ORCID Profile
0000-0002-7930-1206
Current Organisations
Michigan State University
,
Peter MacCallum Cancer Centre
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Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-2020
Publisher: Public Library of Science (PLoS)
Date: 24-11-2014
Publisher: Elsevier BV
Date: 02-2006
DOI: 10.1016/J.PUPT.2005.02.003
Abstract: Endothelial cells line the vessels which transport fluid and cells throughout the body. Although much attention has been paid to these cells in the context of the blood vascular system, endothelial cells also line lymphatic vessels. Recent progress in identifying growth factors which drive the development of lymphatic vessels and molecular markers specific for lymphatics has expanded our understanding of the role the lymphatic system plays in human pathology. Techniques for purifying populations of lymphatic endothelial cells also allow the in vitro analysis of this unique surface to explore its role in tumour metastasis, immune cell function and fluid transport. This review provides a synopsis of the recent data pertaining to the purification and culture of lymphatic endothelial cells, and the interaction of tumour cells with lymphatic endothelium.
Publisher: MDPI AG
Date: 26-10-2023
DOI: 10.3390/NU15214542
Publisher: Wiley
Date: 09-03-2006
DOI: 10.1002/9780470062128.CH4
Abstract: The lymphatic network functions to return fluid, cells and macromolecules to the circulation. Recent characterization of growth factors that control the growth and development of the lymphatics, and markers which specify lymphatic endothelial cells have enhanced our understanding of this system. Members of the VEGF family of factors are key regulators of these vessels with VEGF-C/VEGF-D and VEGFR-3 being the best validated signalling pathways in lymphangiogenesis. The study of these molecules in various pathologies has shown that they are important in the processes of cancer metastasis and in the formation of lymphoedema. Knowledge of these molecular pathways allows for the generation of modulators of these pathways which could form the basis of novel therapeutic approaches.
Publisher: American Association for Cancer Research (AACR)
Date: 02-2016
DOI: 10.1158/1538-7445.FBCR15-B04
Abstract: The Eph family of receptor tyrosine kinases, and their ephrin ligands, are key regulators of cell migration and tissue patterning which are crucial for the growth and assembly of blood vessels during embryonic development and in tumor angiogenesis. In particular, class A Ephs and ephrins are emerging as regulators and clinical targets in the tumor vasculature. EphA3 is expressed in perivascular cells during embryogenesis but is largely absent from mature vasculature. Recently we discovered the expression of EphA3 in the perivascular mesenchymal cells and some endothelial cells of clinical and experimental solid tumors, as well as in the regenerating human endometrium. Targeting of EphA3 in experimental tumors with an activating antibody inhibited tumor growth by disrupting the stroma and vasculature. We now seek to understand at a cellular and molecular level the role of EphA3 in regulating angiogenesis, as well as the factors controlling its expression, using refined in vivo and in vitro models. In a dorsal skin diffusion chamber assay, angiogenesis induced by tumor-secreted factors was inhibited dose-dependently by an activating EphA3 antibody. This indicates that EphA3’s role in regulating tumor-induced angiogenesis does not require direct contact with tumor cells and, as with other Ephs, is likely intrinsic to the various cells comprising blood vessels. In vitro angiogenesis assays such as aortic ring sprouting and embryoid body differentiation assays were subsequently used to investigate the expression and function of EphA3 in endothelial and perivascular cells during vascular growth, in conjunction with EphA3-null and inducible EphA3-shRNA transgenic mice. In embryoid bodies undergoing vasculogenic differentiation, EphA3 was expressed at the intercellular junctions of nascent endothelial tubules, independently of perivascular cell association. 2-dimensional cultures of embryoid body-derived endothelial cells also abundantly expressed EphA3. In aortic ring sprouting assays, EphA3 was expressed in endothelial sprouts and abundantly in associated perivascular cells. Derivation of aortic mural cell cultures endogenously expressing EphA3 provides an important tool for exploring EphA3 regulation and signaling in perivascular cells. Our results indicate that expression of EphA3 in endothelial and perivascular cells characterizes a state of active growth and differentiation during angiogenesis. Notably this expression pattern is common to a number of different angiogenic settings. These data provide further support for EphA3 as an anti-angiogenic target in cancer and other pathologies. Citation Format: Rae H. Farnsworth, Mary E. Vail, Magdaline Costa, Linda Hii, Ross A. Dickins, Andrew G. Elefanty, Edouard G. Stanley, Martin Lackmann. A role for EphA3 in angiogenesis, in vivo and in vitro exploration. [abstract]. In: Proceedings of the Fourth AACR International Conference on Frontiers in Basic Cancer Research 2015 Oct 23-26 Philadelphia, PA. Philadelphia (PA): AACR Cancer Res 2016 (3 Suppl):Abstract nr B04.
Publisher: Mary Ann Liebert Inc
Date: 2017
DOI: 10.1089/ADT.2016.764
Abstract: The lymphatic system is a series of vessels that transport cells and excess fluid from tissues to the blood vascular system. Normally quiescent, the lymphatics can grow or remodel in response to developmental, immunological, or cells pathological stimuli. Lymphatic vessels comprise lymphatic endothelial cells (LECs) that can respond to external growth factors by undergoing proliferation, migration, adhesion, and tube and lumen formation into new vessel structures, a process known as lymphangiogenesis. To understand the key gene and signaling pathways necessary for lymphangiogenesis and lymphatic vessel remodeling, we have developed a three-dimensional LEC tube formation assay to explore the role of kinase signaling in these processes. The collagen-overlay-based assay was used with primary human adult dermal LECs to investigate a library of 60 tyrosine kinase (TK) and TK-like genes by siRNA knockdown. Nine candidate genes were identified and characterized for their ability to modify key parameters of lymphatic tube formation, including tube length, area, thickness, branching, and number of blind-ended sacs. Four genes-ZAP70, IRAK4, RIPK1, and RIPK2-were identified as high-confidence hits after tertiary deconvolution screens and demonstrate the utility of the assay to define LEC genes critical for the formation of tube structures. This assay facilitates the identification of potential molecular targets for novel drugs designed to modulate the remodeling of lymphatics that is important for the metastatic spread of cancer and other pathologies.
Publisher: American Association for Cancer Research (AACR)
Date: 04-2019
DOI: 10.1158/0008-5472.CAN-18-1858
Abstract: The study shows that the remodeling of lymphatic vessels in cancer is influenced by CCL27 and CCL28 chemokines, which may provide a future target to modulate metastatic spread.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 03-10-2017
DOI: 10.1126/SCISIGNAL.AAL2987
Abstract: Lymphatic vessels constitute a specialized vasculature that is involved in development, cancer, obesity, and immune regulation. The migration of lymphatic endothelial cells (LECs) is critical for vessel growth (lymphangiogenesis) and vessel remodeling, processes that modify the lymphatic network in response to developmental or pathological demands. Using the publicly accessible results of our genome-wide siRNA screen, we characterized the migratome of primary human LECs and identified in idual genes and signaling pathways that regulate LEC migration. We compared our data set with mRNA differential expression data from endothelial and stromal cells derived from two in vivo models of lymphatic vessel remodeling, viral infection and contact hypersensitivity-induced inflammation, which identified genes selectively involved in regulating LEC migration and remodeling. We also characterized the top candidates in the LEC migratome in primary blood vascular endothelial cells to identify genes with functions common to lymphatic and blood vascular endothelium. On the basis of these analyses, we showed that
Publisher: Springer Science and Business Media LLC
Date: 17-04-2013
DOI: 10.1007/S10585-013-9581-X
Abstract: Metastasis to regional lymph nodes is an important and early event in many tumors. Vascular endothelial growth factor-C (VEGF-C), VEGF-D and their receptor VEGFR-3, play a role in tumor spread via the lymphatics, although the timing of their involvement is not understood. In contrast, VEGFR-2, activated by VEGF-A, VEGF-C and VEGF-D, is a mediator of angiogenesis and drives primary tumor growth. We demonstrate the critical role for VEGFR-3, but not VEGFR-2, in the early events of metastasis. In a tumor model exhibiting both VEGF-D-dependent angiogenesis and lymphangiogenesis, an antibody to VEGFR-2 (DC101) was capable of inhibiting angiogenesis (79 % reduction in PECAM + blood vessels) and growth (93 % reduction in tumor volume). However, unlike an anti-VEGFR-3 Mab (mF4-31C1), DC101 was not capable of eliminating either tumor lymphangiogenesis or lymphogenous metastasis (60 % reduction of lymph node metastasis by DC101 vs 95 % by mF4-31C1). Early excision of the primary tumors demonstrated that VEGF-D-mediated tumor spread precedes angiogenesis-induced growth. Small but highly metastatic primary human breast cancers had significantly higher lymphatic vessel density (23.1 vessels/mm(2)) than size-matched (11.7) or larger non-metastatic tumors (12.4) thus supporting the importance of lymphatic vessels, as opposed to angiogenesis-mediated primary tumor growth, for nodal metastasis. These results suggest that lymphangiogenesis via VEGF-D is more critical than angiogenesis for nodal metastasis.
Publisher: Elsevier BV
Date: 08-2018
DOI: 10.1016/J.COI.2018.04.008
Abstract: While the link between the lymphatic system and the metastatic spread of cancer is centuries old, understanding of the underlying mechanisms is still evolving. Lymphatic vessels provide a route for tumour cells to reach regional lymph nodes (LNs), which is prognostic of distant organ metastasis and poor survival. However, genomic analyses of metastatic cancer now reveal complex patterns of dissemination. The lymphatic endothelial cells lining lymphatics respond to molecular cues from the tumour microenvironment, mediating growth and remodelling of lymphatic vessels at the primary tumour, draining LNs and distant premetastatic niches. Recent studies emphasise that this not only supports metastasis but also influences antitumour immunity. Understanding the complex interactions between tumour cells, the immune system and lymphatics will be essential to inform developing therapeutic and prognostic approaches to cancer.
Publisher: Informa UK Limited
Date: 13-11-2014
DOI: 10.3109/08977194.2014.982276
Abstract: Eph receptor tyrosine kinases control cell-cell interactions during normal and oncogenic development, and are implicated in a range of processes including angiogenesis, stem cell maintenance and metastasis. They are thus of great interest as targets for cancer therapy. EphA3, originally isolated from leukemic and melanoma cells, is presently one of the most promising therapeutic targets, with multiple tumor-promoting roles in a variety of cancer types. This review focuses on EphA3, its functions in controlling cellular behavior, both in normal and pathological development, and most particularly in cancer.
Publisher: Springer Science and Business Media LLC
Date: 05-08-2013
DOI: 10.1038/ONC.2013.304
Abstract: The growth and dissemination of tumors rely on an altered vascular network, which supports their survival and expansion and provides accessibility to the vasculature and a route of transport for metastasizing tumor cells. The remodeling of vascular structures through generation of new vessels (for ex le, via tumor angiogenesis) is a well studied, even if still quite poorly understood, process in human cancer. Antiangiogenic therapies have provided insight into the contribution of angiogenesis to the biology of human tumors, yet have also revealed the ease with which resistance to antiangiogenic drugs can develop, presumably involving alterations to vascular signaling mechanisms. Furthermore, cellular and/or molecular changes to pre-existing vessels could represent subtle pre-metastatic alterations to the vasculature, which are important for cancer progression. These changes, and associated molecular markers, may forecast the behavior of in idual tumors and contribute to the early detection, diagnosis and prognosis of cancer. This review, which primarily focuses on the blood vasculature, explores current knowledge of how tumor vessels can be remodeled, and the cellular and molecular events responsible for this process.
Publisher: Frontiers Media SA
Date: 20-12-2016
Publisher: MDPI AG
Date: 04-03-2022
DOI: 10.3390/BIOM12030401
Abstract: Primary tumours, particularly from major solid organs, are able to disseminate into the blood and lymphatic system and spread to distant sites. These secondary metastases to other major organs are the most lethal aspect of cancer, accounting for the majority of cancer deaths. The brain is a frequent site of metastasis, and brain metastases are often fatal due to the critical role of the nervous system and the limited options for treatment, including surgery. This creates a need to further understand the complex cell and molecular biology associated with the establishment of brain metastasis, including the changes to the environment of the brain to enable the arrival and growth of tumour cells. Local changes in the vascular network, immune system and stromal components all have the potential to recruit and foster metastatic tumour cells. This review summarises our current understanding of brain vascular microenvironments, fluid circulation and drainage in the context of brain metastases, as well as commenting on current cutting-edge experimental approaches used to investigate changes in vascular environments and alterations in specialised subsets of blood and lymphatic vessel cells during cancer spread to the brain.
Publisher: Informa UK Limited
Date: 21-07-2022
DOI: 10.1080/08977194.2022.2087520
Abstract: Organ-specific metastasis to secondary organs is dependent on the formation of a supportive pre-metastatic niche. This tissue-specific microenvironmental response is thought to be mediated by mutational and epigenetic changes to primary tumour cells resulting in altered cross-talk between cell types. This response is augmented through the release of tumour and stromal signalling mediators including cytokines, chemokines, exosomes and growth factors. Although researchers have elucidated some of the cancer-promoting features that are bespoke to organotropic metastasis to the lungs, it remains unclear if these are organ-specific or generic between organs. Understanding the mechanisms that mediate the metastasis-promoting synergy between the host microenvironment, immunity, and pulmonary structures may elucidate predictive, prognostic and therapeutic markers that could be targeted to reduce the metastatic burden of disease. Herein, we give an updated summary of the known cellular and molecular mechanisms that contribute to the formation of the lung pre-metastatic niche and tissue-specific metastasis.
Publisher: Frontiers Media SA
Date: 12-04-2019
Publisher: American Association for Cancer Research (AACR)
Date: 12-10-2011
DOI: 10.1158/0008-5472.CAN-11-0200
Abstract: Lymph node metastasis, an early and prognostically important event in the progression of many human cancers, is associated with expression of VEGF-D. Changes to lymph node vasculature that occur during malignant progression may create a metastatic niche capable of attracting and supporting tumor cells. In this study, we sought to characterize molecules expressed in lymph node endothelium that could represent therapeutic or prognostic targets. Differential mRNA expression profiling of endothelial cells from lymph nodes that drained metastatic or nonmetastatic primary tumors revealed genes associated with tumor progression, in particular bone morphogenetic protein-4 (BMP-4). Metastasis driven by VEGF-D was associated with reduced BMP-4 expression in high endothelial venules, where BMP-4 loss could remodel the typical high-walled phenotype to thin-walled vessels. VEGF-D expression was sufficient to suppress proliferation of the more typical BMP-4–expressing high endothelial venules in favor of remodeled vessels, and mechanistic studies indicated that VEGF receptor-2 contributed to high endothelial venule proliferation and remodeling. BMP-4 could regulate high endothelial venule phenotype and cellular function, thereby determining morphology and proliferation responses. Notably, therapeutic administration of BMP-4 suppressed primary tumor growth, acting both at the level of tumor cells and tumor stromal cells. Together, our results show that VEGF-D–driven metastasis induces vascular remodeling in lymph nodes. Furthermore, they implicate BMP-4 as a negative regulator of this process, suggesting its potential utility as a prognostic marker or antitumor agent. Cancer Res 71(20) 6547–57. ©2011 AACR.
No related grants have been discovered for Rae Farnsworth.