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Lymphangiogenesis  [PDF]
Catherine R. Tait,Pamela F. Jones
Computational and Mathematical Methods in Medicine , 2003, DOI: 10.1080/10273660310001646860
Abstract: While much effort is given to the modelling of tumour angiogenesis, little attention is paid to lymphangiogenesis and its potential role in tumour progression and metastasis. This is due at least in part to the controversy that surrounds tumour lymphangiogenesis—opinion is divided as to whether tumours actively promote the development of lymph channels in the same way that they promote the development of vasculature. Given that it was decades before Folkman's theory of tumour angiogenesis became widely accepted, it is possible that the concept of tumour lymphangiogenesis will in time also become generally accepted and hence may itself become the subject of mechanistic studies and mathematical modelling. This review summarises the process of lymphangiogenesis and the potential mechanism of its induction in tumours.
Integrins and their ligands in rheumatoid arthritis
Torsten Lowin, Rainer H Straub
Arthritis Research & Therapy , 2011, DOI: 10.1186/ar3464
Abstract: Integrins are a large group of transmembrane proteins that anchor the cell to the extracellular matrix (ECM) or other cells. Upon binding, integrins remodel the ECM by inducing the expression of certain proteases. Integrins control cellular proliferation, migration, and invasion. Whereas in some cases integrins can mediate these effects on their own, they usually signal in the context of growth factor or cytokine receptors [1]. Ligand binding to integrin controls adhesion-dependent proliferation, whereas unligated integrins enhance apoptotic pathways [2]. This is one reason why dysregulated integrin expression or downstream signaling pathways can be observed in almost all forms of cancer, and integrin levels often determine the aggressiveness or propensity to metastasize.Migration, invasion, and proliferation of synovial cells are major problems in rheumatoid arthritis (RA) [3]. This debilitating disease is characterized by an inflamed synovial tissue with a massive influx of immune cells and an inflated synovial lining consisting mainly of synovial fibroblasts (SFs) and macrophages that adhere to the adjacent ECM. These SFs are highly proliferative and contribute significantly to cartilage and bone destruction. In some aspects, they can be considered 'tumor-like' as SFs are resistant to many apoptotic pathways, show increased proliferation, and produce high amounts of matrix metalloproteinases (MMPs) because of dysregulation of the transcription factors AP-1, p53, and nuclear factor-kappa-B (NF-κB) [4]. Fibroblasts, macrophages, but also endothelial cells in synovial tissue show high levels of integrin expression [5]. In RA, not only integrins but also their ligands (for example, fibronectin and collagen as well as their degradation products) are up-regulated [6]. This 'overstimulation' of cells by integrin-mediated signals increases basal secretion of proinflammatory cytokines like interleukin-6 (IL-6) and IL-8 but also levels of various MMPs [7-9].This review int
Lymphangiogenesis and lymph node metastasis in breast cancer
Giles H Cunnick, Wen G Jiang, Tony Douglas-Jones, Gareth Watkins, Kelvin F Gomez, Mike J Morgan, Ashok Subramanian, Kefah Mokbel, Robert E Mansel
Molecular Cancer , 2008, DOI: 10.1186/1476-4598-7-23
Abstract: The cDNA from 153 frozen archived breast samples were analysed with Q-PCR for all seven lymphangiogenic markers. This was correlated with various prognostic factors as well as patient survival.There was significantly greater expression of all 7 markers in malignant compared to benign breast tissue. In addition, there was greater expression in lymph node positive/grade 3 tumours when compared to lymph node negative/grade 1 tumours. In 5 of the markers, there was a greater expression in poor NPI prognostic tumours when compared to favourable prognostic tumours which was not statistically significant. There was no association between recurrence risk and lymphangiogenic marker expression.In summary, the findings from this study show that lymphangiogenesis, measured by specific lymphatic marker expression, is higher in breast cancers than in normal breast tissue. Secondly, breast cancers which have metastasised to the regional lymphatics show higher expression compared to those which have not, although the individual differences for all five markers were not statistically significant.Breast cancer is one of the leading causes of cancer death in the female population in the Western World affecting as many as one in ten women in the UK [1], and its incidence appears to be rising. Although earlier diagnosis and better treatment are now available, many of the mechanisms underlying its ability to metastasise are poorly understood. Breast cancer spreads primarily via the lymphatic system. Regional lymph nodes are usually the first metastatic sites to be involved, often followed by distant metastasis to the lungs, liver and bones. Although various prognostic factors are known, regional lymph node status is the single most important prognostic factor in breast cancer; patients with axillary metastasis at the time of diagnosis have a much worse prognosis than those without metastasis [2,3].Clinical and pathological observations have long suggested that for many other tumours, the
Integrins and extracellular matrix in mechanotransduction
Ramage L
Cell Health and Cytoskeleton , 2012, DOI: http://dx.doi.org/10.2147/CHC.S21829
Abstract: tegrins and extracellular matrix in mechanotransduction Review (2543) Total Article Views Authors: Ramage L Published Date December 2011 Volume 2012:4 Pages 1 - 9 DOI: http://dx.doi.org/10.2147/CHC.S21829 Lindsay Ramage Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, UK Abstract: Integrins are a family of cell surface receptors which mediate cell–matrix and cell–cell adhesions. Among other functions they provide an important mechanical link between the cells external and intracellular environments while the adhesions that they form also have critical roles in cellular signal-transduction. Cell–matrix contacts occur at zones in the cell surface where adhesion receptors cluster and when activated the receptors bind to ligands in the extracellular matrix. The extracellular matrix surrounds the cells of tissues and forms the structural support of tissue which is particularly important in connective tissues. Cells attach to the extracellular matrix through specific cell-surface receptors and molecules including integrins and transmembrane proteoglycans. Integrins work alongside other proteins such as cadherins, immunoglobulin superfamily cell adhesion molecules, selectins, and syndecans to mediate cell–cell and cell–matrix interactions and communication. Activation of adhesion receptors triggers the formation of matrix contacts in which bound matrix components, adhesion receptors, and associated intracellular cytoskeletal and signaling molecules form large functional, localized multiprotein complexes. Cell–matrix contacts are important in a variety of different cell and tissue properties including embryonic development, inflammatory responses, wound healing, and adult tissue homeostasis. This review summarizes the roles and functions of integrins and extracellular matrix proteins in mechanotransduction.
Integrins and extracellular matrix in mechanotransduction  [cached]
Ramage L
Cell Health and Cytoskeleton , 2011,
Abstract: Lindsay RamageQueen’s Medical Research Institute, University of Edinburgh, Edinburgh, UKAbstract: Integrins are a family of cell surface receptors which mediate cell–matrix and cell–cell adhesions. Among other functions they provide an important mechanical link between the cells external and intracellular environments while the adhesions that they form also have critical roles in cellular signal-transduction. Cell–matrix contacts occur at zones in the cell surface where adhesion receptors cluster and when activated the receptors bind to ligands in the extracellular matrix. The extracellular matrix surrounds the cells of tissues and forms the structural support of tissue which is particularly important in connective tissues. Cells attach to the extracellular matrix through specific cell-surface receptors and molecules including integrins and transmembrane proteoglycans. Integrins work alongside other proteins such as cadherins, immunoglobulin superfamily cell adhesion molecules, selectins, and syndecans to mediate cell–cell and cell–matrix interactions and communication. Activation of adhesion receptors triggers the formation of matrix contacts in which bound matrix components, adhesion receptors, and associated intracellular cytoskeletal and signaling molecules form large functional, localized multiprotein complexes. Cell–matrix contacts are important in a variety of different cell and tissue properties including embryonic development, inflammatory responses, wound healing, and adult tissue homeostasis. This review summarizes the roles and functions of integrins and extracellular matrix proteins in mechanotransduction.Keywords: ligand binding, α subunit, subunit, focal adhesion, cell differentiation, mechanical loading, cell–matrix interaction
Lymphangiogenesis in Regional Lymph Nodes Is an Independent Prognostic Marker in Rectal Cancer Patients after Neoadjuvant Treatment  [PDF]
Christiane Jakob, Daniela E. Aust, Birgit Liebscher, Gustavo B. Baretton, Kaustubh Datta, Michael H. Muders
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0027402
Abstract: One of the major prognostic factors in rectal cancer is lymph node metastasis. The formation of lymph node metastases is dependent on the existence of a premetastatic niche. An important factor preceding metastasis are lymph vessels which are located in the lymph node. Accordingly, the occurrence of intranodal lymphangiogenesis is thought to indicate distant metastasis and worse prognosis. To evaluate the significance of lymph node lymphangiogenesis, we studied formalin fixed, paraffin embedded adenocarcinomas and regional lymph nodes of 203 rectal cancer patients who were treated with neoadjuvant radiochemotherapy and consecutive curative surgery with cancer free surgical margins (R0). Regional lymph node lymph vessels were detected by immunohistochemistry for podoplanin (D2-40). Our results show that the presence of lymphatic vessels in regional lymph nodes significantly affects the disease-free survival in univariate and multivariate analyses. In contrast, there was no correlation between peritumoral or intratumoral lymph vessel density and prognosis. Indeed, our study demonstrates the importance of lymphangiogenesis in regional lymph nodes after neoadjuvant radiochemotherapy and consecutive surgery as an independent prognostic marker. Staining for intranodal lymphangiogenesis and methods of intravital imaging of lymphangiogenesis and lymphatic flow may be a useful strategy to predict long-term outcome in rectal cancer patients. Furthermore, addition of VEGF-blocking agents to standardized neoadjuvant treatment schemes might be indicated in advanced rectal cancer.
Tumor-induced lymphangiogenesis in cervical lymph nodes in oral melanoma-bearing mice  [cached]
Ozasa Ryuki,Ohno Jun,Iwahashi Teruaki,Taniguchi Kunihisa
Journal of Experimental & Clinical Cancer Research , 2012, DOI: 10.1186/1756-9966-31-83
Abstract: Background Metastasis via the lymphatic system is promoted by lymphangiogenesis. Alterations of the lymphatic channels during the progression of metastasis to regional lymph nodes (LNs) remain unexplored. To examine whether tumor-induced LN lymphangiogenesis controls metastasis to regional LNs, we investigated cervical LN metastasis in a mouse model of oral melanoma. Methods Injection of B16F10 melanoma cells into mouse tongues replicated spontaneous cervical LN metastasis. We performed histological, immunofluorescent, and histomorphometric analyses of tumor-reactive lymphadenopathy and lymphangiogenesis in tumor-associated LNs. We investigated the expression of vascular endothelial growth factor (VEGF)-C and its receptor, VEGF receptor-3 (VEGFR-3), in tumor cells and tissues, and LNs by reverse transcription polymerase chain reaction and immunofluorescence. Results Tumor-associated LNs comprised sentinel LNs (SLNs) before and after tumor cell invasion (tumor-bearing SLNs), and LNs adjacent or contralateral to tumor-bearing SLNs. Extensive lymphangiogenesis appeared in SLNs before evidence of metastasis. After metastasis was established in SLNs, both LNs adjacent and contralateral to tumor-bearing SLNs demonstrated lymphangiogenesis. Interaction between VEGF-C-positive melanoma cells and VEGFR-3-positive lymphatic vessels was evident in tumor-associated LNs. Conclusions LN lymphangiogenesis contributes a progression of tumor metastasis from SLNs to other regional LNs.
Peritumoral lymphangiogenesis induced by vascular endothelial growth factor C and D promotes lymph node metastasis in breast cancer patients  [cached]
Zhao Ying-Chun,Ni Xiao-Jian,Li Yong,Dai Min
World Journal of Surgical Oncology , 2012, DOI: 10.1186/1477-7819-10-165
Abstract: Background Mounting clinical and experimental data suggest that the migration of tumor cells into lymph nodes is greatly facilitated by lymphangiogenesis. Vascular endothelial growth factor (VEGF)-C and D have been identified as lymphangiogenic growth factors and play an important role in tumor lymphangiogenesis. The purpose of this study was to investigate the location of lymphangiogenesis driven by tumor-derived VEGF-C/D in breast cancer, and to determine the role of intratumoral and peritumoral lymphatic vessel density (LVD) in lymphangiogenesis in breast cancer. Methods The expression levels of VEGF-C/D were determined by immunohistochemistry, and intratumoral LVD and peritumoral LVD were assessed using immunohistochemistry and the D2-40 antibody in 73 patients with primary breast cancer. The associations of intratumoral LVD and peritumoral LVD with VEGF-C/D expression, clinicopathological features and prognosis were assessed. Results VEGF-C and D expression were significantly higher in breast cancer than benign disease (P < 0.01). VEGF-C (P < 0.001) and VEGF-D (P = 0.005) expression were significantly associated with peritumoral LVD, but not intratumoral LVD. Intratumoral LVD was associated with tumor size (P = 0.01). Peritumoral LVD was significantly associated with lymph node metastasis (LNM; P = 0.005), lymphatic vessel invasion (LVI; P = 0.017) and late tumor,node, metastasis (TNM) stage (P = 0.011). Moreover, peritumoral LVD was an independent risk factor for axillary lymph node metastasis, overall survival and disease-free survival in multivariate analysis. Conclusions This study suggests that tumor-derived VEGF-C/D induce peritumoral lymphangiogenesis, which may be one mechanism that leads to lymphatic invasion and metastatic spread. Peritumoral LVD has potential as an independent prognostic factor in breast cancer patients.
The prognostic value of detection of serum VEGF-C level and lymphangiogenesis in mediastinal lymph nodes in the patients with lung cancer  [cached]
Yang SHENTU,Tiancheng ZHAO,Zhengping DING,Yunzhong ZHOU
Chinese Journal of Lung Cancer , 2008,
Abstract: Background and objective There is still lack of special prognostic factor on lung cancer, this study will explore the prognostic value of serum VEGF-C level and lymphangiogenesis of primary cancer and mediastinal lymph nodes in the patients with lung cancer. Methods Thirty patients with NSCLC would accept operation (new group) and 30cases followed up three years postoperative (history group) were chosen respectively. The serum VEGF-C level of new group was tested. The VEGF-C and LYVE-1 expression in the mediastinal lymph nodes were put in practice between two groups. The relationship was analyzed for the serum VEGF-C level, VEGF-C and LYVE-1 expression of primary cancerand mediastinal lymph nodes, mediastinal lymph nodes metastasis and the 3-year survival rate of the patients. Results ①In new group, the serum VEGF-C level of N2 patients was significantly higher than that of non-N2 patients. ②In new group, the serum VEGF-C level was closely correlated with VEGF-C expression of primary cancer. ③In two groups, the primary cancer and mediastinal metastasis lymph nodes had high VEGF-C expression. ④VEGF-C expression of primary cancer and mediastinal lymph nodes was closely correlated with LYVE-1 expression between the two groups. ⑤VEGF-C and LYVE-1 expression of N2 patients was significantly higher than that of non-N2 patients between two groups. ⑥The patients' 3-year-survival rate was closely correlated with VEGF-C expression of primary cancer and mediastinal lymphnodes metastasis. Conclusion Serum VEGF-C level has close correlation with VEGF-C expression of primary cancer, lymphangiogenesis of primary cancer/mediastinal lymph nodes, mediastinal lymph nodes metastasis status and patient's survival rate. Serum VEGF-C level is possible to be used as prognostic factor on lung cancer.
Lymphangiogenesis and Axillary Lymph Node Metastases Correlated with VEGF-C Expression in Two Immunocompetent Mouse Mammary Carcinoma Models  [PDF]
Yuko Ito,Masa-Aki Shibata,Nabil Eid,Junji Morimoto,Yoshinori Otsuki
International Journal of Breast Cancer , 2011, DOI: 10.4061/2011/867152
Abstract: Lymphangiogenesis and the expression of vascular endothelial cell growth factor C (VEGF-C) in tumors have been considered to be causally promoting lymphatic metastasis. There are only a few studies on lymphatic metastasis in immunocompetent allograft mouse models. To study the relationship between VEGF-C-mediated lymphangiogenesis and axillary lymph node metastasis, we used two mouse mammary carcinoma cell lines; the BJMC338 has a low metastatic propensity, whereas the BJMC3879 has a high metastatic propensity although it originated from the former cell line. Each cell line was injected separately into two groups of female BALB/c mice creating in vivo mammary cancer models. The expression level of VEGF-C in BJMC3879 was higher than BJMC338. As the parent cell line, BJMC3879-derived tumors showed higher expression of VEGF-C compared to BJMC338-derived tumors. This higher expression of VEGF-C in BJMC3879-derived tumors was associated with marked increase in infiltrating macrophages and enhanced expression of lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1) reflecting increased tumoral lymphatic density and subsequent induction of axillary lymph node metastasis. Our mouse mammary carcinoma models are allotransplanted tumors showing the same axillary lymph node metastatic spectrum as human breast cancers. Therefore, our mouse models are ideal for exploring the various molecular mechanisms of cancer metastasis. 1. Introduction Based on clinical and pathological observations in human mammary carcinomas, the metastatic spread of mammary carcinoma cells is responsible for the majority of cancer deaths [1–5]. The common pathway of initial cancer dissemination is via lymphatics due to their characteristic endothelial structure with blind-ending capillaries [6]. In addition, metastasis to the regional lymph nodes through the lymphatic vessels is considered to be a common step in the progression of cancer and an important prognostic factor in many types of cancer including breast carcinomas. Lymphatic vessel density (LVD) in many types of solid cancer is associated with lymph node metastasis or poor prognosis, as has been reported in experimental and clinical studies [1–5, 7, 8]. Although mammary carcinoma is well known to have the character for lymph node metastasis, there are only a few mouse mammary carcinoma models showing extensive metastasis to lymph nodes. The chick embryo chorioallantoic membrane [9] and immunodeficient mice, SCID mice, or nude mice were used as xenotransplanted host animals to examine metastasis [10–12]. Recent studies have
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