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Li JJ, Mao JX, Zhong HX, Zhao YY, Teng F, Lu XY, Zhu LY, Gao Y, Fu H, Guo WY. Multifaceted roles of lymphatic and blood endothelial cells in the tumor microenvironment of hepatocellular carcinoma: A comprehensive review. World J Hepatol 2024; 16:537-549. [PMID: 38689749 PMCID: PMC11056903 DOI: 10.4254/wjh.v16.i4.537] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2023] [Revised: 01/11/2024] [Accepted: 03/18/2024] [Indexed: 04/24/2024] Open
Abstract
The tumor microenvironment is a complex network of cells, extracellular matrix, and signaling molecules that plays a critical role in tumor progression and metastasis. Lymphatic and blood vessels are major routes for solid tumor metastasis and essential parts of tumor drainage conduits. However, recent studies have shown that lymphatic endothelial cells (LECs) and blood endothelial cells (BECs) also play multifaceted roles in the tumor microenvironment beyond their structural functions, particularly in hepatocellular carcinoma (HCC). This comprehensive review summarizes the diverse roles played by LECs and BECs in HCC, including their involvement in angiogenesis, immune modulation, lymphangiogenesis, and metastasis. By providing a detailed account of the complex interplay between LECs, BECs, and tumor cells, this review aims to shed light on future research directions regarding the immune regulatory function of LECs and potential therapeutic targets for HCC.
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Affiliation(s)
- Jing-Jing Li
- Department of Liver Surgery and Organ Transplantation, Shanghai Changzheng Hospital, Naval Medical University, Shanghai 200003, China
| | - Jia-Xi Mao
- Department of Liver Surgery and Organ Transplantation, Shanghai Changzheng Hospital, Naval Medical University, Shanghai 200003, China
| | - Han-Xiang Zhong
- Department of Liver Surgery and Organ Transplantation, Shanghai Changzheng Hospital, Naval Medical University, Shanghai 200003, China
| | - Yuan-Yu Zhao
- Department of Liver Surgery and Organ Transplantation, Shanghai Changzheng Hospital, Naval Medical University, Shanghai 200003, China
| | - Fei Teng
- Department of Liver Surgery and Organ Transplantation, Shanghai Changzheng Hospital, Naval Medical University, Shanghai 200003, China
| | - Xin-Yi Lu
- Department of Liver Surgery and Organ Transplantation, Shanghai Changzheng Hospital, Naval Medical University, Shanghai 200003, China
| | - Li-Ye Zhu
- Department of Liver Surgery and Organ Transplantation, Shanghai Changzheng Hospital, Naval Medical University, Shanghai 200003, China
| | - Yang Gao
- Department of Liver Surgery and Organ Transplantation, Shanghai Changzheng Hospital, Naval Medical University, Shanghai 200003, China
| | - Hong Fu
- Department of Liver Surgery and Organ Transplantation, Shanghai Changzheng Hospital, Naval Medical University, Shanghai 200003, China
| | - Wen-Yuan Guo
- Department of Liver Surgery and Organ Transplantation, Shanghai Changzheng Hospital, Naval Medical University, Shanghai 200003, China.
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Giorello MB, Borzone FR, Mora MF, Padin MDR, Wernicke A, Labovsky V, Chasseing NA. RANK in cancer-associated fibroblasts: A valuable prognostic determinant for metastasis in early-stage breast cancer patients. Cancer Biomark 2024; 41:115-132. [PMID: 39240628 PMCID: PMC11492045 DOI: 10.3233/cbm-230523] [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: 01/10/2024] [Accepted: 07/19/2024] [Indexed: 09/07/2024]
Abstract
BACKGROUND The molecular system of receptor activator of nuclear factor kappa-β (RANK) and its ligand (RANKL) plays a role in a variety of physiological and pathological processes. These encompass the regulation of bone metabolism, mammary gland development, immune function, as well as their involvement and tumorigenesis. Nevertheless, limited knowledge exists regarding their function within the tumor microenvironment. METHODS AND RESULTS We explored the significance of RANK expression in cancer-associated fibroblasts (CAFs) as a prognostic biomarker in early breast cancer patients (BCPs) by immunohistochemistry. Results reveal a significant correlation between high RANK expression in CAFs and an increased risk of metastasis (p= 0.006), shorter metastasis-free survival (MFS) [p= 0.007, OR (95%CI) = 2.290 (1.259-4.156)], and lower overall survival (OS) [p= 0.004, OR (95%CI) = 2.469 (1.343-4.541)]. Upon analyzing the phenotype of CD34(-) CAFs isolated from primary tumors in BCPs, we observed co-expression of RANK with CD105 marker by immunofluorescence and flow cytometry, characteristic of mesenchymal stem/stromal cells (MSCs), suggesting the possible cellular origin. Also RANKL-RANK system increase the OCT-4, SOX-2 and DKK-1 (dickkopf 1) gene expression in CD34(-) CAFs by RT-PCR. Moreover, this system plays a crucial role in the migration of these CD34(-) CAFs. CONCLUSIONS These results support the clinical relevance of RANK in CAFs and propose its potential as a future therapeutic target in the treatment of early BCPs.
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Affiliation(s)
- María Belén Giorello
- Laboratorio de Inmunohematología, Instituto de Biología y Medicina Experimental (IBYME), Fundación IBYME, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina
| | - Francisco Raúl Borzone
- Laboratorio de Inmunohematología, Instituto de Biología y Medicina Experimental (IBYME), Fundación IBYME, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina
| | - María Florencia Mora
- Departamento de Anatomía Patológica, Hospital Italiano, Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina
| | - María del Rosario Padin
- Departamento de Anatomía Patológica, Hospital Italiano, Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina
| | - Alejandra Wernicke
- Laboratorio de Inmunohematología, Instituto de Biología y Medicina Experimental (IBYME), Fundación IBYME, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina
- Departamento de Anatomía Patológica, Hospital Italiano, Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina
| | - Vivian Labovsky
- Laboratorio de Inmunohematología, Instituto de Biología y Medicina Experimental (IBYME), Fundación IBYME, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina
| | - Norma Alejandra Chasseing
- Laboratorio de Inmunohematología, Instituto de Biología y Medicina Experimental (IBYME), Fundación IBYME, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina
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Westhoff CC, Müller SK, Jank P, Kalder M, Moll R. Nodal lymphangiogenesis and immunophenotypic variations of sinus endothelium in sentinel and non-sentinel lymph nodes of invasive breast carcinoma. PLoS One 2023; 18:e0280936. [PMID: 36693068 PMCID: PMC9873157 DOI: 10.1371/journal.pone.0280936] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Accepted: 01/11/2023] [Indexed: 01/25/2023] Open
Abstract
Several studies have demonstrated the de novo formation of lymphatic vessels or the reorganization of lymphatic sinus in tumor-draining lymph nodes, partly preceding the detection of lymphatic metastases. This "lymphovascular niche"is supposed to facilitate the survival of metastatic tumor cells. Few studies on nodal lymphangiogenesis in invasive breast cancer (BC) have been published, not considering tumor-free sentinel lymph nodes (SLN) and tumor types. Specimens of SLN and/ or non-SLN (NSLN) of 95 patients with BC were examined immunohistochemically for expression of the lymphatic endothelial marker D2-40 (podoplanin) on lymphatic vessels and the subcapsular sinus. The number of D2-40-positive lymph vessels in metastases was evaluated with two morphometric methods (Chalkley count and number per HPF). Data was explored with respect to TNM parameters, grading, tumor type, size of metastasis, lymph vessel number and hormone receptor/HER2 status with appropriate statistical tests. Lymphangiogenesis was detected exclusively in and around BC metastases with both methods for lymph vessel quantification being equivalent. Lymph vessel number correlated with the size of metastases, being significantly higher in larger metastases (p < 0.001). There was no significant statistical difference with respect to tumor types. Intranodal lymphangiogenesis could not be verified by D2-40 staining in any of the tumor-free lymph nodes examined. However, D2-40 was frequently detected in sinus endothelial/virgultar cells of the subcapsular sinus, partly with strong uniform positivity. Staining intensity and stained proportion of the subcapsular sinus were markedly heterogeneous, significantly correlating with each other both in SLN and NSLN (p < 0.001). A higher proportion of D2-40 stained subcapsular sinus in SLN was significantly associated with worse overall survival (p = 0.0036) and an independent prognostic parameter in multivariate analysis (p = 0.033, HR 2.87). Further studies are necessary to elucidate the biological and clinical significance of the observed immunophenotypic variations of nodal sinus endothelium.
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Affiliation(s)
- Christina C. Westhoff
- Institute of Pathology, Philipps University of Marburg and University Hospital Giessen and Marburg GmbH, Marburg, Germany
- * E-mail:
| | - Sabrina K. Müller
- Institute of Pathology, Philipps University of Marburg and University Hospital Giessen and Marburg GmbH, Marburg, Germany
| | - Paul Jank
- Institute of Pathology, Philipps University of Marburg and University Hospital Giessen and Marburg GmbH, Marburg, Germany
| | - Matthias Kalder
- Department of Gynecology and Obstetrics, Breast Center Regio, Philipps University of Marburg and University Hospital Giessen and Marburg GmbH, Marburg, Germany
| | - Roland Moll
- Institute of Pathology, Philipps University of Marburg and University Hospital Giessen and Marburg GmbH, Marburg, Germany
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Aneuploid Circulating Tumor-Derived Endothelial Cell (CTEC): A Novel Versatile Player in Tumor Neovascularization and Cancer Metastasis. Cells 2020; 9:cells9061539. [PMID: 32599893 PMCID: PMC7349247 DOI: 10.3390/cells9061539] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2020] [Revised: 06/12/2020] [Accepted: 06/22/2020] [Indexed: 12/14/2022] Open
Abstract
Hematogenous and lymphogenous cancer metastases are significantly impacted by tumor neovascularization, which predominantly consists of blood vessel-relevant angiogenesis, vasculogenesis, vasculogenic mimicry, and lymphatic vessel-related lymphangiogenesis. Among the endothelial cells that make up the lining of tumor vasculature, a majority of them are tumor-derived endothelial cells (TECs), exhibiting cytogenetic abnormalities of aneuploid chromosomes. Aneuploid TECs are generated from “cancerization of stromal endothelial cells” and “endothelialization of carcinoma cells” in the hypoxic tumor microenvironment. Both processes crucially engage the hypoxia-triggered epithelial-to-mesenchymal transition (EMT) and endothelial-to-mesenchymal transition (EndoMT). Compared to the cancerization process, endothelialization of cancer cells, which comprises the fusion of tumor cells with endothelial cells and transdifferentiation of cancer cells into TECs, is the dominant pathway. Tumor-derived endothelial cells, possessing the dual properties of cancerous malignancy and endothelial vascularization ability, are thus the endothelialized cancer cells. Circulating tumor-derived endothelial cells (CTECs) are TECs shed into the peripheral circulation. Aneuploid CD31+ CTECs, together with their counterpart CD31- circulating tumor cells (CTCs), constitute a unique pair of cellular circulating tumor biomarkers. This review discusses a proposed cascaded framework that focuses on the origins of TECs and CTECs in the hypoxic tumor microenvironment and their clinical implications for tumorigenesis, neovascularization, disease progression, and cancer metastasis. Aneuploid CTECs, harboring hybridized properties of malignancy, vascularization and motility, may serve as a unique target for developing a novel metastasis blockade cancer therapy.
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Volk-Draper L, Patel R, Bhattarai N, Yang J, Wilber A, DeNardo D, Ran S. Myeloid-Derived Lymphatic Endothelial Cell Progenitors Significantly Contribute to Lymphatic Metastasis in Clinical Breast Cancer. THE AMERICAN JOURNAL OF PATHOLOGY 2019; 189:2269-2292. [PMID: 31421071 DOI: 10.1016/j.ajpath.2019.07.006] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/05/2018] [Revised: 06/20/2019] [Accepted: 07/09/2019] [Indexed: 12/24/2022]
Abstract
Lymphatic metastasis is a high-impact prognostic factor for mortality of breast cancer (BC) patients, and it directly depends on tumor-associated lymphatic vessels. We previously reported that lipopolysaccharide-induced inflammatory lymphangiogenesis is strongly promoted by myeloid-derived lymphatic endothelial cell progenitors (M-LECPs) derived from the bone marrow (BM). As BC recruits massive numbers of provascular myeloid cells, we hypothesized that M-LECPs, within this recruited population, are specifically programmed to promote tumor lymphatics that increase lymph node metastasis. In support of this hypothesis, high levels of M-LECPs were found in peripheral blood and tumor tissues of BC patients. Moreover, the density of M-LECPs and lymphatic vessels positive for myeloid marker proteins strongly correlated with patient node status. It was also established that tumor M-LECPs coexpress lymphatic-specific, stem/progenitor and M2-type macrophage markers that indicate their BM hematopoietic-myeloid origin and distinguish them from mature lymphatic endothelial cells, tumor-infiltrating lymphoid cells, and tissue-resident macrophages. Using four orthotopic BC models, we show that mouse M-LECPs are similarly recruited to tumors and integrate into preexisting lymphatics. Finally, we demonstrate that adoptive transfer of in vitro differentiated M-LECPs, but not naïve or nondifferentiated BM cells, significantly increased metastatic burden in ipsilateral lymph nodes. These data support a causative role of BC-induced lymphatic progenitors in tumor lymphangiogenesis and suggest molecular targets for their inhibition.
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Affiliation(s)
- Lisa Volk-Draper
- Department of Medical Microbiology, Immunology, and Cell Biology, Southern Illinois University School of Medicine, Springfield, Illinois
| | - Radhika Patel
- Department of Medical Microbiology, Immunology, and Cell Biology, Southern Illinois University School of Medicine, Springfield, Illinois
| | - Nihit Bhattarai
- Department of Medical Microbiology, Immunology, and Cell Biology, Southern Illinois University School of Medicine, Springfield, Illinois
| | - Jie Yang
- Department of Medical Microbiology, Immunology, and Cell Biology, Southern Illinois University School of Medicine, Springfield, Illinois
| | - Andrew Wilber
- Department of Medical Microbiology, Immunology, and Cell Biology, Southern Illinois University School of Medicine, Springfield, Illinois; Simmons Cancer Institute, Southern Illinois University School of Medicine, Springfield, Illinois
| | - David DeNardo
- Department of Oncology, Washington University, St. Louis, Missouri
| | - Sophia Ran
- Department of Medical Microbiology, Immunology, and Cell Biology, Southern Illinois University School of Medicine, Springfield, Illinois; Simmons Cancer Institute, Southern Illinois University School of Medicine, Springfield, Illinois.
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Janiszewska M, Tabassum DP, Castaño Z, Cristea S, Yamamoto KN, Kingston NL, Murphy KC, Shu S, Harper NW, Del Alcazar CG, Alečković M, Ekram MB, Cohen O, Kwak M, Qin Y, Laszewski T, Luoma A, Marusyk A, Wucherpfennig KW, Wagle N, Fan R, Michor F, McAllister SS, Polyak K. Subclonal cooperation drives metastasis by modulating local and systemic immune microenvironments. Nat Cell Biol 2019; 21:879-888. [PMID: 31263265 PMCID: PMC6609451 DOI: 10.1038/s41556-019-0346-x] [Citation(s) in RCA: 106] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2018] [Accepted: 05/22/2019] [Indexed: 12/22/2022]
Abstract
Most human tumours are heterogeneous, composed of cellular clones with different properties present at variable frequencies. Highly heterogeneous tumours have poor clinical outcomes, yet the underlying mechanism remains poorly understood. Here, we show that minor subclones of breast cancer cells expressing IL11 and FIGF (VEGFD) cooperate to promote metastatic progression and generate polyclonal metastases composed of driver and neutral subclones. Expression profiling of the epithelial and stromal compartments of monoclonal and polyclonal primary and metastatic lesions revealed that this cooperation is indirect, mediated through the local and systemic microenvironments. We identified neutrophils as a leukocyte population stimulated by the IL11-expressing minor subclone and showed that the depletion of neutrophils prevents metastatic outgrowth. Single-cell RNA-seq of CD45+ cell populations from primary tumours, blood and lungs demonstrated that IL11 acts on bone-marrow-derived mesenchymal stromal cells, which induce pro-tumorigenic and pro-metastatic neutrophils. Our results indicate key roles for non-cell-autonomous drivers and minor subclones in metastasis.
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Affiliation(s)
- Michalina Janiszewska
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
- Department of Molecular Medicine, The Scripps Research Institute, Jupiter, FL, USA
| | - Doris P Tabassum
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Research Square, Durham, NC, USA
| | - Zafira Castaño
- Department of Medicine, Harvard Medical School, Boston, MA, USA
- Hematology Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA
| | - Simona Cristea
- Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA, USA
- Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA
| | - Kimiyo N Yamamoto
- Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA, USA
- Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA
| | - Natalie L Kingston
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Katherine C Murphy
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Shaokun Shu
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Nicholas W Harper
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Carlos Gil Del Alcazar
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Maša Alečković
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Muhammad B Ekram
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
- WuXi NextCODE, Cambridge, MA, USA
| | - Ofir Cohen
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- The Eli and Edythe L. Broad Institute of Harvard and MIT, Cambridge, MA, USA
| | - Minsuk Kwak
- Department of Biomedical Engineering, Yale School of Medicine, New Haven, CT, USA
- Yale Comprehensive Cancer Center, New Haven, CT, USA
| | - Yuanbo Qin
- Department of Medicine, Harvard Medical School, Boston, MA, USA
- Hematology Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA
- EdiGene, Cambridge, MA, USA
| | - Tyler Laszewski
- Hematology Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA
| | - Adrienne Luoma
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, and Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA, USA
| | - Andriy Marusyk
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
- Department of Cancer Imaging and Metabolism, Moffitt Cancer Center, Tampa, FL, USA
| | - Kai W Wucherpfennig
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, and Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA, USA
| | - Nikhil Wagle
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA
- The Eli and Edythe L. Broad Institute of Harvard and MIT, Cambridge, MA, USA
| | - Rong Fan
- Department of Biomedical Engineering, Yale School of Medicine, New Haven, CT, USA
- Yale Comprehensive Cancer Center, New Haven, CT, USA
| | - Franziska Michor
- Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA, USA
- Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA
- The Eli and Edythe L. Broad Institute of Harvard and MIT, Cambridge, MA, USA
- Center for Cancer Evolution, Dana-Farber Cancer Institute, Boston, MA, USA
- Ludwig Center at Harvard, Boston, MA, USA
| | - Sandra S McAllister
- Department of Medicine, Harvard Medical School, Boston, MA, USA
- Hematology Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA
- The Eli and Edythe L. Broad Institute of Harvard and MIT, Cambridge, MA, USA
- Harvard Stem Cell Institute, Cambridge, MA, USA
| | - Kornelia Polyak
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
- Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
- Department of Medicine, Harvard Medical School, Boston, MA, USA.
- The Eli and Edythe L. Broad Institute of Harvard and MIT, Cambridge, MA, USA.
- Center for Cancer Evolution, Dana-Farber Cancer Institute, Boston, MA, USA.
- Ludwig Center at Harvard, Boston, MA, USA.
- Harvard Stem Cell Institute, Cambridge, MA, USA.
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Bousseau S, Vergori L, Soleti R, Lenaers G, Martinez MC, Andriantsitohaina R. Glycosylation as new pharmacological strategies for diseases associated with excessive angiogenesis. Pharmacol Ther 2018; 191:92-122. [DOI: 10.1016/j.pharmthera.2018.06.003] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2018] [Accepted: 06/01/2018] [Indexed: 02/07/2023]
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Martínez-Iglesias O, Olmeda D, Alonso-Merino E, Gómez-Rey S, González-López AM, Luengo E, Soengas MS, Palacios J, Regadera J, Aranda A. The nuclear corepressor 1 and the thyroid hormone receptor β suppress breast tumor lymphangiogenesis. Oncotarget 2018; 7:78971-78984. [PMID: 27806339 PMCID: PMC5346691 DOI: 10.18632/oncotarget.12978] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2016] [Accepted: 10/22/2016] [Indexed: 12/20/2022] Open
Abstract
Vascular Endotelial Growth Factors C and D (VEGF-C and VEGF-D) are crucial regulators of lymphangiogenesis, a main event in the metastatic spread of breast cancer tumors. Although inhibition of lymphangiogenic gene expression might be a useful therapeutic strategy to restrict the progression of cancer, the factors involved in the transcriptional repression of these genes are still unknown. We have previously shown that Nuclear Receptor Corepressor 1 (NCoR) and the thyroid hormone receptor β1 (TRβ) inhibit tumor invasion. Here we show that these molecules repress VEGF-C and VEGF-D gene transcription in breast cancer cells, reducing lymphatic vessel density and sentinel lymph node invasion in tumor xenografts. The clinical significance of these results is stressed by the finding that NCoR and TRβ transcripts correlate negatively with those of the lymphangiogenic genes and the lymphatic vessel marker LYVE-1 in human breast tumors. Our results point to the use of NCoR and TRβ as potential biomarkers for diagnosis or prognosis in breast cancer and suggest that further studies of these molecules as potential targets for anti-lymphangiogenic therapy are warranted.
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Affiliation(s)
- Olaia Martínez-Iglesias
- Instituto de Investigaciones Biomédicas "Alberto Sols", Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid, Spain
| | - David Olmeda
- Molecular Oncology Programme, Centro Nacional de Investigaciones Oncológicas, Universidad Autónoma de Madrid, Spain
| | - Elvira Alonso-Merino
- Instituto de Investigaciones Biomédicas "Alberto Sols", Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid, Spain
| | - Sara Gómez-Rey
- Instituto de Investigaciones Biomédicas "Alberto Sols", Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid, Spain
| | - Ana M González-López
- Instituto de Investigaciones Biomédicas "Alberto Sols", Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid, Spain
| | - Enrique Luengo
- Instituto de Investigaciones Biomédicas "Alberto Sols", Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid, Spain
| | - María S Soengas
- Molecular Oncology Programme, Centro Nacional de Investigaciones Oncológicas, Universidad Autónoma de Madrid, Spain
| | - José Palacios
- Departamento de Anatomía Patológica, Hospital Universitario Ramón y Cajal, Instituto de Investigación Sanitaria Ramón y Cajal (IRYCIS), Universidad de Alcalá, Spain
| | - Javier Regadera
- Departamento de Anatomía, Histología y Neurociencia, Facultad de Medicina, Universidad Autónoma de Madrid, Spain
| | - Ana Aranda
- Instituto de Investigaciones Biomédicas "Alberto Sols", Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid, Spain
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Ma C, Yin H, Zhong J, Zhang Y, Luo C, Che D, Fang Z, Li L, Qin S, Liang J, Qi W, Yang Z, Zhou T, Ma J, Yang X, Gao G. Kallistatin exerts anti-lymphangiogenic effects by inhibiting lymphatic endothelial cell proliferation, migration and tube formation. Int J Oncol 2017; 50:2000-2010. [PMID: 28440474 PMCID: PMC5435323 DOI: 10.3892/ijo.2017.3972] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2017] [Accepted: 04/10/2017] [Indexed: 12/24/2022] Open
Abstract
Kallistatin has been recognized as an endogenous angiogenic inhibitor. However, its effects on lymphatic endothelial cells and lymphangiogenesis remain poorly understood. Lymphangiogenesis is involved in tumor metastasis via the lymphatic vasculature in various types of tumors. The aim of this study was to investigate the effects of kallistatin on lymphangiogenesis and the mechanism of action involved. Treatment with kallistatin recombinant protein or overexpression of kallistatin inhibited the proliferation, migration and tube formation of human lymphatic endothelial cells (hLECs), and induced apoptosis of hLECs. Furthermore, our results showed that the lymphatic vessel density (LVD) was reduced in lung and stomach sections from kallistatin-overexpressing transgenic mice. Treatment with kallistatin recombinant protein decreased the LVD in the implanted gastric xenograft tumors of nude mice. To the best of our knowledge, the present study is the first to demonstrate that kallistatin possesses anti-lymphangiogenic activity in vitro and in vivo. Moreover, kallistatin inhibited proliferation and migration of hLECs by reducing the phosphorylation of ERK and Akt, respectively. These findings suggested that kallistatin may be a promising agent that could be used to suppress cancer metastasis by inhibiting both angiogenesis and lymphangiogenesis.
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Affiliation(s)
- Caiqi Ma
- Program of Molecular Medicine, Affiliated Guangzhou Women and Children's Hospital, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Haofan Yin
- Program of Molecular Medicine, Affiliated Guangzhou Women and Children's Hospital, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Jun Zhong
- Program of Molecular Medicine, Affiliated Guangzhou Women and Children's Hospital, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Yang Zhang
- Program of Molecular Medicine, Affiliated Guangzhou Women and Children's Hospital, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Chuanghua Luo
- Department of Biochemistry, Zhongshan Medical School, Sun Yat-Sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Di Che
- Program of Molecular Medicine, Affiliated Guangzhou Women and Children's Hospital, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Zhenzhen Fang
- Department of Biochemistry, Zhongshan Medical School, Sun Yat-Sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Lei Li
- Reproductive Center, The Third Hospital Affiliated to Guangzhou Medical University, Guangzhou, Guangdong 510150, P.R. China
| | - Shuxing Qin
- Department of Biochemistry, Zhongshan Medical School, Sun Yat-Sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Jieying Liang
- Department of Biochemistry, Zhongshan Medical School, Sun Yat-Sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Weiwei Qi
- Department of Biochemistry, Zhongshan Medical School, Sun Yat-Sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Zhonghan Yang
- Department of Biochemistry, Zhongshan Medical School, Sun Yat-Sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Ti Zhou
- Department of Biochemistry, Zhongshan Medical School, Sun Yat-Sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Jianxing Ma
- Department of Physiology, University of Oklahoma, Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Xia Yang
- Program of Molecular Medicine, Affiliated Guangzhou Women and Children's Hospital, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Guoquan Gao
- Program of Molecular Medicine, Affiliated Guangzhou Women and Children's Hospital, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong 510080, P.R. China
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Abstract
BACKGROUND Metastasis is the main cause of mortality in cancer patients. Two major routes of cancer cell spread are currently being recognized: dissemination via blood vessels (hematogenous spread) and dissemination via the lymphatic system (lymphogenous spread). Here, our current knowledge on the role of both blood and lymphatic vessels in cancer cell metastasis is summarized. In addition, I will discuss why cancer cells select one or both of the two routes to disseminate and I will provide a short description of the passive and active models of intravasation. Finally, lymphatic vessel density (LVD), blood vessel density (BVD), interstitial fluid pressure (IFP) and tumor hypoxia, as well as regional lymph node metastasis and the recently discovered primo vascular system (PVS) will be highlighted as important factors influencing tumor cell motility and spread and, ultimately, clinical outcome. CONCLUSIONS Lymphangiogenesis and angiogenesis are important phenomena involved in the spread of cancer cells and they are associated with a poor prognosis. It is anticipated that new discoveries and advancing knowledge on these phenomena will allow an improvement in the treatment of cancer patients.
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Affiliation(s)
- Roman Paduch
- Department of Virology and Immunology, Institute of Microbiology and Biotechnology, Maria Curie-Skłodowska University, Akademicka 19, 20-033, Lublin, Poland.
- Department of General Ophthalmology, Medical University of Lublin, Chmielna 1, 20-079, Lublin, Poland.
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Dieterich LC, Detmar M. Tumor lymphangiogenesis and new drug development. Adv Drug Deliv Rev 2016; 99:148-160. [PMID: 26705849 DOI: 10.1016/j.addr.2015.12.011] [Citation(s) in RCA: 114] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2015] [Revised: 10/12/2015] [Accepted: 12/09/2015] [Indexed: 02/07/2023]
Abstract
Traditionally, tumor-associated lymphatic vessels have been regarded as passive by-standers, serving simply as a drainage system for interstitial fluid generated within the tumor. However, with growing evidence that tumors actively induce lymphangiogenesis, and that the number of lymphatic vessels closely correlates with metastasis and clinical outcome in various types of cancer, this picture has changed dramatically in recent years. Tumor-associated lymphatic vessels have now emerged as a valid therapeutic target to control metastatic disease, and the first specific anti-lymphangiogenic drugs have recently entered clinical testing. Furthermore, we are just beginning to understand the whole functional spectrum of tumor-associated lymphatic vessels, which not only concerns transport of fluid and metastatic cells, but also includes the regulation of cancer stemness and specific inhibition of immune responses, opening new venues for therapeutic applications. Therefore, we predict that specific targeting of lymphatic vessels and their function will become an important tool for future cancer treatment.
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Rykala J, Przybylowska K, Majsterek I, Pasz-Walczak G, Sygut A, Dziki A, Kuna P. The -553 T/A polymorphism in the promoter region of the FGF2 gene is associated with increased breast cancer risk in Polish women. Arch Med Sci 2015; 11:619-27. [PMID: 26170857 PMCID: PMC4495138 DOI: 10.5114/aoms.2013.35996] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2013] [Revised: 06/12/2013] [Accepted: 06/15/2013] [Indexed: 02/02/2023] Open
Abstract
INTRODUCTION Fibroblast growth factor-2 (FGF2) is an important signalling molecule contributing to angiogenesis, tumour growth and progression and its expression is implicated in breast cancer (BC) development. We investigated whether -553 T/A FGF2 gene polymorphism is associated with the risk and progression of BC in Polish women. MATERIAL AND METHODS The -553 T/A polymorphism was genotyped in 230 breast cancer patients and 245 control subjects, using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) approach. Moreover, FastQuant human angiogenesis array was used to measure FGF2 levels in tumour (n = 127) and serum (n = 76) samples. RESULTS The T/A genotypes (OR = 2.12, 95% CI: 1.20-3.74) (p = 0.08) and the combined heterozygotes T/A and homozygote A/A (OR = 2.18, 95% CI: 1.24-3.83) (p = 0.006) had an increased risk of BC. The median FGF2 levels in the tumours of A allele carriers were significantly increased compared to T/T patients, whereas in serum FGF2 levels were hardly altered among different genotype carriers. Significantly higher frequency of A allele was found in patients with lymph node metastases (OR = 2.53; 95% CI: 1.23-5.17) (p = 0.009) and human epidermal growth factor receptor 2 positive tumour (OR = 3.22, 95% CI: 1.49-6.99) (p = 0.002). Furthermore, Kaplan-Meier survival analysis showed that the A allele predicted worse disease-free survival (DFS) in BC patients. CONCLUSIONS Our study shows for the first time that the -553 T/A FGF2 gene polymorphism may be associated with a risk of BC developing and progression in Polish women and may have prognostic value for the assessment of BC high-risk groups.
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Affiliation(s)
- Jan Rykala
- Department of Plastic, Reconstructive and Aesthetic Surgery, Barlicki Hospital, Medical University of Lodz, Poland
| | - Karolina Przybylowska
- Department of Chemistry and Clinical Biochemistry, Medical University of Lodz, Poland
| | - Ireneusz Majsterek
- Department of Chemistry and Clinical Biochemistry, Medical University of Lodz, Poland
| | | | - Andrzej Sygut
- Department of General and Colorectal Surgery, Medical University of Lodz, Poland
| | - Adam Dziki
- Department of General and Colorectal Surgery, Medical University of Lodz, Poland
| | - Piotr Kuna
- Departments of Internal Medicine, Asthma and Allergy, Medical University of Lodz, Poland
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Luengo-Gil G, González-Billalabeitia E, Chaves-Benito A, García Martínez E, García Garre E, Vicente V, Ayala de la Peña F. Effects of conventional neoadjuvant chemotherapy for breast cancer on tumor angiogenesis. Breast Cancer Res Treat 2015; 151:577-87. [PMID: 25967462 DOI: 10.1007/s10549-015-3421-4] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2015] [Accepted: 05/07/2015] [Indexed: 01/01/2023]
Abstract
The effects of breast cancer conventional chemotherapy on tumor angiogenesis need to be further characterized. Neoadjuvant chemotherapy is an ideal model to evaluate the results of chemotherapy, allowing intra-patient direct comparison of antitumor and antiangiogenic effects. We sought to analyze the effect of neoadjuvant chemotherapy on tumor angiogenesis and its clinical significance in breast cancer. Breast cancer patients (n = 108) treated with neoadjuvant sequential anthracyclines and taxanes were studied. Pre- and post-chemotherapy microvessel density (MVD) and mean vessel size (MVS) were analyzed after CD34 immunohistochemistry and correlated with tumor expression of pro- and antiangiogenic factors (VEGFA, THBS1, HIF1A, CTGF, and PDGFA) by qRT-PCR. Angiogenic measures at diagnosis varied among breast cancer subtypes. Pre-treatment higher MVS was associated with triple-negative subtype and more advanced disease. Higher MVS was correlated with higher VEGFA (p = 0.003), while higher MVD was correlated with lower antiangiogenic factors expression (THBS1, p < 0.0001; CTGF, p = 0.001). Increased angiogenesis at diagnosis (high MVS and glomeruloid microvascular proliferation) and higher VEGFA expression were associated with tumor recurrence (p = 0.048 and 0.009, respectively). Chemotherapy-induced angiogenic response (defined as decreased MVD) was present in 35.2 % of patients. This response correlated with an increase in antiangiogenic factors (THBS1) without changes in VEGFA expression, and it was associated with tumor downstaging, but not with clinical response, pathologic complete response, or prognosis. Global effects of chemotherapy mainly consisted in an increased expression of antiangiogenic factors (THBS1, CTGF), with significant changes neither of tumor VEGFA nor of MVS. Conventionally scheduled neoadjuvant chemotherapy exerts antiangiogenic effects, through an increase in antiangiogenic factors, THBS1 and CTGF, but the expression of VEGFA is maintained after treatment. Better markers of angiogenic response and a better understanding of the cooperation of chemotherapy and antiangiogenic therapy in the neoadjuvant clinical scenario are needed.
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Affiliation(s)
- Ginés Luengo-Gil
- Department of Hematology and Medical Oncology, University Hospital Morales Meseguer, Avda. Marqués de los Vélez, s/n, 30008, Murcia, Spain
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Ji L, Zheng Z, Shi L, Huang Y, Lu B, Wang Z. Andrographolide decreased VEGFD expression in hepatoma cancer cells by inducing ubiquitin/proteasome-mediated cFos protein degradation. Biochim Biophys Acta Gen Subj 2015; 1850:750-8. [DOI: 10.1016/j.bbagen.2015.01.005] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2014] [Revised: 12/24/2014] [Accepted: 01/07/2015] [Indexed: 01/11/2023]
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15
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Poellinger A, El-Ghannam S, Diekmann S, Fischer T, Kristiansen G, Fritzsche F, Fallenberg E, Morawietz L, Diekmann F. Correlation between enhancement characteristics of MR mammography and capillary density of breast lesions. Eur J Radiol 2014; 83:2129-2136. [DOI: 10.1016/j.ejrad.2014.09.007] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2014] [Revised: 09/13/2014] [Accepted: 09/15/2014] [Indexed: 11/25/2022]
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Sasahira T, Kirita T, Yamamoto K, Ueda N, Kurihara M, Matsushima S, Bhawal UK, Bosserhoff AK, Kuniyasu H. Transport and Golgi organisation protein 1 is a novel tumour progressive factor in oral squamous cell carcinoma. Eur J Cancer 2014; 50:2142-51. [DOI: 10.1016/j.ejca.2014.05.006] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2014] [Revised: 04/18/2014] [Accepted: 05/09/2014] [Indexed: 02/03/2023]
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In vivo "MRI phenotyping" reveals changes in extracellular matrix transport and vascularization that mediate VEGF-driven increase in breast cancer metastasis. PLoS One 2013; 8:e63146. [PMID: 23650550 PMCID: PMC3641100 DOI: 10.1371/journal.pone.0063146] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2012] [Accepted: 04/02/2013] [Indexed: 11/19/2022] Open
Abstract
PURPOSE To gain new insights into the relationship between angiogenic factors in breast cancer and their effect on extracellular matrix (ECM) remodeling and metastasis, we characterized and validated the "metastatic signature" of human breast cancer cell lines engineered to overexpress VEGF in terms of in vivo MRI-derived angiogenesis and ECM transport parameters. METHODOLOGY MRI was used to evaluate the effects of overexpressing VEGF-A (VEGF165) on tumor angiogenesis and ECM remodeling in vivo, for two differentially metastatic human breast cancer cell lines: MCF-7 and MDA-MB-231. PRINCIPAL FINDINGS Overexpression of VEGF elevated vascular volume in both MCF-7-VEGF and MDA-MB-231-VEGF tumors relative to their wild-type counterparts, but vascular permeability was elevated only in MCF-7-VEGF tumors. A significant increase in the volume of extravascular fluid drained as well as the number of ECM drainage voxels was detected in MCF-7-VEGF tumors relative to MCF-7 tumors, but not in MDA-MB-231-VEGF versus MDA-MB-231 tumors. The angiogenic effects of VEGF overexpression in both MCF-7-VEGF and MDA-MB-231-VEGF tumors were validated histologically. MCF-7-VEGF tumors exhibited enhanced invasion and a greater fraction of cancer positive lungs and lymph nodes relative to MCF-7 tumors. CONCLUSIONS AND SIGNIFICANCE In vivo MRI and histological data demonstrate that VEGF overexpression results in the progression of noninvasive MCF-7 and invasive MDA-MB-321 tumors to a more angiogenic phenotype. However, VEGF overexpression significantly altered ECM integrity only in MCF-7 tumors, causing them to progress to an invasive and metastatic phenotype. This study for the first time demonstrates the concurrent effects of VEGF overexpression and ECM remodeling on metastasis in vivo. Collectively, these findings demonstrate that in vivo MRI can non-invasively monitor changes in the tumor microenvironment that can potentially predict a cancer's ability to metastasize.
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A meta-analysis of the relationship between lymphatic microvessel density and clinicopathological parameters in breast cancer. Bull Cancer 2013; 100:1-10. [DOI: 10.1684/bdc.2013.1719] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
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Linardou H, Kalogeras KT, Kronenwett R, Kouvatseas G, Wirtz RM, Zagouri F, Gogas H, Christodoulou C, Koutras AK, Samantas E, Pectasides D, Bafaloukos D, Fountzilas G. The prognostic and predictive value of mRNA expression of vascular endothelial growth factor family members in breast cancer: a study in primary tumors of high-risk early breast cancer patients participating in a randomized Hellenic Cooperative Oncology Group trial. Breast Cancer Res 2012; 14:R145. [PMID: 23146280 PMCID: PMC4053134 DOI: 10.1186/bcr3354] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2012] [Accepted: 11/12/2012] [Indexed: 12/30/2022] Open
Abstract
INTRODUCTION The main prognostic variables in early breast cancer are tumor size, histological grade, estrogen receptor/progesterone receptor (ER/PgR) status, number of positive nodes and human epidermal growth factor receptor 2 (HER2) status. The present study evaluated the prognostic and/or predictive value of vascular endothelial growth factor (VEGF) family members in high-risk early breast cancer patients treated with adjuvant chemo-hormonotherapy. METHODS RNA was isolated from 308 formalin-fixed paraffin-embedded primary tumor samples from breast cancer patients enrolled in the HE10/97 trial, evaluating adjuvant dose-dense sequential chemotherapy with epirubicin followed by cyclophosphamide, methotrexate, fluorouracil (CMF) with or without paclitaxel (E-T-CMF versus E-CMF). A fully automated method based on magnetic beads was applied for RNA extraction, followed by one-step quantitative RT-PCR for mRNA analysis of VEGF-A, -B, -C and vascular endothelial growth factor receptor (VEGFR) 1, 2, 3. RESULTS With a median follow-up of 8 years, 109 patients (35%) developed a relapse and 80 patients (26%) died. In high VEGF-C and VEGFR1 mRNA expressing tumors, ER/PgR-negative tumors (Fisher's exact test, P = 0.001 and P = 0.021, respectively) and HER2-positive tumors (P <0.001 and P = 0.028, respectively) were more frequent than in low VEGF-C and VEGFR1 expressing tumors, respectively. From the VEGF family members evaluated, high VEGFR1 mRNA expression (above the 75th percentile) emerged as a significant negative prognostic factor for overall survival (OS; hazard ratio (HR) = 1.60, 95% confidence interval (CI): 1.01 to 2.55, Wald's P = 0.047) and disease-free survival (DFS; HR = 1.67, 95% CI: 1.13 to 2.48, P = 0.010), when adjusting for treatment group. High VEGF-C mRNA expression was predictive for benefit from adjuvant treatment with paclitaxel (E-T-CMF arm) for OS (test for interaction, Wald's P = 0.038), while in multivariate analysis the interaction of VEGF-C with taxane treatment was significant for both OS (Wald's P = 0.019) and DFS (P = 0.041) and continuous VEGF-B mRNA expression values for OS (P = 0.019). CONCLUSIONS The present study reports, for the first time, that VEGF-C mRNA overexpression, as assessed by qRT-PCR, has a strong predictive value in high-risk early breast cancer patients undergoing adjuvant paclitaxel-containing treatment. Further studies are warranted to validate the prognostic and/or predictive value of VEGF-B, VEGF-C and VEGFR1 in patients treated with adjuvant therapies and to reveal which members of the VEGF family could possibly be useful markers in identifying patients who will benefit most from anti-VEGF strategies. TRIAL REGISTRATION Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12611000506998.
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DING MINGXING, FU XIAOYAN, TAN HAIDONG, WANG RUIQUAN, CHEN ZHIMEI, DING SHIPING. The effect of vascular endothelial growth factor C expression in tumor-associated macrophages on lymphangiogenesis and lymphatic metastasis in breast cancer. Mol Med Rep 2012; 6:1023-9. [DOI: 10.3892/mmr.2012.1043] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2012] [Accepted: 08/15/2012] [Indexed: 11/05/2022] Open
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Trinh XB, van Dam PA, Vermeulen PB, Van Laere SJ, Van den Eynden GG, Tjalma WAA, Dirix LY. VEGF-A-independent and angiogenesis-dependent tumour growth in patients with metastatic breast cancer. Clin Transl Oncol 2012; 13:805-8. [PMID: 22082645 DOI: 10.1007/s12094-011-0737-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND The mechanisms of tumour progression during anti-VEGF-A treatment are poorly understood. PATIENTS AND MATERIALS Two patients with metastatic breast cancer are described who developed new metastases while receiving anti-VEGF-A treatment. Angiogenic parameters were determined by CD34/Ki67 double staining, Chalkley counts (CC) and endothelial cell proliferation fractions (ECP). RT-PCR Taqman low-density arrays with a gene panel of 94 angiogenesis-related genes were performed on both metastases and compared to 10 unselected primary breast tumours. RESULTS Both lesions showed a high and intermediate CC of, respectively, 7.5±0.62 and 4.8±0.2. Both lesions had elevated ECP values of 14% and 8%. Low-density array screening showed that VEGFR1 mRNA was overexpressed in both samples (z-score=7.85 and 7.81) compared to control samples (out of range [min-max]). Additional analysis confirmed this finding at the protein level by immunohistochemistry. CONCLUSION These observations suggest that tumour progression under continuous anti-VEGF-A continues to be angiogenesis dependent. Further exploration is needed to identify the mechanisms of anti-VEGF-A resistance in order to design combination-targeted therapies.
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Affiliation(s)
- X Bich Trinh
- Translational Cancer Research Group-Antwerp, Oncology Centre, St. Augustinus Hospital, Wilrijk-Antwerp, Belgium
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TVEDSKOV TOVEFILTENBORG, BARTELS ANNETTE, JENSEN MAJBRITT, PAASCHBURG BIRGITTE, KROMAN NIELS, BALSLEV EVA, BRÜNNER NILS. Evaluating TIMP-1, Ki67, and HER2 as markers for non-sentinel node metastases in breast cancer patients with micrometastases to the sentinel node. APMIS 2011; 119:844-52. [DOI: 10.1111/j.1600-0463.2011.02768.x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
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Farnsworth RH, Karnezis T, Shayan R, Matsumoto M, Nowell CJ, Achen MG, Stacker SA. A role for bone morphogenetic protein-4 in lymph node vascular remodeling and primary tumor growth. Cancer Res 2011; 71:6547-57. [PMID: 21868759 DOI: 10.1158/0008-5472.can-11-0200] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Lymph node metastasis, an early and prognostically important event in the progression of many human cancers, is associated with expression of VEGF-D. Changes to lymph node vasculature that occur during malignant progression may create a metastatic niche capable of attracting and supporting tumor cells. In this study, we sought to characterize molecules expressed in lymph node endothelium that could represent therapeutic or prognostic targets. Differential mRNA expression profiling of endothelial cells from lymph nodes that drained metastatic or nonmetastatic primary tumors revealed genes associated with tumor progression, in particular bone morphogenetic protein-4 (BMP-4). Metastasis driven by VEGF-D was associated with reduced BMP-4 expression in high endothelial venules, where BMP-4 loss could remodel the typical high-walled phenotype to thin-walled vessels. VEGF-D expression was sufficient to suppress proliferation of the more typical BMP-4-expressing high endothelial venules in favor of remodeled vessels, and mechanistic studies indicated that VEGF receptor-2 contributed to high endothelial venule proliferation and remodeling. BMP-4 could regulate high endothelial venule phenotype and cellular function, thereby determining morphology and proliferation responses. Notably, therapeutic administration of BMP-4 suppressed primary tumor growth, acting both at the level of tumor cells and tumor stromal cells. Together, our results show that VEGF-D-driven metastasis induces vascular remodeling in lymph nodes. Furthermore, they implicate BMP-4 as a negative regulator of this process, suggesting its potential utility as a prognostic marker or antitumor agent.
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Affiliation(s)
- Rae H Farnsworth
- Ludwig Institute for Cancer Research, University of Melbourne, Parkville, Australia
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Kandemir NO, Barut F, Bektas S, Ozdamar SO. Can Lymphatic Vascular Density Be Used in Determining Metastatic Spreading Potential of Tumor in Invasive Ductal Carcinomas? Pathol Oncol Res 2011; 18:253-62. [DOI: 10.1007/s12253-011-9436-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2010] [Accepted: 07/07/2011] [Indexed: 02/06/2023]
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Kim K, Cho SY, Kim BJ, Kim MH, Choi SC, Ryu SY. The type of metastasis is a prognostic factor in disseminated cervical cancer. J Gynecol Oncol 2010; 21:186-90. [PMID: 20922142 DOI: 10.3802/jgo.2010.21.3.186] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2010] [Revised: 08/11/2010] [Accepted: 08/18/2010] [Indexed: 11/30/2022] Open
Abstract
OBJECTIVE THE OBJECTIVES OF THIS STUDY WERE TWOFOLD: to verify whether the type of metastasis (lymphatic vs. hematogenous) is a prognostic factor, and to identify molecular markers associated with survival in patients with disseminated cervical cancer. METHODS Between April 1997 and May 2008, 30 patients with disseminated cervical cancer who had supraclavicular lymph node (N=13) or hematogenous metastases (N=17) were initially treated at our institute. We reviewed medical records to extract clinicopathologic variables. For 17 patients with available pathological specimens, we evaluated the association of immunohistochemical staining for metalloproteinase (MMP)-2, vascular endothelial growth factor (VEGF)-A, and laminin V gamma (LAMC)-2 with survival and clinicopathologic variables via a log-rank test and Cox regression analysis. RESULTS Patients who had only lymphatic metastasis (odds ratio [OR], 5.3; 95% confidence interval [CI], 1.4 to 19.5) or completed initial treatment (OR, 3.2; 95% CI, 1.1 to 9.9) showed better survival than patients who did not, but none of the molecular markers were associated with survival. Out of 13 patients with only lymphatic metastasis, three patients who had received volume-directed radiation with concurrent chemotherapy had a long-term survival of over two years. However, patients with hematogenous metastasis showed extremely poor prognosis. CONCLUSION The type of metastasis and completion of initial treatment were associated with prolonged survival in patients with disseminated cervical cancer, and over 20% of patients with lymphatic metastasis were salvaged with volume-directed radiation with concurrent chemotherapy. None of the molecular markers were associated with survival in patients with disseminated cervical cancer.
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Affiliation(s)
- Kidong Kim
- Department of Obstetrics and Gynecology, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, Korea
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Ran S, Volk L, Hall K, Flister MJ. Lymphangiogenesis and lymphatic metastasis in breast cancer. ACTA ACUST UNITED AC 2009; 17:229-51. [PMID: 20036110 DOI: 10.1016/j.pathophys.2009.11.003] [Citation(s) in RCA: 189] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2009] [Revised: 04/11/2009] [Accepted: 10/23/2009] [Indexed: 01/03/2023]
Abstract
Lymphatic metastasis is the main prognostic factor for survival of patients with breast cancer and other epithelial malignancies. Mounting clinical and experimental data suggest that migration of tumor cells into the lymph nodes is greatly facilitated by lymphangiogenesis, a process that generates new lymphatic vessels from pre-existing lymphatics with the aid of circulating lymphatic endothelial progenitor cells. The key protein that induces lymphangiogenesis is vascular endothelial growth factor receptor-3 (VEGFR-3), which is activated by vascular endothelial growth factor-C and -D (VEGF-C and VEGF-D). These lymphangiogenic factors are commonly expressed in malignant, tumor-infiltrating and stromal cells, creating a favorable environment for generation of new lymphatic vessels. Clinical evidence demonstrates that increased lymphatic vessel density in and around tumors is associated with lymphatic metastasis and reduced patient survival. Recent evidence shows that breast cancers induce remodeling of the local lymphatic vessels and the regional lymphatic network in the sentinel and distal lymph nodes. These changes include an increase in number and diameter of tumor-draining lymphatic vessels. Consequently, lymph flow away from the tumor is increased, which significantly increases tumor cell metastasis to draining lymph nodes and may contribute to systemic spread. Collectively, recent advances in the biology of tumor-induced lymphangiogenesis suggest that chemical inhibitors of this process may be an attractive target for inhibiting tumor metastasis and cancer-related death. Nevertheless, this is a relatively new field of study and much remains to be established before the concept of tumor-induced lymphangiogenesis is accepted as a viable anti-metastatic target. This review summarizes the current concepts related to breast cancer lymphangiogenesis and lymphatic metastasis while highlighting controversies and unanswered questions.
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Affiliation(s)
- Sophia Ran
- Department of Medical Microbiology, Immunology and Cell Biology, Southern Illinois University School of Medicine, 801 N. Rutledge, Springfield, IL 62794-9678, USA
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Wangsa D, Heselmeyer-Haddad K, Ried P, Eriksson E, Schäffer AA, Morrison LE, Luo J, Auer G, Munck-Wikland E, Ried T, Lundqvist EA. Fluorescence in situ hybridization markers for prediction of cervical lymph node metastases. THE AMERICAN JOURNAL OF PATHOLOGY 2009; 175:2637-45. [PMID: 19893027 PMCID: PMC2789632 DOI: 10.2353/ajpath.2009.090289] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 08/21/2009] [Indexed: 02/06/2023]
Abstract
The presence of lymph node metastases is associated with poor prognosis in early stage cervical cancer. As of yet, no molecular markers predicting lymph node metastases have been identified. We examined single genetic markers and a composite marker, comprised of three fluorescence in situ hybridization (FISH) probes targeting the genes LAMP3, PROX1, and PRKAA1, in pretreatment cervical biopsies from 16 lymph node positive cases and 15 lymph node negative controls from women with stage IB and IIA cervical cancer. In addition, we determined clonal patterns by including CCND1 to compare the clonal constitution of primary tumors and associated lymph node metastases. The composite FISH marker allowed for classification of patients into those with and without lymph node metastases with a sensitivity and specificity of 75% and 87%, respectively (P = 0.001). The positive predictive value and negative predictive value were 86% and 76%, respectively. Clonal patterns varied among the tumors. In many cases, changes between the primary tumor and lymph node metastases in the most common clones may indicate that certain clones have a growth advantage for establishing metastases in lymph nodes. We conclude that the composite FISH marker may be useful for determining risk for subsequent development of lymph node metastases in patients with cervical cancer.
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Affiliation(s)
- Darawalee Wangsa
- Department of Oncology-Pathology, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden
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