Studies of the tumor-vasculature interface : role of TGF-beta 1-induced epithelial to mesenchymal transition
Author: Pang, Mei-Fong
Date: 2013-02-15
Location: Föreläsningssal Farmakologi, Karolinska Institutet, Campus Solna
Time: 09.30
Department: Inst för medicinsk biokemi och biofysik / Dept of Medical Biochemistry and Biophysics
Abstract
Tumor metastasis is a complex multistep process. Among key steps that occur during metastatic spread are acquisition of tumor cell motility, intravasation of tumor cells into blood or lymphatic vessels and extravasation of tumor cells at distal sites. However, the precise mechanisms that govern these metastatic steps remain elusive. This thesis aimed to bridge the fields of tumor and vascular biology to provide new insights into the metastatic process. Results are presented indicating a role of the cytokine transforming growth factor beta (TGF-β) in activating breast cancer cells for dissemination through the lymphatic system through re-activation of a latent development process termed epithelial to mesenchymal transition (EMT). Furthermore, essential roles of the coxsackie-and adenovirus receptor (CAR) for lymph vessel development, and the sphingosine-1-phosphate receptor (S1PR1) for blood vessel stabilization are presented. We expect the findings to have impact on our understanding of the interface between tumor and vascular biology and to influence future strategies to target cancer metastasis.
In paper I, we present data identifying an essential role of CAR for normal development of lymphatic vessels in the mouse. We show that genetic deletion of the CAR gene (Cxadr) from E12.5 during mouse development leads to subcutaneous edema, hemorrhage and embryonic death. The lymphatic vessels in CAR-deficient mice were dilated and structurally abnormal with the presence of gaps and holes at lymphatic endothelial cell-cell junctions. In addition, blood-filled lymphatics were observed in CAR-deficient mice suggesting an incomplete separation between the blood and lymphatic vascular systems. The data demonstrate that CAR plays a crucial role in the development of lymphatic vasculature in mice through formation of lymphatic endothelial cell-cell junctions.
In paper II, we demonstrate that S1PR1 plays critical role in suppressing angiogenesis and promoting vascular stability during mouse development. S1PR1 signaling promotes cell-cell adhesion and prevents sprouting angiogenesis whereas S1PR1-deficiency leads to hypersprouting angiogenesis. These data suggest that S1PR1 signaling might protect developing blood vessels from abnormal angiogenic signals through promotion of vascular stability.
In paper III, we show that TGF-β-induced EMT promotes chemotactic migration of tumor cells through the lymphatic system by mediating crosstalk between tumor cells and lymphatic endothelial cells through the chemokine receptor 7 (CCR7) and its chemokine ligand, CCL21. Reversal of EMT process through p38 MAPK inhibition inhibited tumor cell invasion in vitro and migration towards the lymphatics in vivo suggesting that p38 MAPK inhibition may be a useful therapeutic approach to inhibit tumor cell dissemination through the lymphatic system.
In paper IV, we describe development of a novel co-culture system to study tumor cell migration and interaction with lymphatic endothelial cells within a 3-dimensional matrix component. This assay allows manipulation of tumor properties or matrix components and can be used as a platform to screen for pharmacological agents which inhibit tumor-endothelial interactions.
In paper I, we present data identifying an essential role of CAR for normal development of lymphatic vessels in the mouse. We show that genetic deletion of the CAR gene (Cxadr) from E12.5 during mouse development leads to subcutaneous edema, hemorrhage and embryonic death. The lymphatic vessels in CAR-deficient mice were dilated and structurally abnormal with the presence of gaps and holes at lymphatic endothelial cell-cell junctions. In addition, blood-filled lymphatics were observed in CAR-deficient mice suggesting an incomplete separation between the blood and lymphatic vascular systems. The data demonstrate that CAR plays a crucial role in the development of lymphatic vasculature in mice through formation of lymphatic endothelial cell-cell junctions.
In paper II, we demonstrate that S1PR1 plays critical role in suppressing angiogenesis and promoting vascular stability during mouse development. S1PR1 signaling promotes cell-cell adhesion and prevents sprouting angiogenesis whereas S1PR1-deficiency leads to hypersprouting angiogenesis. These data suggest that S1PR1 signaling might protect developing blood vessels from abnormal angiogenic signals through promotion of vascular stability.
In paper III, we show that TGF-β-induced EMT promotes chemotactic migration of tumor cells through the lymphatic system by mediating crosstalk between tumor cells and lymphatic endothelial cells through the chemokine receptor 7 (CCR7) and its chemokine ligand, CCL21. Reversal of EMT process through p38 MAPK inhibition inhibited tumor cell invasion in vitro and migration towards the lymphatics in vivo suggesting that p38 MAPK inhibition may be a useful therapeutic approach to inhibit tumor cell dissemination through the lymphatic system.
In paper IV, we describe development of a novel co-culture system to study tumor cell migration and interaction with lymphatic endothelial cells within a 3-dimensional matrix component. This assay allows manipulation of tumor properties or matrix components and can be used as a platform to screen for pharmacological agents which inhibit tumor-endothelial interactions.
List of papers:
I. Momina Mirza, Mei-Fong Pang, Mohamad Amr Zaini, Paula Haiko, Tuomas Tammela, Kari Alitalo, Lennart Philipson, Jonas Fuxe and Kerstin Sollerbrant. (2012) Essential Role of Coxsackie – and Adenovirus Receptor (CAR) in Development of the Lymphatic System in Mice. PLoS ONE. 7(5): e37523.
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II. Konstantin Gaengel, Colin Niaudet*, Kazuhiro Hagikura, Bàrbara Laviña Siemsen, Lars Muhl, Jennifer J. Hofmann, Lwaki Ebarasi, Staffan Nyström, Simin Rymo, Long Long Chen, Mei-Fong Pang, Yi Jin, Elisabeth Raschperger, Pernilla Roswall, Dörte Schulte, Rui Benedito, Jimmy Larsson, Mats Hellström, Jonas Fuxe, Per Uhlén, Ralf Adams, Lars Jakobsson, Arindam Majumdar, Dietmar Vestweber, Anne Uv, Christer Betsholtz. (2012) The sphingosine-1-phosphate receptor S1P1 negative regulates sprouting angiogenesis by modulating the interplay between VE-Cadherin and VEGFR2. Developmental Cell. 23 (3): pp 587-599.
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III. Mei-Fong Pang, Anna-Maria Georgoudaki, Kazuhiro Hagikura, Malin Jansson, Malin Sund, Christer Betsholtz, Mikael C. I. Karlsson and Jonas Fuxe. TGF-β-induced Epithelial-Mesenchymal Transition Activates Breast Cancer Cells for Lymphatic Dissemination. [Submitted]
IV. Mei-Fong Pang, Yi Jin, Lars Jakobsson and Jonas Fuxe. A Three-Dimensional Beads Invasion Assay to Study Tumor Cell Migration and Interaction with Lymphatic Endothelial Cells. [Manuscript]
I. Momina Mirza, Mei-Fong Pang, Mohamad Amr Zaini, Paula Haiko, Tuomas Tammela, Kari Alitalo, Lennart Philipson, Jonas Fuxe and Kerstin Sollerbrant. (2012) Essential Role of Coxsackie – and Adenovirus Receptor (CAR) in Development of the Lymphatic System in Mice. PLoS ONE. 7(5): e37523.
Fulltext (DOI)
Pubmed
View record in Web of Science®
II. Konstantin Gaengel, Colin Niaudet*, Kazuhiro Hagikura, Bàrbara Laviña Siemsen, Lars Muhl, Jennifer J. Hofmann, Lwaki Ebarasi, Staffan Nyström, Simin Rymo, Long Long Chen, Mei-Fong Pang, Yi Jin, Elisabeth Raschperger, Pernilla Roswall, Dörte Schulte, Rui Benedito, Jimmy Larsson, Mats Hellström, Jonas Fuxe, Per Uhlén, Ralf Adams, Lars Jakobsson, Arindam Majumdar, Dietmar Vestweber, Anne Uv, Christer Betsholtz. (2012) The sphingosine-1-phosphate receptor S1P1 negative regulates sprouting angiogenesis by modulating the interplay between VE-Cadherin and VEGFR2. Developmental Cell. 23 (3): pp 587-599.
Fulltext (DOI)
Pubmed
View record in Web of Science®
III. Mei-Fong Pang, Anna-Maria Georgoudaki, Kazuhiro Hagikura, Malin Jansson, Malin Sund, Christer Betsholtz, Mikael C. I. Karlsson and Jonas Fuxe. TGF-β-induced Epithelial-Mesenchymal Transition Activates Breast Cancer Cells for Lymphatic Dissemination. [Submitted]
IV. Mei-Fong Pang, Yi Jin, Lars Jakobsson and Jonas Fuxe. A Three-Dimensional Beads Invasion Assay to Study Tumor Cell Migration and Interaction with Lymphatic Endothelial Cells. [Manuscript]
Institution: Karolinska Institutet
Supervisor: Fuxe, Jonas
Issue date: 2013-01-28
Rights:
Publication year: 2013
ISBN: 978-91-7549-014-4
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