | - Paul A Johnston
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, 15261, USA; UPMC-Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, 15261, USA
| | - Shilpa Sant
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, 15261, USA; UPMC-Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, 15261, USA; Department of Bioengineering, Swanson School of Engineering, University of Pittsburgh, Pittsburgh, PA, 15261, USA; McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, 15261, USA.
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Testa U, Pelosi E, Castelli G. Endothelial Progenitors in the Tumor Microenvironment. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1263:85-115. [PMID: 32588325 DOI: 10.1007/978-3-030-44518-8_7] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Tumor vascularization refers to the formation of new blood vessels within a tumor and is considered one of the hallmarks of cancer. Tumor vessels supply the tumor with oxygen and nutrients, required to sustain tumor growth and progression, and provide a gateway for tumor metastasis through the blood or lymphatic vasculature. Blood vessels display an angiocrine capacity of supporting the survival and proliferation of tumor cells through the production of growth factors and cytokines. Although tumor vasculature plays an essential role in sustaining tumor growth, it represents at the same time an essential way to deliver drugs and immune cells to the tumor. However, tumor vasculature exhibits many morphological and functional abnormalities, thus resulting in the formation of hypoxic areas within tumors, believed to represent a mechanism to maintain tumor cells in an invasive state.Tumors are vascularized through a variety of modalities, mainly represented by angiogenesis, where VEGF and other members of the VEGF family play a key role. This has represented the basis for the development of anti-VEGF blocking agents and their use in cancer therapy: however, these agents failed to induce significant therapeutic effects.Much less is known about the cellular origin of vessel network in tumors. Various cell types may contribute to tumor vasculature in different tumors or in the same tumor, such as mature endothelial cells, endothelial progenitor cells (EPCs), or the same tumor cells through a process of transdifferentiation. Early studies have suggested a role for bone marrow-derived EPCs; these cells do not are true EPCs but myeloid progenitors differentiating into monocytic cells, exerting a proangiogenic effect through a paracrine mechanism. More recent studies have shown the existence of tissue-resident endothelial vascular progenitors (EVPs) present at the level of vessel endothelium and their possible involvement as cells of origin of tumor vasculature.
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Affiliation(s)
- Ugo Testa
- Department of Oncology, Istituto Superiore di Sanità, Rome, Italy.
| | - Elvira Pelosi
- Department of Oncology, Istituto Superiore di Sanità, Rome, Italy
| | - Germana Castelli
- Department of Oncology, Istituto Superiore di Sanità, Rome, Italy
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Occurrence of Vascular Lake Phenomenon Before Embolization for the Prediction of Lipiodol Uptake for Intermediate-Stage Hepatocellular Carcinoma Patients that Underwent cTACE. Cardiovasc Intervent Radiol 2020; 43:1460-1467. [PMID: 32500251 DOI: 10.1007/s00270-020-02501-w] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2019] [Accepted: 04/18/2020] [Indexed: 02/07/2023]
Abstract
PURPOSE To compare Lipiodol uptake and tumor response in intermediate-stage hepatocellular carcinoma (HCC) with and without pre-embolization vascular lake phenomenon (VLP) and to identify the incidence and predictive factors of this phenomenon, in patients treated by conventional transarterial chemoembolization (cTACE). MATERIALS AND METHODS This retrospective study included 151 consecutive patients with intermediate HCC totaling 232 nodules, who underwent cTACE from June 2015 to October 2018. Patients were divided into two groups according to the presence of VLP before embolization. Initial Lipiodol uptake was assessed using post-cTACE computed tomography (CT) within 1-1.5 months after cTACE. Enhanced CT or magnetic resonance imaging was performed at 6 months after the procedure to assess local recurrence and distant metastasis. RESULTS The VLP was demonstrated in 21.85% (33/151) patients and 16.81% (39/232) nodules on the super-selective angiography. On nodule-based analysis, significantly better Lipiodol uptake (p < 0.001) and higher ORR (60.61% vs. 26.49%, p < 0.001) and DCR (87.88% vs. 51.66%, p < 0.001) were observed in the VLP group compared to the non-VLP group. The multivariate logistic regression analysis showed that the presence of VLP (OR 6.431, 95% CI 2.495-16.579) might be a predictive factor for better Lipiodol uptake. Univariate and multivariate logistic regression analysis showed that poor differentiation of tumor (OR 6.397, 95% CI 2.804-19.635) remained predictive for the VLP. CONCLUSION The incidence of VLP before embolization is 21.19%. The presence of VLP is well correlated with tumor Lipiodol uptake after cTACE and may be a new predictive factor for evaluation of cTACE efficacy and prognosis of intermediate HCC.
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