Vascular development and safeguard mechanisms against tumorigenesis : oncogene-induced apoptosis and cellular senescence
Author: Hejll, Eduar
Date: 2012-09-13
Location: Aulan MTC, Nobels väg 16, KI Solna Campus
Time: 13.00
Department: Inst för mikrobiologi, tumör- och cellbiologi / Dept of Microbiology, Tumor and Cell Biology
Abstract
Angiogenesis, apoptosis and senescence are all cellular processes that have an impact on tumor development. Angiogenesis or the new vessel formation from pre-existing ones is known to be required for invasive tumor growth and metastasis. Apoptosis and cellular senescence are both considered crucial safeguards mechanisms against neoplastic transformation. The MYC oncogene plays an important role in the regulation of all three of these as well as many other fundamental processes crucial for cell growth and tumorigenesis.
In the first part of this thesis we explored endothelial cell migration by the exposure of human vein endothelial cells (HUVECs) and human umbilical artery endothelial cells (HUAECs) to stable hill-shaped gradients of vascular endothelial growth factor (VEGF) and fibroblast growth factor 2 (FGF2). Time-lapse analysis showed that a gradient of VEGFA165 efficiently induced chemotaxis of endothelial cells of different vascular origin. Stable gradients of FGF2 were able to attract venular but no arterial endothelial cells. In addition to the directed migration of endothelial cells, we also investigated the lymphatic vessel formation in the developing mice kidney. Immunohistochemical analysis of kidney explants and whole mount of dissected kidney suggested that renal lymphatic vessel formation predominately occurs via invasive sprouting from surrounding lymphatic plexus.
In the second part of this thesis, we first aimed to clarify the relative importance of the intrinsic (mitochondrial) and extrinsic (death receptor) anti apoptotic pathways in the in vivo MYC driven transformation of hematopoietic stem cells. Expression of MYC alone resulted in the development of both myeloid and T-lymphoid tumors within two months after transplantation of HSCs. Expression of MYC together with BCL-XL or BCL-2 (inhibiting the intrinsic pathway) resulted in almost immediate development of AML like disease. In contrast, expression of MYC together with FLIPL (inhibiting the extrinsic pathway) did not accelerate tumorigenesis. These results suggest that MYC-induced transformation of HSC accelerates and polarizes hematopoietic tumor development towards aggressive AML by co-expression of inhibitors of the intrinsic but not the extrinsic pathway of apoptosis.
Secondly, we aimed to determine whether pharmacological inhibition of cyclin dependent kinase 2 (CDK2) interferes with MYC-driven tumor development in vivo trough senescence. Mice transplanted with HSCs expressing MYC and BCL-XL as briefly described above were treated with a specific CDK2 inhibitor on daily basis via intraperitoneal injections or osmotic minipumps. Despite the very aggressive AML development in this model, CDK2 targeting significantly delayed the onset of disease and improved mice survival by restoring senescence. The senescence induction correlated with induction of p19ARF, p21CIP1 and activation of pRb. This suggests that pro-senescence therapy via CDK2 inhibition should be further evaluated as a new potential strategy to combat MYC-driven AML and possibly other MYC-related tumors.
In the first part of this thesis we explored endothelial cell migration by the exposure of human vein endothelial cells (HUVECs) and human umbilical artery endothelial cells (HUAECs) to stable hill-shaped gradients of vascular endothelial growth factor (VEGF) and fibroblast growth factor 2 (FGF2). Time-lapse analysis showed that a gradient of VEGFA165 efficiently induced chemotaxis of endothelial cells of different vascular origin. Stable gradients of FGF2 were able to attract venular but no arterial endothelial cells. In addition to the directed migration of endothelial cells, we also investigated the lymphatic vessel formation in the developing mice kidney. Immunohistochemical analysis of kidney explants and whole mount of dissected kidney suggested that renal lymphatic vessel formation predominately occurs via invasive sprouting from surrounding lymphatic plexus.
In the second part of this thesis, we first aimed to clarify the relative importance of the intrinsic (mitochondrial) and extrinsic (death receptor) anti apoptotic pathways in the in vivo MYC driven transformation of hematopoietic stem cells. Expression of MYC alone resulted in the development of both myeloid and T-lymphoid tumors within two months after transplantation of HSCs. Expression of MYC together with BCL-XL or BCL-2 (inhibiting the intrinsic pathway) resulted in almost immediate development of AML like disease. In contrast, expression of MYC together with FLIPL (inhibiting the extrinsic pathway) did not accelerate tumorigenesis. These results suggest that MYC-induced transformation of HSC accelerates and polarizes hematopoietic tumor development towards aggressive AML by co-expression of inhibitors of the intrinsic but not the extrinsic pathway of apoptosis.
Secondly, we aimed to determine whether pharmacological inhibition of cyclin dependent kinase 2 (CDK2) interferes with MYC-driven tumor development in vivo trough senescence. Mice transplanted with HSCs expressing MYC and BCL-XL as briefly described above were treated with a specific CDK2 inhibitor on daily basis via intraperitoneal injections or osmotic minipumps. Despite the very aggressive AML development in this model, CDK2 targeting significantly delayed the onset of disease and improved mice survival by restoring senescence. The senescence induction correlated with induction of p19ARF, p21CIP1 and activation of pRb. This suggests that pro-senescence therapy via CDK2 inhibition should be further evaluated as a new potential strategy to combat MYC-driven AML and possibly other MYC-related tumors.
List of papers:
I. Endothelial cell migration in stable gradients of vascular endothelial growth factor A and fibroblast growth factor 2: effects on chemotaxis and chemokinesis. Irmeli Barkefors, Sébastien Le Jan, Lars Jakobsson, Eduar Hejll, Gustav Carlson, Henrik Johansson, Jonas Jarvius, Jeong Won Park, Noo Li Jeon and Johan Kreuger. J Biol Chem. 2008, 283,13905-13912.
Fulltext (DOI)
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II. In vivo and ex vivo studies of lymphatic vessel formation in the developing mouse kidneys. Eduar Hejll, Fredrik Lanner, Filip Farnebo, Lars-Gunnar Larsson and Leif Oxburgh. [Manuscript]
III. Inhibition of the intrinsic but not the extrinsic apoptosis pathway accelerates and drives Myc-driven tumorigenesis towards acute myeloid leukemia. Högstrand K, Hejll E, Sander B, Rozell B, Larsson LG, Grandien A. PLoS One. 2012;7(2):e31366. Epub 2012 Feb 29
Fulltext (DOI)
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IV. Restoration of senescence upon Cdk2 inactivation delays MYC-driven acute myeloblastic leukemia. Eduar Hejll, Matteo Bocci, Vedrana Tabor, Per hydbring, Alf Grandien and Lars-Gunnar Larsson. [Manuscript]
I. Endothelial cell migration in stable gradients of vascular endothelial growth factor A and fibroblast growth factor 2: effects on chemotaxis and chemokinesis. Irmeli Barkefors, Sébastien Le Jan, Lars Jakobsson, Eduar Hejll, Gustav Carlson, Henrik Johansson, Jonas Jarvius, Jeong Won Park, Noo Li Jeon and Johan Kreuger. J Biol Chem. 2008, 283,13905-13912.
Fulltext (DOI)
Pubmed
View record in Web of Science®
II. In vivo and ex vivo studies of lymphatic vessel formation in the developing mouse kidneys. Eduar Hejll, Fredrik Lanner, Filip Farnebo, Lars-Gunnar Larsson and Leif Oxburgh. [Manuscript]
III. Inhibition of the intrinsic but not the extrinsic apoptosis pathway accelerates and drives Myc-driven tumorigenesis towards acute myeloid leukemia. Högstrand K, Hejll E, Sander B, Rozell B, Larsson LG, Grandien A. PLoS One. 2012;7(2):e31366. Epub 2012 Feb 29
Fulltext (DOI)
Pubmed
View record in Web of Science®
IV. Restoration of senescence upon Cdk2 inactivation delays MYC-driven acute myeloblastic leukemia. Eduar Hejll, Matteo Bocci, Vedrana Tabor, Per hydbring, Alf Grandien and Lars-Gunnar Larsson. [Manuscript]
Institution: Karolinska Institutet
Supervisor: Larsson, Lars-Gunnar
Issue date: 2012-08-23
Rights:
Publication year: 2012
ISBN: 978-91-7457-867-6
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