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Jiao W, Li H, Wu Y, Wen Q, Wang W, Tian J, Ren Y, Ma J, Zhao D, Zhao J, Zhang Y, Han G. Dual Targeted Nanoparticles Encapsulating Cantharidin for Treatment of Hepatocellular Carcinoma and Lymphatic Metastasis. ACS APPLIED NANO MATERIALS 2024; 7:20609-20625. [DOI: 10.1021/acsanm.4c03587] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
Affiliation(s)
- Wenwen Jiao
- Henan Province Engineering Research Center of High Value Utilization to Natural Medical Resource in Yellow River Basin, School of Pharmacy, Henan University, Kaifeng 475004, China
- Department of Pharmacy, The First Affiliated Hospital of Henan University, Kaifeng 475004, China
- State Key Laboratory of Antiviral Drugs, Henan University, Kaifeng 475004, China
- Kaifeng Key Lab for Application of Local Chrysanthemum Morifolium in Food & Drug, Kaifeng 475004, China
| | - Hao Li
- Henan Province Engineering Research Center of High Value Utilization to Natural Medical Resource in Yellow River Basin, School of Pharmacy, Henan University, Kaifeng 475004, China
- State Key Laboratory of Antiviral Drugs, Henan University, Kaifeng 475004, China
- Kaifeng Key Lab for Application of Local Chrysanthemum Morifolium in Food & Drug, Kaifeng 475004, China
| | - Yingjie Wu
- Henan Province Engineering Research Center of High Value Utilization to Natural Medical Resource in Yellow River Basin, School of Pharmacy, Henan University, Kaifeng 475004, China
- State Key Laboratory of Antiviral Drugs, Henan University, Kaifeng 475004, China
- Kaifeng Key Lab for Application of Local Chrysanthemum Morifolium in Food & Drug, Kaifeng 475004, China
| | - Qing Wen
- Henan Province Engineering Research Center of High Value Utilization to Natural Medical Resource in Yellow River Basin, School of Pharmacy, Henan University, Kaifeng 475004, China
- State Key Laboratory of Antiviral Drugs, Henan University, Kaifeng 475004, China
- Kaifeng Key Lab for Application of Local Chrysanthemum Morifolium in Food & Drug, Kaifeng 475004, China
| | - Wenzhen Wang
- Henan Province Engineering Research Center of High Value Utilization to Natural Medical Resource in Yellow River Basin, School of Pharmacy, Henan University, Kaifeng 475004, China
- State Key Laboratory of Antiviral Drugs, Henan University, Kaifeng 475004, China
- Kaifeng Key Lab for Application of Local Chrysanthemum Morifolium in Food & Drug, Kaifeng 475004, China
| | - Jia Tian
- Henan Province Engineering Research Center of High Value Utilization to Natural Medical Resource in Yellow River Basin, School of Pharmacy, Henan University, Kaifeng 475004, China
- State Key Laboratory of Antiviral Drugs, Henan University, Kaifeng 475004, China
- Kaifeng Key Lab for Application of Local Chrysanthemum Morifolium in Food & Drug, Kaifeng 475004, China
| | - Yulong Ren
- Henan Province Engineering Research Center of High Value Utilization to Natural Medical Resource in Yellow River Basin, School of Pharmacy, Henan University, Kaifeng 475004, China
- State Key Laboratory of Antiviral Drugs, Henan University, Kaifeng 475004, China
- Kaifeng Key Lab for Application of Local Chrysanthemum Morifolium in Food & Drug, Kaifeng 475004, China
| | - Jinyuan Ma
- Henan Province Engineering Research Center of High Value Utilization to Natural Medical Resource in Yellow River Basin, School of Pharmacy, Henan University, Kaifeng 475004, China
- State Key Laboratory of Antiviral Drugs, Henan University, Kaifeng 475004, China
- Kaifeng Key Lab for Application of Local Chrysanthemum Morifolium in Food & Drug, Kaifeng 475004, China
| | - Danxiang Zhao
- Henan Province Engineering Research Center of High Value Utilization to Natural Medical Resource in Yellow River Basin, School of Pharmacy, Henan University, Kaifeng 475004, China
- State Key Laboratory of Antiviral Drugs, Henan University, Kaifeng 475004, China
- Kaifeng Key Lab for Application of Local Chrysanthemum Morifolium in Food & Drug, Kaifeng 475004, China
| | - Junli Zhao
- Henan Province Engineering Research Center of High Value Utilization to Natural Medical Resource in Yellow River Basin, School of Pharmacy, Henan University, Kaifeng 475004, China
- State Key Laboratory of Antiviral Drugs, Henan University, Kaifeng 475004, China
- Kaifeng Key Lab for Application of Local Chrysanthemum Morifolium in Food & Drug, Kaifeng 475004, China
| | - Yu Zhang
- Henan Province Engineering Research Center of High Value Utilization to Natural Medical Resource in Yellow River Basin, School of Pharmacy, Henan University, Kaifeng 475004, China
- State Key Laboratory of Antiviral Drugs, Henan University, Kaifeng 475004, China
- Kaifeng Key Lab for Application of Local Chrysanthemum Morifolium in Food & Drug, Kaifeng 475004, China
| | - Guang Han
- Henan Province Engineering Research Center of High Value Utilization to Natural Medical Resource in Yellow River Basin, School of Pharmacy, Henan University, Kaifeng 475004, China
- State Key Laboratory of Antiviral Drugs, Henan University, Kaifeng 475004, China
- Kaifeng Key Lab for Application of Local Chrysanthemum Morifolium in Food & Drug, Kaifeng 475004, China
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Malekan M, Haass NK, Rokni GR, Gholizadeh N, Ebrahimzadeh MA, Kazeminejad A. VEGF/VEGFR axis and its signaling in melanoma: Current knowledge toward therapeutic targeting agents and future perspectives. Life Sci 2024; 345:122563. [PMID: 38508233 DOI: 10.1016/j.lfs.2024.122563] [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: 01/20/2024] [Revised: 03/10/2024] [Accepted: 03/13/2024] [Indexed: 03/22/2024]
Abstract
Melanoma is responsible for most skin cancer-associated deaths globally. The progression of melanoma is influenced by a number of pathogenic processes. Understanding the VEGF/VEGFR axis, which includes VEGF-A, PlGF, VEGF-B, VEGF-C, and VEGF-D and their receptors, VEGFR-1, VEGFR-2, and VEGFR-3, is of great importance in melanoma due to its crucial role in angiogenesis. This axis generates multifactorial and complex cellular signaling, engaging the MAPK/ERK, PI3K/AKT, PKC, PLC-γ, and FAK signaling pathways. Melanoma cell growth and proliferation, migration and metastasis, survival, and acquired resistance to therapy are influenced by this axis. The VEGF/VEGFR axis was extensively examined for their potential as diagnostic/prognostic biomarkers in melanoma patients and results showed that VEGF overexpression can be associated with unfavorable prognosis, higher level of tumor invasion and poor response to therapy. MicroRNAs linking to the VEGF/VEGFR axis were identified and, in this review, divided into two categories according to their functions, some of them promote melanoma angiogenesis (promotive group) and some restrict melanoma angiogenesis (protective group). In addition, the approach of treating melanoma by targeting the VEGF/VEGFR axis has garnered significant interest among researchers. These agents can be divided into two main groups: anti-VEGF and VEGFR inhibitors. These therapeutic options may be a prominent step along with the modern targeting and immune therapies for better coverage of pathological processes leading to melanoma progression and therapy resistance.
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Affiliation(s)
- Mohammad Malekan
- Student Research Committee, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.
| | | | - Ghasem Rahmatpour Rokni
- Department of Dermatology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Nasim Gholizadeh
- Department of Dermatology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Mohammad Ali Ebrahimzadeh
- Pharmaceutical Sciences Research Center, School of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran
| | - Armaghan Kazeminejad
- Department of Dermatology, Antimicrobial Resistance Research Center, Communicable Diseases Institute, Mazandaran University of Medical Sciences,Sari, Iran
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Cazzato G, Ingravallo G, Ribatti D. Angiogenesis Still Plays a Crucial Role in Human Melanoma Progression. Cancers (Basel) 2024; 16:1794. [PMID: 38791873 PMCID: PMC11120419 DOI: 10.3390/cancers16101794] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Revised: 05/03/2024] [Accepted: 05/06/2024] [Indexed: 05/26/2024] Open
Abstract
Angiogenesis plays a pivotal role in tumor progression, particularly in melanoma, the deadliest form of skin cancer. This review synthesizes current knowledge on the intricate interplay between angiogenesis and tumor microenvironment (TME) in melanoma progression. Pro-angiogenic factors, including VEGF, PlGF, FGF-2, IL-8, Ang, TGF-β, PDGF, integrins, MMPs, and PAF, modulate angiogenesis and contribute to melanoma metastasis. Additionally, cells within the TME, such as cancer-associated fibroblasts, mast cells, and melanoma-associated macrophages, influence tumor angiogenesis and progression. Anti-angiogenic therapies, while showing promise, face challenges such as drug resistance and tumor-induced activation of alternative angiogenic pathways. Rational combinations of anti-angiogenic agents and immunotherapies are being explored to overcome resistance. Biomarker identification for treatment response remains crucial for personalized therapies. This review highlights the complexity of angiogenesis in melanoma and underscores the need for innovative therapeutic approaches tailored to the dynamic TME.
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Affiliation(s)
- Gerardo Cazzato
- Section of Molecular Pathology, Department of Precision and Regenerative Medicine and Ionian Area (DiMePRe-J), University of Bari “Aldo Moro”, 70124 Bari, Italy;
| | - Giuseppe Ingravallo
- Section of Molecular Pathology, Department of Precision and Regenerative Medicine and Ionian Area (DiMePRe-J), University of Bari “Aldo Moro”, 70124 Bari, Italy;
| | - Domenico Ribatti
- Department of Translational Biomedicine and Neuroscience, University of Bari Medical School, 70124 Bari, Italy;
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Blasko F, Horvathova L. The relationship between the tumor and its innervation: historical, methodical, morphological, and functional assessments - A minireview. Endocr Regul 2024; 58:68-82. [PMID: 38563296 DOI: 10.2478/enr-2024-0008] [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] [Indexed: 04/04/2024] Open
Abstract
The acceptance of the tumor as a non-isolated structure within the organism has opened a space for the study of a wide spectrum of potential direct and indirect interactions, not only between the tumor tissue and its vicinity, but also between the tumor and its macroenvironment, including the nervous system. Although several lines of evidence have implicated the nervous system in tumor growth and progression, for many years, researchers believed that tumors lacked innervation and the notion of indirect neuro-neoplastic interactions via other systems (e.g., immune, or endocrine) predominated. The original idea that tumors are supplied not only by blood and lymphatic vessels, but also autonomic and sensory nerves that may influence cancer progression, is not a recent phenomenon. Although in the past, mainly due to the insufficiently sensitive methodological approaches, opinions regarding the presence of nerves in tumors were inconsistent. However, data from the last decade have shown that tumors are able to stimulate the formation of their own innervation by processes called neo-neurogenesis and neo-axonogenesis. It has also been shown that tumor infiltrating nerves are not a passive, but active components of the tumor microenvironment and their presence in the tumor tissue is associated with an aggressive tumor phenotype and correlates with poor prognosis. The aim of the present review was to 1) summarize the available knowledge regarding the course of tumor innervation, 2) present the potential mechanisms and pathways for the possible induction of new nerve fibers into the tumor microenvironment, and 3) highlight the functional significance/consequences of the nerves infiltrating the tumors.
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Affiliation(s)
- Filip Blasko
- Institute of Experimental Endocrinology, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovakia
- Institute of Physiology, Faculty of Medicine, Comenius University Bratislava, Bratislava, Slovakia
| | - Lubica Horvathova
- Institute of Experimental Endocrinology, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovakia
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Barricklow Z, DiVincenzo MJ, Angell CD, Carson WE. Ulcerated Cutaneous Melanoma: A Review of the Clinical, Histologic, and Molecular Features Associated with a Clinically Aggressive Histologic Phenotype. Clin Cosmet Investig Dermatol 2022; 15:1743-1757. [PMID: 36065342 PMCID: PMC9440663 DOI: 10.2147/ccid.s372287] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2022] [Accepted: 08/02/2022] [Indexed: 12/05/2022]
Abstract
The presence of ulceration in melanoma is associated with poor clinical outcomes and is the third most powerful predictor of survival in the AJCC Melanoma Staging System after tumor thickness and mitotic activity. The aggressive biological behavior associated with ulceration has been hypothesized to be the result of an intrinsic biological attribute that favors dissemination and presents locally with the loss of epidermal integrity. Among the features of ulcerated melanoma, many show promise as potential prognostic tools, markers of differential immunogenicity and indicators of oncogenic drivers of invasion and metastasis. The incidence of ulcerated melanoma is greater in males, increases with age and with systemic inflammatory risk factors (diabetes, smoking, low vitamin D, elevated body mass index). Patients with ulcerated primary tumors seem to exclusively benefit from adjuvant interferon (IFN) therapy, which is likely the consequence of an altered tumor microenvironment. When ulceration is present, there is a higher density of macrophages and dendritic cells and enhanced expression of pro-inflammatory cytokines, such as IL-6. There is also an increased expression of proteins involved in tumor antigen presentation in ulcerated melanomas. Histologically, vascular density, vasculogenic mimicry and angiotropism are all significantly correlated with ulceration in melanoma. The presence of ulceration is associated with reduced protein expression of E-cadherin and PTEN and elevated levels of N-cadherin and the matrix metalloproteinases. Differential microRNA expression also holds promise as a potential prognostic biomarker of malignancy and disease spread within the setting of ulceration. However, the molecular and cellular differences associated with the ulcerated state are complex and further study will aid in determining how these differences can be harnessed to improve care for patients with melanoma.
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Affiliation(s)
- Zoe Barricklow
- The Arthur G. James Cancer Hospital and Solove Research Institute, The Ohio, State University, Columbus, OH, USA
| | - Mallory J DiVincenzo
- The Arthur G. James Cancer Hospital and Solove Research Institute, The Ohio, State University, Columbus, OH, USA
- Department of Veterinary Biosciences, The Ohio State University, Columbus, OH, USA
| | - Colin D Angell
- The Arthur G. James Cancer Hospital and Solove Research Institute, The Ohio, State University, Columbus, OH, USA
| | - William E Carson
- The Arthur G. James Cancer Hospital and Solove Research Institute, The Ohio, State University, Columbus, OH, USA
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Lai PY, Shih TY, Chang YH, Chou YS, Wu TH, Su YY, Chang CH, Kuo WC. In Vivo Longitudinal Tracking of Lymphangiogenesis and Angiogenesis in Cutaneous Melanoma Mouse Model Using Multifunctional Optical Coherence Tomography. JID INNOVATIONS 2021; 1:100010. [PMID: 34909714 PMCID: PMC8659800 DOI: 10.1016/j.xjidi.2021.100010] [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: 11/02/2020] [Revised: 02/12/2021] [Accepted: 02/15/2021] [Indexed: 11/24/2022] Open
Abstract
Melanoma is a high-risk skin cancer because it tends to metastasize early and ultimately leads to death. In this study, we introduced a noninvasive multifunctional optical coherence tomography (MFOCT) for the early detection of premetastatic pathogenesis in cutaneous melanoma by label-free imaging of microstructures (i.e., providing the thickness and the scattering information) and microcirculation (i.e., providing depth-resolved angiography and lymphangiography). Using MFOCT-based approaches, we presented an in vivo longitudinal observation of the tumor microenvironment in BrafV600E/V600E;Pten−/− mice with inducible melanoma monitored for 42 days. Quantitative analysis of MFOCT images identified an increased number of lymphatic and vascular vessels during tumor progression and faster lymphangiogenesis (beginning on day 21) than angiogenesis (beginning on day 28) in the melanoma microenvironment. We further observed lymphatic vessel enlargement from the first week of melanoma development, implying tumor cells interacting with the vessels and increased likelihood of metastasis. MFOCT identified cutaneous melanoma‒associated angiogenesis and lymphangiogenesis before the possible visual perception of the tumor (≥42 days) and before metastasis could be diagnosed using micropositron emission tomography (35 days). Thus, the proposed quantitative analysis using MFOCT has the potential for early detection of cutaneous melanoma progression or prediction of metastatic melanoma in a mouse model. However, retrospective and extensive experiments still need to be performed in the future to confirm the value of MFOCT in clinical application.
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Affiliation(s)
- Pei-Yu Lai
- Institute of Biophotonics, National Yang Ming Chiao Tung University, Taipei, Taiwan.,Institute of Biophotonics, National Yang-Ming University, Taipei, Taiwan
| | - Tai-Yu Shih
- Institute of Biophotonics, National Yang Ming Chiao Tung University, Taipei, Taiwan.,Institute of Biophotonics, National Yang-Ming University, Taipei, Taiwan
| | - Yu-Huan Chang
- Institute of Biophotonics, National Yang Ming Chiao Tung University, Taipei, Taiwan.,Institute of Biophotonics, National Yang-Ming University, Taipei, Taiwan
| | - Ya-Shuan Chou
- Skin Institute, Hualien Tzu Chi Hospital, Hualien, Taiwan.,Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ting-Hua Wu
- Skin Institute, Hualien Tzu Chi Hospital, Hualien, Taiwan
| | - Yu-Ya Su
- Skin Institute, Hualien Tzu Chi Hospital, Hualien, Taiwan.,Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chung-Hsing Chang
- Skin Institute, Hualien Tzu Chi Hospital, Hualien, Taiwan.,Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan.,Institute of Medical Sciences, Tzu Chi University, Hualien, Taiwan.,Research Center for Applied Sciences, Academia Sinica, Taipei, Taiwan
| | - Wen-Chuan Kuo
- Institute of Biophotonics, National Yang Ming Chiao Tung University, Taipei, Taiwan.,Institute of Biophotonics, National Yang-Ming University, Taipei, Taiwan
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Kulwatno J, Gearhart J, Gong X, Herzog N, Getzin M, Skobe M, Mills KL. Growth of tumor emboli within a vessel model reveals dependence on the magnitude of mechanical constraint. Integr Biol (Camb) 2021; 13:1-16. [PMID: 33443535 DOI: 10.1093/intbio/zyaa024] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Revised: 09/02/2020] [Accepted: 12/03/2020] [Indexed: 01/18/2023]
Abstract
Tumor emboli-aggregates of tumor cells within vessels-pose a clinical challenge as they are associated with increased metastasis and tumor recurrence. When growing within a vessel, tumor emboli are subject to a unique mechanical constraint provided by the tubular geometry of the vessel. Current models of tumor emboli use unconstrained multicellular tumor spheroids, which neglect this mechanical interplay. Here, we modeled a lymphatic vessel as a 200 μm-diameter channel in either a stiff or soft, bioinert agarose matrix to create a vessel-like constraint model (VLCM), and we modeled colon or breast cancer tumor emboli with aggregates of HCT116 or SUM149PT cells, respectively. The stiff matrix VLCM constrained the tumor emboli to the cylindrical channel, which led to continuous growth of the emboli, in contrast to the growth rate reduction that unconstrained spheroids exhibit. Emboli morphology in the soft matrix VLCM, however, was dependent on the magnitude of mechanical mismatch between the matrix and the cell aggregates. In general, when the elastic modulus of the matrix of the VLCM was greater than the emboli (EVLCM/Eemb > 1), the emboli were constrained to grow within the channel, and when the elastic modulus of the matrix was less than the emboli (0 < EVLCM/Eemb < 1), the emboli bulged into the matrix. Due to a large difference in myosin II expression between the cell lines, we hypothesized that tumor cell aggregate stiffness is an indicator of cellular force-generating capability. Inhibitors of myosin-related force generation decreased the elastic modulus and/or increased the stress relaxation of the tumor cell aggregates, effectively increasing the mechanical mismatch. The increased mechanical mismatch after drug treatment was correlated with increased confinement of tumor emboli growth along the channel, which may translate to increased tumor burden due to the increased tumor volume within the diffusion distance of nutrients and oxygen.
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Affiliation(s)
- Jonathan Kulwatno
- Department of Biomedical Engineering, Rensselaer Polytechnic Institute, Troy, NY, USA.,Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY, USA
| | - Jamie Gearhart
- Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY, USA.,Department of Mechanical, Aerospace, and Nuclear Engineering, Rensselaer Polytechnic Institute, Troy, NY, USA
| | - Xiangyu Gong
- Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY, USA.,Department of Mechanical, Aerospace, and Nuclear Engineering, Rensselaer Polytechnic Institute, Troy, NY, USA
| | - Nora Herzog
- Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY, USA.,Department of Mechanical, Aerospace, and Nuclear Engineering, Rensselaer Polytechnic Institute, Troy, NY, USA
| | - Matthew Getzin
- Department of Biomedical Engineering, Rensselaer Polytechnic Institute, Troy, NY, USA.,Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY, USA
| | - Mihaela Skobe
- Department of Oncological Sciences & Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Kristen L Mills
- Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY, USA.,Department of Mechanical, Aerospace, and Nuclear Engineering, Rensselaer Polytechnic Institute, Troy, NY, USA
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Špirić Z, Vještica M, Erić M. Survival prediction in patients with cutaneous melanoma by tumour lymphangiogenesis. Acta Clin Belg 2020; 75:379-387. [PMID: 31210586 DOI: 10.1080/17843286.2019.1629076] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
Objectives: Melanoma induces lymphangiogenesis by secreting lymphangiogenic growth factors. The aim of this study was to examine the role of tumour lymphangiogenesis in survival of patients with cutaneous melanoma. Methods: Immunostaining of one hundred melanoma specimens was done with lymphatic-specific antibody D2-40. The quantification of tumour lymphangiogenesis - lymphatic vessel density (LVD) and lymphatic vessel area (LVA) - was calculated by computer-assisted morphometric analysis. Results: High intratumoural LVD, high peritumoural LVD, male gender, greater tumour thickness and Clark level IV/V were significantly associated with shorter disease-free survival (p= 0.001, p= 0.004, p= 0.004, p= 0.000 and p= 0.008, respectively) and melanoma-specific survival (p= 0.002, p= 0.002, p= 0.001, p= 0.000 and p= 0.017, respectively), while the trunk melanoma site was significantly associated only with shorter disease-free survival (p= 0.033). No significant association of LVA with survival was found. At multivariate analysis, peritumoural LVD [hazard ratio (HR) = 2.143, 95% confidence interval (CI) 1.097-4.189, p= 0.026)] and melanoma thickness (HR = 1.276, 95%CI 1.106-1.473, p= 0.001) were independent predictors of disease-free survival, while intratumoural LVD (HR = 3.446, 95%CI 1.465-8.109, p= 0.005), peritumoural LVD (HR = 2.742, 95%CI 1.313-5.725, p= 0.007) and gender (HR = 2.880, 95%CI 1.304-6.362, p= 0.009) were independent predictors of melanoma-specific survival. Conclusion: Тhis study shows that LVD enables better prediction of survival than melanoma thickness and other clinical-pathological parameters. Intratumoural LVD is the most significant predictor of melanoma-specific survival, while only peritumoural LVD has a significant impact on both, a disease-free survival and a melanoma-specific survival.
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Affiliation(s)
- Zorica Špirić
- Department of Nuclear Medicine and Thyroid Gland Diseases, University Clinical Centre of the Republic of Srpska, Banja Luka, Republic of Srpska, Bosnia and Herzegovina
| | - Milka Vještica
- Department of Oncology, University Clinical Centre of the Republic of Srpska, Banja Luka, Republic of Srpska, Bosnia and Herzegovina
| | - Mirela Erić
- Department of Anatomy, Faculty of Medicine, University of Novi Sad, Novi Sad, Serbia
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Meireson A, Devos M, Brochez L. IDO Expression in Cancer: Different Compartment, Different Functionality? Front Immunol 2020; 11:531491. [PMID: 33072086 PMCID: PMC7541907 DOI: 10.3389/fimmu.2020.531491] [Citation(s) in RCA: 132] [Impact Index Per Article: 26.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Accepted: 08/25/2020] [Indexed: 12/11/2022] Open
Abstract
Indoleamine 2,3-dioxygenase 1 (IDO1) is a cytosolic haem-containing enzyme involved in the degradation of tryptophan to kynurenine. Although initially thought to be solely implicated in the modulation of innate immune responses during infection, subsequent discoveries demonstrated IDO1 as a mechanism of acquired immune tolerance. In cancer, IDO1 expression/activity has been observed in tumor cells as well as in the tumor-surrounding stroma, which is composed of endothelial cells, immune cells, fibroblasts, and mesenchymal cells. IDO1 expression/activity has also been reported in the peripheral blood. This manuscript reviews available data on IDO1 expression, mechanisms of its induction, and its function in cancer for each of these compartments. In-depth study of the biological function of IDO1 according to the expressing (tumor) cell can help to understand if and when IDO1 inhibition can play a role in cancer therapy.
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Affiliation(s)
- Annabel Meireson
- Department of Dermatology, Ghent University Hospital, Ghent, Belgium.,Cancer Research Institute Ghent, Ghent, Belgium
| | - Michael Devos
- Department of Dermatology, Ghent University Hospital, Ghent, Belgium
| | - Lieve Brochez
- Department of Dermatology, Ghent University Hospital, Ghent, Belgium.,Cancer Research Institute Ghent, Ghent, Belgium
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10
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Vesci L, Carollo V, Rosi A, De Santis R. Therapeutic efficacy of intra-tumor AvidinOX and low systemic dose biotinylated cetuximab, with and without cisplatin, in an orthotopic model of head and neck cancer. Oncol Lett 2019; 17:3529-3536. [PMID: 30867794 DOI: 10.3892/ol.2019.10003] [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: 07/19/2018] [Accepted: 01/17/2019] [Indexed: 11/05/2022] Open
Abstract
In a previous study, the efficacy of low intraperitoneal doses of biotinylated cetuximab (bCet) in mice with subcutaneous tumor xenografts of human head and neck cancer (HNC) treated intra-tumors with AvidinOX was reported. Taking into account that the current standard treatment for HNC is the combination of cetuximab and cisplatin, the present study investigated the activity of AvidinOX-targeted bCet with and without cisplatin in an orthotopic model. The results confirmed that administration of intra-tumor AvidinOX makes an otherwise inactive dose of bCet effective in reducing tumor growth, and the addition of a low dose of cisplatin further improved tumor growth inhibition. Supporting the in vivo data, immunohistochemical staining of tumor masses from mice treated with AvidinOX, bCet and cisplatin exhibited the highest tumor cell damage and the lowest angiogenic activity among all treatment groups, measured as the number of γ-H2A.X and cleaved caspase-3-positive cells, and vascular endothelial growth factor-C and platelet and endothelial cell adhesion molecule 1-positive cells, respectively. AvidinOX is currently under clinical investigation to assess its use in delivering radioactive biotin to inoperable tumor lesions (ClinicalTrials.gov: NCT02053324 and NCT03188328). The present study further supported the potential clinical use of AvidinOX to target low bCet doses to inoperable tumor lesions, with or without an additional low dose of cisplatin. Since low doses of highly expensive monoclonal antibodies become effective with AvidinOX and low dose cisplatin, such therapies promise to be cheaper and less toxic than current treatments.
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Affiliation(s)
- Loredana Vesci
- Biotechnology R&D, Alfasigma S.p.A., Pomezia, I-00071 Rome, Italy
| | | | - Antonio Rosi
- Biotechnology R&D, Alfasigma S.p.A., Pomezia, I-00071 Rome, Italy
| | - Rita De Santis
- Biotechnology R&D, Alfasigma S.p.A., Pomezia, I-00071 Rome, Italy
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11
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Seyed Jafari SM, Wiedmer C, Cazzaniga S, Frangež Ž, Shafighi M, Beltraminelli H, Weber B, Simon HU, Hunger RE. Correlation of Vascular Endothelial Growth Factor subtypes and their receptors with melanoma progression: A next-generation Tissue Microarray (ngTMA) automated analysis. PLoS One 2018; 13:e0207019. [PMID: 30408085 PMCID: PMC6224082 DOI: 10.1371/journal.pone.0207019] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2018] [Accepted: 10/22/2018] [Indexed: 12/25/2022] Open
Abstract
INTRODUCTION Finding new markers to assess prognosis of melanoma without the necessity to perform a surgical interventions is an important goal in melanoma research. The current study aimed to assess the correlation of clinical course and prognosis of primary and metastatic melanoma with expression of VEGF family and their receptors. METHODS A ngTMA block was made from the randomly selected paraffin tissue blocks of the patients with melanocytic nevi, primary and metastatic melanoma. Then sections cut from ngTMA-block were immunohistochemically stained with proper antibodies. Expression of these proteins was investigated using automated image analysis and compared among the study groups. RESULTS We analyzed the tissue of 238 patients with following diagnoses: 101 (42.4%) with a diagnosis of nevus, 86 (36.1%) Malignant melanoma and 51 (21.4%) metastasis. Median follow-up time for the malignant lesions was 5.71 years. Among the tested antigen, VEGF-C (p = 0.016), VEGF-R2 (p<0.001) and VEGF-R3 (p = 0.002) were significantly higher expressed in the metastatic tissues. When these scores were assessed in multiple regression models, the only independent factor linked to patient's diagnosis was VEGF-R2 (p<0.001). In addition, groups of highly correlated variables (VEGF-C and VEGF-R3, VEGF-A and VEGF-R1) were found to form separate sub-clusters. On the other side, high values of VEGF-C were associated with both overall and disease-free survival with a statically significant HR of 2.76 (95% CI: 1.27, 5.98; p = 0.01) and 2.82 (95%CI: 1.62, 4.91; p<0.001), respectively. CONCLUSIONS This study shows that VEGF-C and VEGF-R2 might represent new prognostic marker in MM. However, further prospective studies are warranted to test their real efficacy as a prognostic marker.
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Affiliation(s)
- S. Morteza Seyed Jafari
- Department of Dermatology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
- * E-mail:
| | - Christina Wiedmer
- Department of Dermatology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Simone Cazzaniga
- Department of Dermatology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
- Centro Studi GISED, Bergamo, Italy
| | - Živa Frangež
- Institute of Pharmacology, University of Bern, Bern, Switzerland
| | - Maziar Shafighi
- Department of Biomedical Research, University of Bern, Bern, Switzerland
| | - Helmut Beltraminelli
- Department of Dermatology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Benedikt Weber
- Department of Dermatology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
- Department of Dermatology, Medical University of Vienna, Vienna, Austria
| | - Hans-Uwe Simon
- Institute of Pharmacology, University of Bern, Bern, Switzerland
| | - Robert E. Hunger
- Department of Dermatology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
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12
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Potez M, Trappetti V, Bouchet A, Fernandez-Palomo C, Güç E, Kilarski WW, Hlushchuk R, Laissue J, Djonov V. Characterization of a B16-F10 melanoma model locally implanted into the ear pinnae of C57BL/6 mice. PLoS One 2018; 13:e0206693. [PMID: 30395629 PMCID: PMC6218054 DOI: 10.1371/journal.pone.0206693] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2018] [Accepted: 10/17/2018] [Indexed: 01/15/2023] Open
Abstract
The common experimental use of B16-F10 melanoma cells focuses on exploring their metastatic potential following intravenous injection into mice. In this study, B16-F10 cells are used to develop a primary tumor model by implanting them directly into the ears of C57BL/6J mice. The model represents a reproducible and easily traceable tool for local tumor growth and for making additional in vivo observations, due to the localization of the tumors. This model is relatively simple and involves (i) surgical opening of the ear skin, (ii) removal of a square-piece of cartilage followed by (iii) the implantation of tumor cells with fibrin gel. The remodeling of the fibrin gel within the cartilage chamber, accompanying tumor proliferation, results in the formation of blood vessels, lymphatics and tissue matrix that can be readily distinguished from the pre-existing skin structures. Moreover, this method avoids the injection-enforced artificial spread of cells into the pre-existing lymphatic vessels. The tumors have a highly reproducible exponential growth pattern with a tumor doubling time of around 1.8 days, reaching an average volume of 85mm3 16 days after implantation. The melanomas are densely cellular with proliferative indices of between 60 and 80%. The induced angiogenesis and lymphangiogenesis resulted in the development of well-vascularized tumors. Different populations of immunologically active cells were also present in the tumor; the population of macrophages decreases with time while the population of T cells remained quasi constant. The B16-F10 tumors in the ear frequently metastasized to the cervical lymph nodes, reaching an incidence of 75% by day 16. This newly introduced B16-F10 melanoma model in the ear is a powerful tool that provides a new opportunity to study the local tumor growth and metastasis, the associated angiogenesis, lymphangiogenesis and tumor immune responses. It could potentially be used to test different treatment strategies.
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Affiliation(s)
- Marine Potez
- Institute of Anatomy, University of Bern, Bern, Switzerland
| | | | - Audrey Bouchet
- Institute of Anatomy, University of Bern, Bern, Switzerland
| | | | - Esra Güç
- Institute of Bioengineering and Swiss Institute for Experimental Cancer Research, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
| | - Witold W. Kilarski
- Institute of Bioengineering and Swiss Institute for Experimental Cancer Research, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
| | | | - Jean Laissue
- Institute of Anatomy, University of Bern, Bern, Switzerland
| | - Valentin Djonov
- Institute of Anatomy, University of Bern, Bern, Switzerland
- * E-mail:
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13
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Liao S, Bouta EM, Morris LM, Jones D, Jain RK, Padera TP. Inducible Nitric Oxide Synthase and CD11b +Gr1 + Cells Impair Lymphatic Contraction of Tumor-Draining Lymphatic Vessels. Lymphat Res Biol 2018; 17:294-300. [PMID: 30358484 DOI: 10.1089/lrb.2018.0013] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
Background: Metastatic tumor cells spread through lymphatic vessels and colonize draining lymph nodes (LNs). It is known that tumors induce lymphangiogenesis to enhance lymphatic metastasis and that metastatic cancer cells are carried by lymph flow to LNs. Methods and Results: Here, we investigated the molecular and cellular regulation of collecting lymphatic vessel contraction in vessels draining a metastatic tumor using intravital microscopy. In tumor-draining collecting lymphatic vessels, we found vessel contraction was suppressed. The infiltration of peritumor tissue by inducible nitric oxide synthase positive and CD11b+Gr1+ myeloid cells played a critical role in the suppression of lymphatic contraction. Depletion of Gr1+ cells with an anti-Gr1 antibody improved contraction of tumor-draining lymphatic vessels. In addition, inducing tumor cell death restored lymphatic contraction in nude mice. Conclusions: These findings indicate that tumors contribute to regulation of lymphatic transport in a reversible manner, warranting further investigation into the role of impaired lymphatic transport in cancer progression.
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Affiliation(s)
- Shan Liao
- 1 Edwin L. Steele Laboratory, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Echoe M Bouta
- 1 Edwin L. Steele Laboratory, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Linda M Morris
- 1 Edwin L. Steele Laboratory, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Dennis Jones
- 1 Edwin L. Steele Laboratory, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Rakesh K Jain
- 1 Edwin L. Steele Laboratory, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Timothy P Padera
- 1 Edwin L. Steele Laboratory, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
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14
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Bordry N, Broggi MAS, de Jonge K, Schaeuble K, Gannon PO, Foukas PG, Danenberg E, Romano E, Baumgaertner P, Fankhauser M, Wald N, Cagnon L, Abed-Maillard S, Maby-El Hajjami H, Murray T, Ioannidou K, Letovanec I, Yan P, Michielin O, Matter M, Swartz MA, Speiser DE. Lymphatic vessel density is associated with CD8 + T cell infiltration and immunosuppressive factors in human melanoma. Oncoimmunology 2018; 7:e1462878. [PMID: 30221058 PMCID: PMC6136869 DOI: 10.1080/2162402x.2018.1462878] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2017] [Revised: 02/25/2018] [Accepted: 03/13/2018] [Indexed: 12/11/2022] Open
Abstract
Increased density of tumor-associated lymphatic vessels correlates with poor patient survival in melanoma and other cancers, yet lymphatic drainage is essential for initiating an immune response. Here we asked whether and how lymphatic vessel density (LVD) correlates with immune cell infiltration in primary tumors and lymph nodes (LNs) from patients with cutaneous melanoma. Using immunohistochemistry and quantitative image analysis, we found significant positive correlations between LVD and CD8+ T cell infiltration as well as expression of the immunosuppressive molecules inducible nitric oxide synthase (iNOS) and 2,3-dioxygénase (IDO). Interestingly, similar associations were seen in tumor-free LNs adjacent to metastatic ones, indicating loco-regional effects of tumors. Our data suggest that lymphatic vessels play multiple roles at tumor sites and LNs, promoting both T cell infiltration and adaptive immunosuppressive mechanisms. Lymph vessel associated T cell infiltration may increase immunotherapy success rates provided that the treatment overcomes adaptive immune resistance.
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Affiliation(s)
- Natacha Bordry
- Clinical Tumor Biology and Immunotherapy Group, Department of Oncology and Ludwig Cancer Research, University of Lausanne (UNIL), Lausanne, Switzerland
- Institute of Bioengineering and Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
| | - Maria A. S. Broggi
- Institute of Bioengineering and Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
- Institute for Molecular Engineering, University of Chicago, Chicago, IL, USA
| | - Kaat de Jonge
- Clinical Tumor Biology and Immunotherapy Group, Department of Oncology and Ludwig Cancer Research, University of Lausanne (UNIL), Lausanne, Switzerland
| | - Karin Schaeuble
- Clinical Tumor Biology and Immunotherapy Group, Department of Oncology and Ludwig Cancer Research, University of Lausanne (UNIL), Lausanne, Switzerland
| | - Philippe O. Gannon
- Department of Oncology, Lausanne University Hospital Center (CHUV) and University of Lausanne, Lausanne, Switzerland
| | - Periklis G. Foukas
- Department of Oncology, Lausanne University Hospital Center (CHUV) and University of Lausanne, Lausanne, Switzerland
- Department of Surgery, CHUV, Lausanne, Switzerland
| | - Esther Danenberg
- Department of Oncology, Lausanne University Hospital Center (CHUV) and University of Lausanne, Lausanne, Switzerland
| | - Emanuela Romano
- Department of Oncology, Lausanne University Hospital Center (CHUV) and University of Lausanne, Lausanne, Switzerland
- Department of Oncology, INSERM U932, Institut Curie, Paris, FRANCE
| | - Petra Baumgaertner
- Clinical Tumor Biology and Immunotherapy Group, Department of Oncology and Ludwig Cancer Research, University of Lausanne (UNIL), Lausanne, Switzerland
- Department of Oncology, Lausanne University Hospital Center (CHUV) and University of Lausanne, Lausanne, Switzerland
| | - Manuel Fankhauser
- Institute of Bioengineering and Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
| | - Noémie Wald
- Clinical Tumor Biology and Immunotherapy Group, Department of Oncology and Ludwig Cancer Research, University of Lausanne (UNIL), Lausanne, Switzerland
| | - Laurène Cagnon
- Department of Oncology, Lausanne University Hospital Center (CHUV) and University of Lausanne, Lausanne, Switzerland
| | - Samia Abed-Maillard
- Department of Oncology, Lausanne University Hospital Center (CHUV) and University of Lausanne, Lausanne, Switzerland
| | - Hélène Maby-El Hajjami
- Clinical Tumor Biology and Immunotherapy Group, Department of Oncology and Ludwig Cancer Research, University of Lausanne (UNIL), Lausanne, Switzerland
| | - Timothy Murray
- Clinical Tumor Biology and Immunotherapy Group, Department of Oncology and Ludwig Cancer Research, University of Lausanne (UNIL), Lausanne, Switzerland
| | - Kalliopi Ioannidou
- Clinical Tumor Biology and Immunotherapy Group, Department of Oncology and Ludwig Cancer Research, University of Lausanne (UNIL), Lausanne, Switzerland
| | | | - Pu Yan
- Department of Pathology, CHUV, Lausanne, Switzerland
| | - Olivier Michielin
- Department of Oncology, Lausanne University Hospital Center (CHUV) and University of Lausanne, Lausanne, Switzerland
| | - Maurice Matter
- Department of Oncology, Lausanne University Hospital Center (CHUV) and University of Lausanne, Lausanne, Switzerland
- Department of Surgery, CHUV, Lausanne, Switzerland
| | - Melody A. Swartz
- Institute of Bioengineering and Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
- 2nd Department of Pathology, Attikon University Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Daniel E. Speiser
- Clinical Tumor Biology and Immunotherapy Group, Department of Oncology and Ludwig Cancer Research, University of Lausanne (UNIL), Lausanne, Switzerland
- Department of Oncology, Lausanne University Hospital Center (CHUV) and University of Lausanne, Lausanne, Switzerland
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15
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Fujiwara M, Suzuki T, Kasuya A, Shimauchi T, Fukamizu H, Tokura Y. Lymphatic transit rate as a predictive parameter for nodal metastasis in primary limb malignant melanoma. J Dermatol Sci 2018; 90:27-34. [PMID: 29289416 DOI: 10.1016/j.jdermsci.2017.12.013] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2017] [Revised: 12/02/2017] [Accepted: 12/20/2017] [Indexed: 12/24/2022]
Abstract
BACKGROUND The status of sentinel lymph node (SLN) is one of the most predictive prognostic factors in patients with clinically localized malignant melanomas (MMs). However, since the positive SLN metastatic rate is as low as 20%, it is desirable to minimize SLN biopsy performance with imaging. By dynamic lymphoscintigraphy, we have proposed the lymphatic transit rate (LTR), the value that the distance between the primary lesion and SLN is divided by scintigraphic saturation time. LTR represents the scintigraphic saturation velocity and can be used for evaluation of metastasis of skin cancers. METHODS Dynamic lymphoscintigraphy data from 36 lymph nodes in 36 patients with primary MM on the limb were analyzed. The initial sites of the MMs were the lower limb in 24 patients and the upper limb in 12 patients. Histopathologically, nodal metastasis was found in 10 patients. RESULTS In the lower limb MM, the mean LTRs were 3.49 cm/min in histologically non-metastatic SLNs and 4.49 cm/min in histologically metastatic SLNs (P = 0.0056). In the upper limb MM, the mean LTRs were 2.59 cm/min in non-metastatic SLNs and 3.94 cm/min in metastatic SLNs (P = 0.0162). Thus, significantly higher LTRs were obtained in the metastatic SLNs. All SLNs with LTR < 4.0 cm/min in the lower limb MM and those with LTR < 3.0 cm/min in the upper limb MM were non-metastatic. CONCLUSION LTR is a useful predictive indicator for nodal metastasis and SLN biopsy performance in MMs.
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Affiliation(s)
- Masao Fujiwara
- Department of Plastic and Reconstructive Surgery, Hamamatsu University School of Medicine, Hamamatsu, Japan.
| | - Takahiro Suzuki
- Department of Dermatology, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Akira Kasuya
- Department of Dermatology, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Takatoshi Shimauchi
- Department of Dermatology, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Hidekazu Fukamizu
- Department of Plastic and Reconstructive Surgery, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Yoshiki Tokura
- Department of Dermatology, Hamamatsu University School of Medicine, Hamamatsu, Japan
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Špirić Z, Eri Ž, Erić M. Lymphatic vessel density and VEGF-C expression as independent predictors of melanoma metastases. J Plast Reconstr Aesthet Surg 2017; 70:1653-1659. [PMID: 28756123 DOI: 10.1016/j.bjps.2017.06.040] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2017] [Accepted: 06/25/2017] [Indexed: 11/24/2022]
Abstract
INTRODUCTION In many patients, the clinical behaviour of cutaneous melanoma is very difficult to predict by traditional histologic and clinical parameters. This study aimed to examine the role of quantitative parameters of tumour lymphangiogenesis and vascular endothelial growth factor (VEGF)-C in predicting metastatic risk in patients with cutaneous melanoma. METHODS One hundred melanoma specimens were stained with lymphatic-specific antibody D2-40 and with anti-VEGF-C antibody. Quantitative parameters of lymphangiogenesis-lymphatic vessel density (LVD) and lymphatic vessel area (LVA)-were determined by computer-assisted morphometric analysis. Moderate or strong staining was assessed as a positive expression of VEGF-C in tumour cells. RESULTS Univariate analysis revealed that intratumoural LVD, peritumoural LVD, VEGF-C expression in tumour cells, melanoma thickness, Clark level, ulceration, gender and histologic type were significant predictors of lymph node metastasis (p = 0.000, p = 0.000, p = 0.000, p = 0.000, p = 0.005, p = 0.005, p = 0.011 and p = 0.027, respectively). No significant association of intratumoural and peritumoural LVA with metastases was found. In multivariate analysis, independent predictors of metastatic risks were melanoma thickness [odds ratio OR = 1.655, 95% confidence interval (CI) 1.102-2.484, p = 0.015], intratumoural LVD (OR = 1.086, 95% CI 1.027-1.148, p = 0.004), peritumoural LVD (OR = 1.050, 95% CI 1.008-1.094, p = 0.020) and a positive VEGF-C expression in tumour cells (OR = 20.337, 95% CI 2.579-160.350, p = 0.004). CONCLUSIONS This study identified intratumoural and peritumoural LVD and the VEGF-C expression in tumour cells as more significant predictors of metastatic risk than melanoma thickness, ulceration and other clinical-pathological parameters.
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Affiliation(s)
- Zorica Špirić
- Department of Nuclear Medicine and Thyroid Gland Diseases, University Clinical Centre of the Republic of Srpska, 12 Beba bb Street, 78 000, Banja Luka, Republic of Srpska, Bosnia and Herzegovina.
| | - Živka Eri
- Department of Pathology, Institute for Pulmonary Diseases of Vojvodina, Put Doktora Goldmana Street, 21 204, Sremska Kamenica, Serbia
| | - Mirela Erić
- Department of Anatomy, Faculty of Medicine, University of Novi Sad, Hajduk Veljkova 3 Street, 21 000, Novi Sad, Serbia
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17
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Han D, Thomas DC, Zager JS, Pockaj B, White RL, Leong SPL. Clinical utilities and biological characteristics of melanoma sentinel lymph nodes. World J Clin Oncol 2016; 7:174-188. [PMID: 27081640 PMCID: PMC4826963 DOI: 10.5306/wjco.v7.i2.174] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2015] [Revised: 12/05/2015] [Accepted: 02/16/2016] [Indexed: 02/06/2023] Open
Abstract
An estimated 73870 people will be diagnosed with melanoma in the United States in 2015, resulting in 9940 deaths. The majority of patients with cutaneous melanomas are cured with wide local excision. However, current evidence supports the use of sentinel lymph node biopsy (SLNB) given the 15%-20% of patients who harbor regional node metastasis. More importantly, the presence or absence of nodal micrometastases has been found to be the most important prognostic factor in early-stage melanoma, particularly in intermediate thickness melanoma. This review examines the development of SLNB for melanoma as a means to determine a patient’s nodal status, the efficacy of SLNB in patients with melanoma, and the biology of melanoma metastatic to sentinel lymph nodes. Prospective randomized trials have guided the development of practice guidelines for use of SLNB for melanoma and have shown the prognostic value of SLNB. Given the rapidly advancing molecular and surgical technologies, the technical aspects of diagnosis, identification, and management of regional lymph nodes in melanoma continues to evolve and to improve. Additionally, there is ongoing research examining both the role of SLNB for specific clinical scenarios and the ways to identify patients who may benefit from completion lymphadenectomy for a positive SLN. Until further data provides sufficient evidence to alter national consensus-based guidelines, SLNB with completion lymphadenectomy remains the standard of care for clinically node-negative patients found to have a positive SLN.
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18
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Pasquali S, Montesco MC, Ginanneschi C, Baroni G, Miracco C, Urso C, Mele F, Lombardi AR, Quaglino P, Cattaneo L, Staibano S, Botti G, Visca P, Zannoni M, Soda G, Corti B, Pilloni L, Anselmi L, Lissia A, Vannucchi M, Manieli C, Massi D. Lymphatic and blood vasculature in primary cutaneous melanomas of the scalp and neck. Head Neck 2015; 37:1596-602. [PMID: 24931916 DOI: 10.1002/hed.23801] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2014] [Revised: 04/12/2014] [Accepted: 06/11/2014] [Indexed: 01/07/2023] Open
Abstract
BACKGROUND Scalp/neck melanomas have a poor prognosis, possibly because of a rich vascular supply that prompts tumor cells' dissemination. METHODS We compared the accuracy of immunohistochemical (IHC) staining with morphology for the identification of lymphovascular invasion in 156 scalp/neck melanomas. We then analyzed the association of vessel invasion and density with pathological features and survival. RESULTS IHC-detected lymphatic vessel invasion (LVI) and blood vessel invasion (BVI) were identified in 34.6% and 13.5% of cases, respectively. IHC increased the LVI/BVI detection compared to morphology (40.4% vs 16.6%; p < .001). The degree of peritumoral and intratumoral blood vessel density (BVD) was greater than lymphatic vessel density (LVD). Ulceration was the only factor independently associated with intratumoral (p = .029) and peritumoral (p = .047) BVD. Tumor thickness was the only independent predictor of survival (p = .002). CONCLUSION IHC allows accurate assessment of lymphovascular invasion in scalp/neck melanomas. In these tumors, we observed a high incidence of BVI, which deserves further investigations.
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Affiliation(s)
- Sandro Pasquali
- Melanoma and Sarcomas Unit, Veneto Institute of Oncology, Padova, Italy
| | | | | | | | | | | | - Fabio Mele
- "Di Venere" and "San Paolo" Hospital, Bari, Italy
| | | | | | | | | | | | - Paolo Visca
- National Cancer Institute "Regina Elena,", Roma, Italy
| | - Marina Zannoni
- Azienda Ospedaliero Universitaria Integrata Verona, Verona, Italy
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Špirić Z, Erić M, Eri Ž, Skrobić M. Significantly high lymphatic vessel density in cutaneous metastasizing melanoma. Hippokratia 2015; 19:210-215. [PMID: 27418778 PMCID: PMC4938466] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/06/2023]
Abstract
BACKGROUND Cutaneous melanoma has the propensity to early metastatic spread via the lymphatic vessels. Recent studies have found a positive correlation between an increased number of tumor-associated lymphatics and lymph node metastasis. The aim of this study was to determine whether there was a difference in the lymphatic vessel density (LVD) when cutaneous metastasizing melanomas were compared with nonmetastasizing melanomas and nevi. METHODS Ninety-five melanoma specimens (45 with lymph node metastasis, 50 nonmetastasizing) and 22 nevi specimens (7 compound, 5 intradermal, 4 blue, and 6 dysplastic) were investigated by immunostaining for the lymphatic endothelial marker D2-40. The quantification of lymphatics was conducted by computer-assisted morphometric analysis. Metastasizing and nonmetastasizing melanoma specimens were matched according to their thickness into three classes ≤2.0 mm, 2.01 - 4.0 mm, >4.0 mm. RESULTS Metastasizing melanomas thick 2.01-4.0 mm and thicker than 4.0 mm, showed a significantly higher intratumoral and peritumoral LVD compared with nonmetastasizing melanomas (2.01-4.0 mm, p =0.006 and p =0.032, respectively; >4.0 mm, p =0.045 and p =0.026, respectively). No significant difference in intratumoral and peritumoral LVD was found between metastasizing and nonmetastasizing melanomas of thickness ≤2.0 mm. Metastasizing melanomas showed a significantly higher intratumoral LVD compared with compound, intradermal, blue and dysplastic nevi p <0.001, p =0.002, p =0.002 and p <0.001, respectively), and significantly higher peritumoral LVD compared with compound nevi (p=0.039). Total average LVD was significantly higher in metastasizing melanomas than in nonmetastasizing melanomas (p <0.001), compound, intradermal, blue and dysplastic nevi (p <0.001, p <0.001, p =0.001 and p <0.001, respectively). CONCLUSIONS This study shows higher LVD in metastasizing melanomas compared with nonmetastasizing melanomas and nevi. In melanomas with intermediate thickness and in thick melanomas, higher intratumoral and peritumoral LVD are significantly associated with lymph node metastasis. This finding suggests that LVD can be a useful marker for identifying melanomas which are at a higher risk for the metastasis development. Hippokratia 2015; 19 (3): 210-215.
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Affiliation(s)
- Z Špirić
- Department of Nuclear Medicine and Thyroid Diseases, Clinical Centre Banja Luka, Republic of Srpska, Bosnia and Herzegovina
| | - M Erić
- Department of Anatomy, Faculty of Medicine, University of Novi Sad, Novi Sad, Serbia
| | - Ž Eri
- Department of Pathology, Institute for Pulmonary Diseases of Vojvodina, Sremska Kamenica, Faculty of Medicine, University of Novi Sad, Novi Sad, Serbia
| | - M Skrobić
- Department of Nuclear Medicine, Faculty of Medicine, University of Banja Luka, Banja Luka, Republic of Srpska, Bosnia and Herzegovina
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20
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Špirić Z, Eri Ž, Erić M. Significance of Vascular Endothelial Growth Factor (VEGF)-C and VEGF-D in the Progression of Cutaneous Melanoma. Int J Surg Pathol 2015; 23:629-37. [PMID: 25911567 DOI: 10.1177/1066896915583694] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
INTRODUCTION Induction of tumor lymphangiogenesis by vascular endothelial growth factor (VEGF)-C and VEGF-D promotes metastasis in many human cancers. AIM The aim of this study was to examine the role of VEGF-C and VEGF-D in lymphangiogenesis and lymph node metastasis in patients with cutaneous melanoma. MATERIALS AND METHODS Fifty-four melanoma specimens (18 with lymph node metastasis, 36 nonmetastatic) were investigated by immunostaining for VEGF-C, VEGF-D, and for lymphatic endothelial marker D2-40. VEGF-C and VEGF-D expression was assessed as a percentage and intensity of stained tumor cells, tumor-associated macrophages and fibroblasts. The quantification of lymphangiogenesis was conducted by computer-assisted morphometric analysis. RESULTS The expressions of both VEGF-C and VEGF-D in tumor cells were significantly higher in lymph node metastatic melanomas compared with nonmetastatic melanomas (P = .015 VEGF-C; P = .005 VEGF-D). There was no statistically significant difference between metastatic and nonmetastatic melanomas regarding the expression of VEGF-C and VEGF-D in macrophages and fibroblasts. Metastatic melanomas showed a significantly higher intratumoral and peritumoral lymphatic vessel density (LVD) compared with nonmetastatic melanomas (P = .000 intratumoral, P = .000 peritumoral). Melanomas with VEGF-C positive tumor cells showed a significantly higher intratumoral and peritumoral LVD compared with VEGF-C negative tumor cells group of melanomas (P = .006 intratumoral, P = .010 peritumoral). VEGF-C expression in macrophages, fibroblasts, as well as VEGF-D expression in tumor cells, macrophages, and fibroblasts, showed no correlation with the intratumoral and peritumoral LVD. CONCLUSIONS Our findings show the significance of VEGF-C in tumor cells in the induction of intratumoral and peritumoral lymphangiogenesis. This study suggests that both VEGF-C and VEGF-D in tumor cells promote lymph node metastasis, and that the immunohistochemical analysis of expression can be a useful tool for predicting clinical behavior of cutaneous melanoma.
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Affiliation(s)
- Zorica Špirić
- Clinical Center of Banja Luka, Republic of Srpska, Bosnia and Herzegovina
| | - Živka Eri
- Faculty of Medicine, University of Novi Sad, Novi Sad, Serbia
| | - Mirela Erić
- Faculty of Medicine, University of Novi Sad, Novi Sad, Serbia
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Pastushenko I, Vermeulen PB, Carapeto FJ, Van den Eynden G, Rutten A, Ara M, Dirix LY, Van Laere S. Blood microvessel density, lymphatic microvessel density and lymphatic invasion in predicting melanoma metastases: systematic review and meta-analysis. Br J Dermatol 2015; 170:66-77. [PMID: 24134623 DOI: 10.1111/bjd.12688] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/11/2013] [Indexed: 02/06/2023]
Abstract
In malignant melanoma (MM) there is an urgent need to identify new markers with predictive value superior to the traditional clinical and histological parameters. Angiogenesis and lymphangiogenesis have been recognized as critical processes in tumour growth and metastasis development, and numerous studies have evaluated the significance of these parameters in predicting the prognosis in solid tumours, including MM. We set out to determine whether angiogenesis, lymphangiogenesis and lymphatic invasion (LI) are valuable prognostic markers in MM. We systematically reviewed the available literature and subsequently performed a meta-analysis on the compiled data. To be eligible for the systematic review, a study had to provide the microvessel density (MVD), the lymphatic vessel density (LVD) or information about LI, assessed by immunohistochemistry on the primary site in patients with MM. To be evaluable for the meta-analysis, a study also had to provide information on clinical outcome. We approached selected studies with the Reporting recommendations for tumour marker (REMARK) criteria, verifying whether they had followed the recommendations. In total, nine angiogenesis, seven lymphangiogenesis and 10 LI studies were included in our meta-analysis, representing 419, 474 and 802 patients, respectively. Using meta-analysis, we showed that peritumoral LVD and the presence of LI have prognostic value for patients with MM. In contrast, MVD and intratumoral LVD did not have prognostic value in these patients. LVD and LI seem to have prognostic value for patients with MM.
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Affiliation(s)
- I Pastushenko
- Department of Dermatology, Hospital Clínico Universitario 'Lozano Blesa', Calle San Juan Bosco 15, Zaragoza, 50009, Spain
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22
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Lymphangiogenesis: Implications for Diagnosis, Treatment, and Prognosis in Patients With Melanoma. ACTAS DERMO-SIFILIOGRAFICAS 2015. [DOI: 10.1016/j.adengl.2014.11.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
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23
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Malkan AD, Sandoval JA. Controversial tumors in pediatric surgical oncology. Curr Probl Surg 2014; 51:478-520. [PMID: 25524425 DOI: 10.1067/j.cpsurg.2014.11.004] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2014] [Accepted: 11/17/2014] [Indexed: 12/13/2022]
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24
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Dadras SS, Lin RJ, Razavi G, Kawakami A, Du J, Feige E, Milner DA, Loda MF, Granter SR, Detmar M, Widlund HR, Horstmann MA, Fisher DE. A novel role for microphthalmia-associated transcription factor-regulated pigment epithelium-derived factor during melanoma progression. THE AMERICAN JOURNAL OF PATHOLOGY 2014; 185:252-65. [PMID: 25447045 DOI: 10.1016/j.ajpath.2014.09.012] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/11/2014] [Revised: 09/03/2014] [Accepted: 09/05/2014] [Indexed: 10/24/2022]
Abstract
Microphthalmia-associated transcription factor (MITF) acts via pigment epithelium-derived factor (PEDF), an antiangiogenic protein, to regulate retinal pigment epithelium migration. PEDF expression and/or regulation during melanoma development have not been investigated previously. Using immunohistochemistry, we determined expression of PEDF in common and dysplastic melanocytic nevi, melanoma in situ, invasive melanoma, and metastatic melanoma (n = 102). PEDF expression was consistently decreased in invasive and metastatic melanoma, compared with nevi and melanoma in situ (P < 0.0001). PEDF was lost in thicker melanomas (P = 0.003), and correlated with depth of invasion (P = 0.003) and distant metastasis (P = 0.0331), but only marginally with mitotic index, AJCC stage, nodal metastasis, or blood vascular density (0.05 < P < 0.10). Quantitative real-time PCR and microarray analyses confirmed PEDF down-regulation at the mRNA level in several melanoma lines, compared with melanocytes. MITF positively correlated with PEDF expression in invasive melanomas (P = 0.0003). Searching for PEDF regulatory mechanisms revealed two occupied conserved E-boxes (DNA recognition elements) in the first intron of the human and mouse PEDF promoter regions, confirmed by binding assays. Dominant-negative and siRNA approaches in vivo demonstrated direct transcriptional influence of MITF on PEDF, establishing the PEDF gene (SERPINF1) as a MITF target in melanocytes and melanoma cells. These findings suggest that loss of PEDF expression promotes early invasive melanoma growth.
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Affiliation(s)
- Soheil S Dadras
- Cutaneous Biology Research Center and Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts.
| | - Richard J Lin
- Department of Pediatric Hematology/Oncology, Melanoma Program in Medical Oncology, Boston, Massachusetts
| | - Gita Razavi
- Department of Pathology, Stanford University School of Medicine, Stanford, California
| | - Akinori Kawakami
- Cutaneous Biology Research Center and Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts
| | - Jinyan Du
- Merrimack Pharmaceuticals, Cambridge, Massachusetts
| | - Erez Feige
- Department of Pediatric Hematology/Oncology, Melanoma Program in Medical Oncology, Boston, Massachusetts
| | - Daniel A Milner
- Department of Pediatric Hematology/Oncology, Melanoma Program in Medical Oncology, Boston, Massachusetts
| | | | - Scott R Granter
- Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts
| | - Michael Detmar
- Cutaneous Biology Research Center and Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts
| | - Hans R Widlund
- Department of Pediatric Hematology/Oncology, Melanoma Program in Medical Oncology, Boston, Massachusetts
| | - Martin A Horstmann
- Research Institute and Clinic of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - David E Fisher
- Cutaneous Biology Research Center and Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts; Department of Pediatric Hematology/Oncology, Melanoma Program in Medical Oncology, Boston, Massachusetts
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25
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Activin A is anti-lymphangiogenic in a melanoma mouse model. J Invest Dermatol 2014; 135:212-221. [PMID: 25084052 DOI: 10.1038/jid.2014.328] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2014] [Revised: 07/22/2014] [Accepted: 07/23/2014] [Indexed: 02/07/2023]
Abstract
Melanoma spreads primarily to the sentinel lymph nodes, and its risk correlates with lymphangiogenesis, which is mainly driven by vascular endothelial growth factor (VEGF)-C. However, anti-lymphangiogenic factors are poorly characterized. We have shown in a melanoma model that Wnt1 reduces lymphangiogenesis by reducing VEGF-C expression. Screening this model for additional potentially anti-lymphangiogenic factors identified increased activin A expression and reduced expression of the antagonist, follistatin (FST), in Wnt1(+) cells. Activin A is known to reduce blood vessel formation, but the effects on lymphangiogenesis are unknown. Here we show that human primary melanoma expresses significantly higher levels of activin A and lower levels of FST compared with nevi and melanoma metastasis. Using our mouse model with melanoma cells overexpressing Wnt1, FST, Wnt1/FST, or the inhibin βA subunit (INHBA, resulting in activin A expression), we found both activin A and Wnt1 to reduce lymphangiogenesis. Whereas Wnt1 also reduced metastasis, this was not seen with activin A. In vitro, activin A phosphorylated SMAD2 in both melanoma and lymphatic endothelium but, although it reduced sprouting of lymphatic endothelium, it enhanced the migration of melanoma cells. In conclusion, activin A is an anti-lymphangiogenic factor, but because of its pleiotropic effects on cell mobility it appears not suitable as a pharmacological target.
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Lymphangiogenesis and its correlation with the VEGF expression and the sentinel lymph node in cutaneous melanomas. BIOMED RESEARCH INTERNATIONAL 2014; 2014:372979. [PMID: 25089267 PMCID: PMC4096056 DOI: 10.1155/2014/372979] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/01/2014] [Revised: 05/18/2014] [Accepted: 05/18/2014] [Indexed: 02/02/2023]
Abstract
The aim of the study is to evaluate the density of intratumoral and peritumoral lymphatic vessels in primary cutaneous melanomas and to assess their correlation with the status of sentinel lymph nodes and the VEGF expression in tumor cells and stromal cells. A total of 40 patients were enrolled in the study: the melanomas were radically excised with the extirpation of the sentinel lymph node. The study subjects were divided into two groups: 20 cases with positive and 20 cases with negative sentinel lymph node results. The density of lymphatic vessels was evaluated by the antibody D2-40 and the VEGF expression was investigated in the semiquantitative way. The VEGF expression in melanoma cells and the stromal cells was negative to variable positive at both SLN negative and SLN positive patients in all pT stages. In the group of SLN positive patients, the density of intratumoral lymphatic vessels was low up to moderate, while it was observed to be absent, somewhere on the low level in the group of SLN negative patients. On the other side, the density of peritumoral lymphatic vessels was equally numerous at both SLN negative and SLN positive patients. The lymphatic invasion was found out at 4 SLN positive patients only. The ulceration was chiefly in the group of LN positive patients. The results show that the density of lymphangiogenesis and the intensity of the VEGF expression are considered to be an unreliable predictor of melanoma metastasis to the sentinel lymph node, but the ulceration and the lymphatic invasion can predict the potential for metastasis.
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Pastushenko I, Conejero C, Carapeto FJ. Lymphangiogenesis: implications for diagnosis, treatment, and prognosis in patients with melanoma. ACTAS DERMO-SIFILIOGRAFICAS 2014; 106:7-16. [PMID: 24890812 DOI: 10.1016/j.ad.2014.02.013] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2013] [Revised: 01/06/2014] [Accepted: 02/14/2014] [Indexed: 01/01/2023] Open
Abstract
Disease course in melanoma often cannot be accurately predicted by means of the prognostic factors usually considered in patients with melanoma; therefore, new factors are clearly needed. Increasingly robust scientific evidence shows that tumor lymph vessels play a key role in melanoma that metastasizes by lymphatic and hematogenous pathways. We review current knowledge and examine the implications of lymphangiogenesis in the diagnosis, treatment, and prognosis of patients with melanoma.
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Affiliation(s)
- I Pastushenko
- Servicio de Dermatología, Hospital Clínico Universitario Lozano Blesa, Zaragoza, España.
| | - C Conejero
- Servicio de Dermatología, Hospital Clínico Universitario Lozano Blesa, Zaragoza, España
| | - F J Carapeto
- Facultad de Medicina, Universidad de Zaragoza, Zaragoza, España
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Kan S, Konishi E, Arita T, Ikemoto C, Takenaka H, Yanagisawa A, Katoh N, Asai J. Podoplanin expression in cancer-associated fibroblasts predicts aggressive behavior in melanoma. J Cutan Pathol 2014; 41:561-7. [PMID: 24588302 DOI: 10.1111/cup.12322] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2013] [Revised: 02/24/2014] [Accepted: 02/25/2014] [Indexed: 11/27/2022]
Abstract
BACKGROUND Recent studies have showed podoplanin expression in several tumors, which has been associated with lymph node metastasis and poor prognosis. Podoplanin expression in cancer-associated fibroblasts also correlates with tumor progression. However, the association of podoplanin expression with melanomas remains unclear. METHODS To clarify the prognostic significance of podoplanin in melanoma, podoplanin expression in tumor cells and cancer-associated fibroblasts was examined by immunohistochemistry in tissue samples collected from 55 melanoma patients. RESULTS Podoplanin expression in tumor cells was identified in 38 patients (69.1%) but did not show correlation with characteristics of tumor progression such as tumor thickness (p = 0.52) and sentinel lymph node (SLN) metastasis (p = 0.79). Podoplanin expression in cancer-associated fibroblasts was observed in 25 patients (45.5%), 11 of whom (44.0%) had SLN metastasis. In contrast, only 4 of 30 patients (13.3%) with podoplanin-negative cancer-associated fibroblasts exhibited SLN metastasis. Podoplanin-positive cancer-associated fibroblasts were associated with increased tumor thickness and SLN metastasis. Furthermore, patients with podoplanin-positive cancer-associated fibroblasts had poorer survival than those with podoplanin-negative cancer-associated fibroblasts (p = 0.0148). CONCLUSION The presence of podoplanin expression in cancer-associated fibroblasts correlates with aggressive behavior in melanoma and might therefore serve as a useful prognostic factor for patients with melanoma.
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Affiliation(s)
- Saori Kan
- Department of Dermatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
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29
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Pasquali S, Mocellin S, Mozzillo N, Maurichi A, Quaglino P, Borgognoni L, Solari N, Piazzalunga D, Mascheroni L, Giudice G, Patuzzo R, Caracò C, Ribero S, Marone U, Santinami M, Rossi CR. Nonsentinel lymph node status in patients with cutaneous melanoma: results from a multi-institution prognostic study. J Clin Oncol 2014; 32:935-41. [PMID: 24516022 DOI: 10.1200/jco.2013.50.7681] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Abstract
PURPOSE We investigated whether the nonsentinel lymph node (NSLN) status in patients with melanoma improves the prognostic accuracy of common staging features; then we formulated a proposal for including the NSLN status in the current melanoma staging system. PATIENTS AND METHODS We retrospectively collected the clinicopathologic data of 1,538 patients with positive SLN status who underwent completion lymph node dissection (CLND) at nine Italian centers. Multivariable Cox regression survival analysis was used to identify independent prognostic factors. Literature meta-analysis was used to summarize the available evidence on the prognostic value of the NSLN status in patients with positive SLN. RESULTS NSLN metastasis was observed in 353 patients (23%). After a median follow-up of 45 months, NSLN status was an independent prognostic factor for melanoma-specific survival (hazard ratio [HR] = 1.34; 95% CI, 1.18 to 1.52; P < .001). NSLN status efficiently stratified the prognosis of patients with two to three positive lymph nodes (n = 387; HR = 1.39; 95% CI, 1.07 to 1.81; P = .013), independently of other staging features. Searching the literature, this patient subgroup was investigated in other two studies. Pooling the results (n = 620 patients; 284 NSLN negative and 336 NSLN positive), we found that NSLN status is a highly significant prognostic factor (summary HR = 1.59; 95% CI, 1.27 to 1.98; P < .001) in patients with two to three positive lymph nodes. CONCLUSION These findings support the independent prognostic value of the NSLN status in patients with two to three positive lymph nodes, suggesting that this information should be considered for the routine staging in patients with melanoma.
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Affiliation(s)
- Sandro Pasquali
- Sandro Pasquali, Simone Mocellin, and Carlo Riccardo Rossi, University of Padova; Carlo Riccardo Rossi, Veneto Institute of Oncology, Padova; Nicola Mozzillo and Corrado Caracò, National Cancer Institute "Pascale," Naples; Andrea Maurichi and Ugo Marone, National Cancer Institute; Luigi Mascheroni, San Pio X Hospital, Milan; Pietro Quaglino, Roberto Patuzzo, and Mario Santinami, University of Turin, Turin; Lorenzo Borgognoni, Tuscan Tumor Institute, Florence; Nicola Solari and Simone Ribero, National Cancer Research Institute of Genova, Genova; Dario Piazzalunga, Riuniti Hospital, Bergamo; and Giuseppe Giudice, University of Bari, Bari, Italy
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Mandalà M, Massi D. Tissue prognostic biomarkers in primary cutaneous melanoma. Virchows Arch 2014; 464:265-81. [PMID: 24487785 DOI: 10.1007/s00428-013-1526-x] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2013] [Accepted: 12/03/2013] [Indexed: 01/04/2023]
Abstract
Cutaneous melanoma (CM) causes the greatest number of skin cancer-related deaths worldwide. Predicting CM prognosis is important to determine the need for further investigation, counseling of patients, to guide appropriate management (particularly the need for postoperative adjuvant therapy), and for assignment of risk status in groups of patients entering clinical trials. Since recurrence rate is largely independent from stages defined by morphological and morphometric criteria, there is a strong need for identification of additional robust prognostic factors to support decision-making processes. Most data on prognostic biomarkers in melanoma have been evaluated in tumor tissue samples by conventional morphology and immunohistochemistry (IHC) as well as DNA and RNA analyses. In the present review, we critically summarize main high-quality studies investigating IHC-based protein biomarkers of melanoma outcome according to Reporting Recommendations for Tumor Marker Prognostic Studies (REMARK)-derived criteria. Pathways have been classified and conveyed in the "biologic road" previously described by Hanahan and Weinberg. Data derived from genomic and transcriptomic technologies have been critically reviewed to better understand if any of investigated proteins or gene signatures should be incorporated into clinical practice or still remain a field of melanoma research. Despite a wide body of research, no molecular prognostic biomarker has yet been translated into clinical practice. Conventional tissue biomarkers, such as Breslow thickness, ulceration, mitotic rate and lymph node positivity, remain the backbone prognostic indicators in melanoma.
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Affiliation(s)
- Mario Mandalà
- Unit of Clinical and Translational Research, Medical Oncology, Department of Oncology and Hematology, Papa Giovanni XXIII Hospital, Bergamo, Italy
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31
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Du LC, Chen XC, Wang D, Wen YJ, Wang CT, Wang XM, Kan B, Wei YQ, Zhao X. VEGF-D-induced draining lymphatic enlargement and tumor lymphangiogenesis promote lymph node metastasis in a xenograft model of ovarian carcinoma. Reprod Biol Endocrinol 2014; 12:14. [PMID: 24502459 PMCID: PMC3929486 DOI: 10.1186/1477-7827-12-14] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2013] [Accepted: 12/29/2013] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Vascular endothelial growth factor (VEGF)-D has been shown to promote lymph node metastasis in several cancers. Although generally overexpressed in ovarian carcinoma, its role in nodal dissemination of this cancer is unclear. To clarify the role of VEGF-D and the underlying molecular mechanisms, we investigated the function of VEGF-D using a mouse xenograft model of ovarian cancer. METHODS Human ovarian serous adenocarcinoma SKOV3 cells were transfected with VEGF-D recombinant plasmid DNA, or with control vectors. The cells were injected subcutaneously into the footpads of nude mice. Tumor growth was evaluated weekly. Draining lymphatics were observed grossly with Evan's blue lymphangiography. Tumoral lymphatics were delineated with both Evan's blue and LYVE-1 immunostaining. Tumor metastases to lymph nodes were evaluated by H&E and CA125/CD40 staining. Expression of VEGF-D in primary tumors and levels of CA125 in involved lymph nodes were examined by immunohistochemistry. Tumor cell apoptosis was analyzed by Hoechst dyeing. RESULTS Mice bearing VEGF-D overexpressing xenografts showed a significantly higher rate of lymph node metastasis and markedly greater tumor volume compared with the controls. The functional lymphatic vessels were denser and enlarged in marginal and central tumor portions. Additionally, higher CA125 expression was observed in the involved lymph nodes. Mice bearing VEGF-D overexpressing xenografts also exhibited a markedly lower apoptotic index compared with the controls. CONCLUSIONS Our data demonstrate the important role of VEGF-D in promoting lymph node metastasis by increasing tumor lymphangiogenesis, stimulating draining lymphatic vessel formation, and enhancing tumor invasiveness. Our findings show that VEGF-D can be a promising therapeutic target for ovarian cancer.
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Affiliation(s)
- Li-Cheng Du
- Department of Surgery, Shandong Provincial Hospital affiliated to Shandong University, Jingwu Road, Jinan, China
| | - Xian-Cheng Chen
- Department of Gynecology and Obstetrics, Second West China Hospital, West China Medical School, Sichuan University, South Renmin Road, Chengdu, China
| | - Dong Wang
- Department of Surgery, Shandong Provincial Hospital affiliated to Shandong University, Jingwu Road, Jinan, China
| | - Yan-Jun Wen
- National Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, South Renmin Road, Chengdu, China
| | - Chun-Ting Wang
- National Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, South Renmin Road, Chengdu, China
| | - Xue-Mei Wang
- Department of Gynecology and Obstetrics, Second West China Hospital, West China Medical School, Sichuan University, South Renmin Road, Chengdu, China
| | - Bing Kan
- National Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, South Renmin Road, Chengdu, China
| | - Yu-Quan Wei
- National Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, South Renmin Road, Chengdu, China
| | - Xia Zhao
- Department of Gynecology and Obstetrics, Second West China Hospital, West China Medical School, Sichuan University, South Renmin Road, Chengdu, China
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Difference of interferon-α and interferon-β on melanoma growth and lymph node metastasis in mice. Melanoma Res 2014; 23:114-24. [PMID: 23358428 DOI: 10.1097/cmr.0b013e32835e7713] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Interferon (IFN)-α and IFN-β are type I IFNs which are known to exert an antitumor effect on malignant melanoma. The aim of this study was to evaluate and compare the efficacy of IFN-α2b and IFN-β1a on primary tumor growth and lymph node metastasis, and to examine the mechanisms of lymph node metastasis. The efficacy of IFN-α2b and IFN-β1a was evaluated using a human melanoma xenograft model. We further examined the effect of IFNs on lymphangiogenic growth factors in human melanoma cells. IFN-β1a showed a stronger antiproliferative and proapoptotic effect, whereas IFN-α2b inhibited tumor growth and lymph node metastasis through inhibition of lymphangiogenesis. Both IFN-α2b and IFN-β1a were effective in inhibiting lymph node metastasis compared with the control. Microvessel density decreased in tumors treated with IFN-α2b and IFN-β1a compared with the control, without statistical significance. Lymphatic vessel density decreased significantly only in tumors treated with IFN-α2b (P<0.05). Both IFN-α2b and IFN-β1a decreased in-vitro and in-vivo vascular endothelial growth factor (VEGF)-C and VEGF receptor-3 protein expression and secretory VEGF-C level in vitro. IFN-α2b showed an earlier and sustained effect in decreasing VEGF-C and VEGF receptor-3 protein expression and a superior effect in decreasing the secretory VEGF-C level compared with IFN-β1a. Our investigation shows that both IFN-α2b and IFN-β1a exerted different antitumor and antimetastatic effects in human melanoma xenograft. Moreover, the present findings indicate that inhibition of lymphangiogenesis is another possible antimetastatic action mechanism of IFN-α2b.
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Belkin DA, Mitsui H, Felsen D, Carucci JA. VEGF-C-producing macrophages in cutaneous squamous cell carcinoma. ACTA ACUST UNITED AC 2014. [DOI: 10.1586/edm.11.66] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
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Mansfield AS, Markovic SN. Inhibition of Angiogenesis for the Treatment of Metastatic Melanoma. Curr Oncol Rep 2013; 15:492-9. [DOI: 10.1007/s11912-013-0334-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
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Lymphatic invasion predicts aggressive behavior in melanocytic tumors of uncertain malignant potential (MELTUMP). Am J Surg Pathol 2013; 37:669-75. [PMID: 23552384 DOI: 10.1097/pas.0b013e318288ff47] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Lymphatic invasion (LI) identified by immunohistochemical (IHC) staining is common in primary cutaneous melanoma, and LI has been shown to be an independent prognostic factor in melanoma. Its prognostic significance in melanocytic tumors of uncertain malignant potential (MELTUMPs) has not been well characterized. This study included 32 patients with provisional diagnoses of MELTUMP. Lesions were evaluated for tumor thickness, the presence of ulceration, mitotic figures, mitotic figures at the base, tumor infiltrating lymphocytes, as well as peritumoral and intratumoral lymphatic density. Dual IHC staining was used to microscopically detect lymphatic endothelium (podoplanin) containing melanoma cells (S100), with the aid of multispectral imaging in select cases. Univariate analysis was performed to identify associations between clinical and pathologic variables and melanoma-related events. The 32 patients had a median follow-up of 111 months. Two patients subsequently died of melanoma-related disease, 1 died of unknown causes, 5 developed nodal metastases, and the remainder showed no evidence of progressive disease. LI was identified in 8/32 patients (25%) by dual IHC staining, which included the 2 patients who died of melanoma-related disease, 1 patient with bulky nodal metastasis, 1/4 patients with microscopic nodal metastases, and 4 patients who showed no evidence of progressive disease. The presence of LI was associated with melanoma metastases or melanoma-related death (P=0.05). The presence of LI by dual IHC in MELTUMPs is associated with a poorer prognosis, specifically with melanoma metastasis, and may therefore serve as a useful prognostic factor for risk stratification of patients with these diagnostically challenging lesions.
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Park JY, Amankwah EK, Anic GM, Lin HY, Walls B, Park H, Krebs K, Madden M, Maddox K, Marzban S, Fang S, Chen W, Lee JE, Wei Q, Amos CI, Messina JL, Sondak VK, Sellers TA, Egan KM. Gene variants in angiogenesis and lymphangiogenesis and cutaneous melanoma progression. Cancer Epidemiol Biomarkers Prev 2013; 22:827-34. [PMID: 23462921 PMCID: PMC3708315 DOI: 10.1158/1055-9965.epi-12-1129] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Angiogenesis and lymphangiogenesis are important in the progression of melanoma. We investigated associations between genetic variants in these pathways with sentinel lymph node (SLN) metastasis and mortality in 2 independent series of patients with melanoma. METHODS Participants at Moffitt Cancer Center were 552 patients, all Caucasian, with primary cutaneous melanoma referred for SLN biopsy. A total of 177 patients had SLN metastasis, among whom 60 died from melanoma. Associations between 238 single-nucleotide polymorphisms (SNP) in 26 genes and SLN metastasis were estimated as ORs and 95% confidence intervals (CI) using logistic regression. Competing risk regression was used to estimate HRs and 95% CI for each SNP and melanoma-specific mortality. We attempted to replicate significant findings using data from a genome-wide association study comprising 1,115 patients with melanoma who were referred for SLN biopsy from MD Anderson Cancer Center (MDACC), among whom 189 patients had SLN metastasis and 92 patients died from melanoma. RESULTS In the Moffitt dataset, we observed significant associations in 18 SNPs with SLN metastasis and 17 SNPs with mortality. Multiple SNPs in COL18A1, EGF receptor (EGFR), FLT1, interleukin (IL)-10, platelet-derived growth factor D (PDGFD), PIK3CA, and toll-like receptor (TLR)-3 were associated with the risk of SLN metastasis and/or patient mortality. The MDACC data set replicated an association between mortality and rs2220377 in PDGFD. Furthermore, in a meta-analysis, 3 additional SNPs were significantly associated with SLN metastasis (EGFR rs723526 and TLR3 rs3775292) and melanoma-specific death (TLR3 rs7668666). CONCLUSIONS These findings suggest that genetic variation in angiogenesis and lymphangiogenesis contributes to regional nodal metastasis and progression of melanoma. IMPACT Additional research attempting to replicate these results is warranted.
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Affiliation(s)
- Jong Y Park
- Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, USA.
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Pasquali S, van der Ploeg APT, Mocellin S, Stretch JR, Thompson JF, Scolyer RA. Lymphatic biomarkers in primary melanomas as predictors of regional lymph node metastasis and patient outcomes. Pigment Cell Melanoma Res 2013; 26:326-37. [PMID: 23298266 DOI: 10.1111/pcmr.12064] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2011] [Accepted: 01/02/2013] [Indexed: 11/26/2022]
Abstract
Recently developed lymphatic-specific immunohistochemical markers can now be utilized to assess intratumoral and/or peritumoral lymphatic vessel density (LVD), to detect lymphatic vessel invasion (LVI) by melanoma cells and to identify lymphatic marker expression in melanoma cells themselves. We systematically reviewed the available evidence for the expression of lymphatic markers as predictors of regional node metastasis and survival in melanoma patients. The currently available evidence suggests that LVD (particularly in a peritumoral location) and LVI are predictors of sentinel node metastasis and poorer survival. Nevertheless, adherence to international guidelines in the conduct and reporting of the studies was generally poor, with wide methodologic variations and heterogeneous findings. Larger, carefully conducted and well-reported studies that confirm these preliminary findings are required before it would be appropriate to recommend the routine application of costly and time-consuming immunohistochemistry for lymphatic markers in the routine clinical assessment of primary cutaneous melanomas.
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Affiliation(s)
- Sandro Pasquali
- Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia.
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Dadras SS. An Unexpected Role for EGF in Lymphangiogenesis-Mediated Melanoma Metastasis to Sentinel Lymph Nodes. J Invest Dermatol 2013; 133:14-6. [DOI: 10.1038/jid.2012.436] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
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Lack of Functioning Intratumoral Lymphatics in Colon and Pancreas Cancer Tissue. Lymphat Res Biol 2012; 10:112-7. [DOI: 10.1089/lrb.2012.0008] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
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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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Abstract
This article is an up-to-date overview of the potential uses and limitations of immunohistochemistry (IHC) in melanocytic lesions. The information is intended to assist dermatopathologists and dermatologists who read slides to appropriately use IHC in this setting. In addition, dermatologists who do not review microscopic slides will better understand the rationale of the pathologist when reading and interpreting the pathology report.
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Affiliation(s)
- Tammie Ferringer
- Department of Dermatology, Geisinger Medical Center, Danville, PA 17822, USA.
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Cianfarani F, Mastroeni S, Odorisio T, Passarelli F, Cattani C, Mannooranparampil TJ, Fortes C, Failla CM. Expression of vascular endothelial growth factor-C in primary cutaneous melanoma predicts sentinel lymph node positivity. J Cutan Pathol 2012; 39:826-34. [PMID: 22804631 DOI: 10.1111/j.1600-0560.2012.01955.x] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2011] [Revised: 02/21/2012] [Accepted: 04/07/2012] [Indexed: 12/18/2022]
Abstract
BACKGROUND Vascular endothelial growth factor-C (VEGF-C), a lymphatic vessel growth factor, has been involved in the formation of lymph nodal metastases in different tumor types. Early evidences indicate that VEGF-C expression in human primary melanoma could be predictive of lymph nodal metastases, whereas the role of lymphangiogenesis is still controversial. METHODS By immunohistochemical analysis, we investigated VEGF-C or CC chemokine receptor 7 expression, together with the lymphatic and blood vessel network, in 36 patients with primary skin melanomas and metastases at the sentinel lymph node biopsy (SLN-positive), and 26 melanoma patients with negative SLN biopsy (SLN-negative). RESULTS We found that VEGF-C expression in primary melanoma specimens was significantly associated with SLN-positive (p < 0.001), particularly in thin melanomas. An association between augmented peritumoral lymphatic vessel area and SLN-positive (p < 0.02) was also seen. Conversely, no association between either expression of the CC chemokine receptor 7 in the primary tumor, or intratumoral lymphatic vessel or peritumoral and intratumoral blood vessel area, and SLN-positive was found. CONCLUSIONS Our results, taking into account the expression of either VEGF-C or related histopathological markers, indicated the possibility to use VEGF-C immunohistochemistry as a marker of metastatic progression, especially in thin cutaneous melanomas.
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Shayan R, Karnezis T, Murali R, Wilmott JS, Ashton MW, Taylor GI, Thompson JF, Hersey P, Achen MG, Scolyer RA, Stacker SA. Lymphatic vessel density in primary melanomas predicts sentinel lymph node status and risk of metastasis. Histopathology 2012; 61:702-10. [DOI: 10.1111/j.1365-2559.2012.04310.x] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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Wang TB, Chen ZG, Wei XQ, Wei B, Dong WG. Serum vascular endothelial growth factor-C and lymphoangiogenesis are associated with the lymph node metastasis and prognosis of patients with colorectal cancer. ANZ J Surg 2012; 81:694-9. [PMID: 22295309 DOI: 10.1111/j.1445-2197.2010.05539.x] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND The study aims to investigate the relationship among serum vascular endothelial growth factor (SVEGF-C), VEGF-C expression and lymph vessel density (LVD) in tumour tissue, and their influence to colorectal carcinoma (CRC). METHODS The SVEGF-C concentration of 110 patients with CRC and 40 healthy donors was examined by ELISA. The 110 tumour tissues and 40 normal colorectal specimens were examined by immunohistochemical staining (SP method) with VEGF-C and podoplanin (lymphatic vessel specific antibody). Kaplan–Meier survival analysis determined the influence on CRC prognosis. RESULTS CRC SVEGF-C level (889.0 ± 264.0 pg/mL) significantly exceeded (P = 0.000) the control level (373.2 ± 97.3 ng/L), and was significantly higher in T3, lymph node metastasis (LNM), distant metastasis, and pTNM groups III and IV. LNM prediction sensitivity, specificity, and accuracy of SVEGF-C were 85.7, 80.0 and 83.6%, respectively (875 pg/mL cut-off). VEGF-C expression was elevated in CRC versus control patients (P = 0.000), and was significantly related to LNM and pTNM stages III and IV. Mean LVD in CRC (6.3 ± 0.7/200 HP) significantly exceeded control mean (3.0 ± 0.7/200 HP) (P = 0.000). LVD was significantly higher in LNM and pTNM stages III and IV. SVEGF-C level was significantly higher in VEGF-C positive versus negative patients (P = 0.000), and was related to LVD (P = 0.009). Kaplan–Meier ranking of prognostic factors was SVEGF-C level (P = 0.000), VEGF-C expression (P = 0.001) and LVD (P = 0.012). CONCLUSION SVEGF-C level, VEGF-C and LVD are related to LNM and poor prognosis in patients with CRC. SVEGF-C may be a biomarker for LNM in CRC.
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Affiliation(s)
- Tian-Bao Wang
- Department of Surgery, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China.
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CCR7-expressing B16 melanoma cells downregulate interferon-γ-mediated inflammation and increase lymphangiogenesis in the tumor microenvironment. Oncogenesis 2012; 1:e9. [PMID: 23552640 PMCID: PMC3412639 DOI: 10.1038/oncsis.2012.9] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
The expression of the CC chemokine receptor-7 (CCR7) by cancers, including melanoma, augments lymph node (LN) metastasis, but little is known about its role in lymphangiogenesis and anti-tumor immunity. We injected control B16 murine melanoma cells (pLNCX2-B16) and CCR7-overexpressing B16 cells (CCR7-B16) in murine footpads and compared resulting tumors at the protein and mRNA level using immunostaining, Affymetrix gene microarray and quantitative reverse-transcriptase PCR. Although control and CCR7-B16 primary tumors were of similar size, LN metastasis was dramatically enhanced in CCR7-B16 tumors. Microarray analysis of leukocyte-depleted pLNCX2-B16 and CCR7-B16 tumor cell suspensions showed that three major groups of genes linked to interferon (IFN)-γ signaling pathways (for example, STAT1, CXCR 9-11, CCL5 and CXCL10, major histocompatibility complex (MHC) I and MHC II) were downregulated in the CCR7-B16 tumor microenvironment, suggesting activation through CCR7 can downregulate pathways critical for host anti-tumor immunity. In addition, mRNA expression of the lymphatic marker podoplanin was upregulated in CCR7-B16 tumors by 3.35-fold versus control tumors. Anti-podoplanin monoclonal antibody staining revealed a three-fold increase in intratumoral CCL21-expressing lymphatic vessels, as well as a two-fold increase in the number of invading tumor cells per lymphatic vessel in CCR7-B16 versus control tumors. Enhanced anti-vascular endothelial growth factor C (VEGF-C) staining was present in CCR7-B16 versus control tumors, suggesting that VEGF-C may have a role in the CCR7-mediated lymphangiogenesis. In summary, CCR7-B16 tumors show a striking decrease in IFN-γ-mediated inflammatory gene expression in contrast to increased expression of VEGF-C, CCL21 and podoplanin by lymphatic vessels. Enhanced lymphangiogenesis may contribute to the dramatic increase in LN metastasis that is observed in the CCR7-expressing tumors.
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Objective assessment of blood and lymphatic vessel invasion and association with macrophage infiltration in cutaneous melanoma. Mod Pathol 2012; 25:493-504. [PMID: 22080065 PMCID: PMC3318158 DOI: 10.1038/modpathol.2011.182] [Citation(s) in RCA: 92] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/02/2022]
Abstract
The aims of this study were to investigate the role of vascular invasion (blood and lymphatic), vessel density and the presence of tumour-associated macrophages as prognostic markers in 202 cutaneous melanoma patients. Sections of primary melanoma were stained with lymphatic-specific antibody D2-40 to assess lymphatic vessel invasion and density in intratumoural and peritumoural areas; an antibody against endothelial marker CD34 was used to determine blood vessel invasion and density, and an antibody against CD68 was used to determine macrophage counts. Immunohistochemically determined vascular invasion (combined blood and lymphatic) was compared with that determined using haematoxylin and eosin (H&E) staining. The use of immunohistochemistry increased detection of vascular invasion from 8-30% of patients, and histological exam of H&E-stained tissue was associated with a false positive rate of 64%. Lymphatic vessel invasion occurred at a much higher frequency than blood vessel invasion (27 and 4% of patients, respectively). Although immunohistochemically detected vessel invasion was significantly associated with histological markers of adverse prognosis, such as increased Breslow thickness, ulceration and mitotic rate (all P<0.001), no associations with relapse-free or overall survival were observed. High macrophage counts were significantly associated with markers of aggressive disease, such as Breslow thickness, ulceration and mitotic rate (P<0.001, P<0.001, P=0.005, respectively), and lymphatic vessel invasion and high microvessel density (P=0.002 and P=0.003, respectively). These results suggest that vascular invasion is more accurately detected using immunohistochemistry and occurs predominantly via lymphatic vessels. The association of vessel characteristics with histological characteristics of the primary melanoma provides evidence for their biological importance in melanoma, but that they were not associated with clinical outcome attests to the value of existing histological prognostic biomarkers. We note that a high macrophage count may be associated with neovascularisation and primary tumour growth, and may also promote invasion through lymphatic vessels.
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Abstract
Melanoma is an immunogenic tumor that has developed methods to successfully evade immune recognition, while paradoxically spreading through the lymphatic system. Increasing evidence supports that melanoma-derived factors suppress regional immunity within the host. At a very early stage, melanoma communicates with the tumor-draining lymph nodes, and prepares them for seeding of metastatic disease by stimulating lymphangiogenesis and downregulation of the sentinel lymph node immunity well before the malignant cells arrive. Investigations have demonstrated that the induction of suppressor cells, peripheral tolerance, and a less tumor-responsive Th2 cytokine environment may provide a hospitable environment for subsequent lymphatic metastasis. Patients with early-stage disease may benefit from the restoration of the regional immune function to a level that controls the progression of residual occult metastases and ensures a durable clinical response. Herein we provide a succinct summary of the current progress in this field in order to guide future investigations.
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Affiliation(s)
- Travis E Grotz
- Division of Surgery, Mayo Clinic, Rochester, Minnesota 55905, USA
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Chung MK, Do IG, Jung E, Son YI, Jeong HS, Baek CH. Lymphatic vessels and high endothelial venules are increased in the sentinel lymph nodes of patients with oral squamous cell carcinoma before the arrival of tumor cells. Ann Surg Oncol 2011; 19:1595-601. [PMID: 22124758 DOI: 10.1245/s10434-011-2154-9] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2011] [Indexed: 01/08/2023]
Abstract
PURPOSE To investigate the change of vasculature in the sentinel lymph node (SLN) of patients with oral squamous cell carcinoma. METHODS Immunohistochemical staining of SLNs in 58 patients was performed with two monoclonal antibodies (MAb): anti-D2-40 MAb for lymphatic endothelial cells, and anti-MECA-79 MAb for high endothelial venules (HEV). Twelve metastatically involved (m(+)) SLNs, 120 uninvolved (m(-)) SLNs, and 35 non-SLNs (control) were available for analyses. Vessel densities were measured by computer-assisted analyses in the entire region of SLN. Correlations were assessed between vessel density and clinicopathologic variables, including vascular endothelial growth factor C of primary tumor. RESULTS Lymphatic vessel density (LVD) in SLNs was higher than that in control LNs [2361.8 μm(2)/high-power field (HPF) (624.3-4758.5) vs. 1621.9 μm(2)/HPF (465.3-3453.5), P = 0.005]. LVD of m(-) SLNs [2662.4 μm(2)/HPF (624.3-4758.5)] and m(±) SLNs [4946.6 μm(2)/HPF (2009.3-8698.8)] were both statistically significantly higher compared to control. HEV densities in m(-) SLNs [14029.7 μm(2)/HPF (10465.7-17927.1)] as well as m(±) SLNs [18258.5 μm(2)/HPF (8408.9-27706.0)] were also significantly higher than those in control [10350.5 μm(2)/HPF (7807.8-12541.1)]. By multivariate analysis, the degree of vascular endothelial growth factor C expression of primary tumor showed significant correlation with LVD of SLNs (odds ratio 9.46, 95% confidence interval 1.73-51.5, P = 0.009), which was not the case in HEV. CONCLUSIONS Lymphatic vessels and HEVs were increased in SLNs, regardless of metastatic status of SLNs. Vascular endothelial growth factor C expression of primary tumor may contribute to the premetastatic change within SLNs of oral squamous cell carcinoma.
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Affiliation(s)
- Man Ki Chung
- Department of Otorhinolaryngology-Head and Neck Surgery, Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, Republic of Korea
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Xu X, Chen L, Guerry D, Dawson PR, Hwang WT, VanBelle P, Elder DE, Zhang PJ, Ming ME, Schuchter L, Gimotty PA. Lymphatic invasion is independently prognostic of metastasis in primary cutaneous melanoma. Clin Cancer Res 2011; 18:229-37. [PMID: 22096024 DOI: 10.1158/1078-0432.ccr-11-0490] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
PURPOSE Lymphatic invasion (LI) in primary cutaneous melanomas was recently found to be common. In this study, we evaluated LI as an independent prognostic factor. EXPERIMENTAL DESIGN This study included 251 patients with vertical growth phase (VGP) primary cutaneous melanomas who had paraffin-fixed lesional tissue and were in a prospective cohort seen between 1972 and 1991, had no clinical evidence of regional nodal disease at diagnosis, and had at least ten years of follow-up. Dual immunohistochemical staining was used to detect lymphatic endothelium (podoplanin) and melanoma cells (S-100). Multivariate logistic regression for ten-year metastasis was used to define independent prognostic factors, and a prognostic tree was developed to characterize and discriminate risk groups. Kaplan-Meier disease-free survival curves for those with and without LI within current American Joint Committee on Cancer stages were compared using the log-rank statistic. RESULTS LI was observed in 43% (108 of 251) of the study melanomas. The multivariate model for ten-year metastasis identified four independent prognostic factors: tumor thickness, mitotic rate, LI, and anatomic site. The prognostic tree identified a group of patients with thin (≤1 mm thick) melanomas and poor prognosis: stage IB melanomas with LI. Survival curves for time to first metastasis showed significantly poorer prognosis for patients with LI compared with those without it for both stages IB and IIA. CONCLUSIONS LI is common across the range of tumor thicknesses in primary VGP melanomas. It is an independent prognostic factor and significantly increases the risk of metastasis in patients in clinical stages IB and IIA.
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Affiliation(s)
- Xiaowei Xu
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
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Clinical relevance of detection of lymphovascular invasion in primary melanoma using endothelial markers D2-40 and CD34. Am J Surg Pathol 2011; 35:1441-9. [PMID: 21881483 DOI: 10.1097/pas.0b013e31822573f5] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Immunohistochemistry (IHC) using endothelial markers may facilitate the detection of lymphovascular invasion (LVI) in primary melanoma; however, the clinical implications of enhanced detection are unknown. We evaluated whether the use of lymphatic endothelial marker D2-40 and panvascular marker CD34 increases LVI positivity relative to routine histology alone and then evaluated the prognostic relevance of LVI detected using these markers in terms of disease-free (DFS) and overall survival (OS). A total of 246 primary melanomas were assessed for LVI using D2-40, CD34, and routine histology. Associations between LVI positivity and clinicopathologic variables, DFS, and OS were compared using univariate and multivariate analyses. The use of endothelial markers increased the rate of LVI positivity (18% using D2-40 and/or CD34 vs. 3% by routine histology, P<0.0001). On univariate analysis, IHC-detected LVI was significantly associated with more adverse clinicopathologic variables (thickness, ulceration, mitoses, and nodular subtype) compared with LVI detected by routine histology (thickness and ulceration only). In a multivariate model controlling for stage, LVI detected using IHC markers remained a significant marker of both reduced DFS [hazard ratio (HR), 2.01; 95% confidence interval (CI): 1.27-3.18; P=0.003] and OS (HR, 2.08; 95% CI: 1.25-3.46; P=0.005). Results show that D2-40 and CD34 increase the detection of LVI in primary melanoma and that cases missed by routine histology have prognostic relevance.
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