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TGF-β Family Signaling in Tumor Angiogenesis

Eleftheriou, Nikolas LU (2017)
Abstract
Angiogenesis provides growing tumors a source of nutrients and oxygen, and a route for metastatic dissemination. In recent years anti-angiogenic therapies that primarily target the vascular endothelial growth factor (VEGF) signaling cascade have entered the clinic. However in practice, these have encountered unexpected mechanisms of resistance in many solid tumors, highlighting the need for further understanding of the basic biology behind alternative signaling pathways that drive angiogenesis. The transforming growth factor (TGF)-β superfamily of ligands and receptors are critical for vascular development and are widely implicated in cancer. Here we investigate the TGF-β signaling activity through endothelial cells (EC), including their... (More)
Angiogenesis provides growing tumors a source of nutrients and oxygen, and a route for metastatic dissemination. In recent years anti-angiogenic therapies that primarily target the vascular endothelial growth factor (VEGF) signaling cascade have entered the clinic. However in practice, these have encountered unexpected mechanisms of resistance in many solid tumors, highlighting the need for further understanding of the basic biology behind alternative signaling pathways that drive angiogenesis. The transforming growth factor (TGF)-β superfamily of ligands and receptors are critical for vascular development and are widely implicated in cancer. Here we investigate the TGF-β signaling activity through endothelial cells (EC), including their impact on tumor angiogenesis and metastatic dissemination, through genetic modification and therapeutic inhibition.
In papers I, II and IV we investigated the in vivo activing receptor-like kinase (ALK)1/bone morphogenetic protein (BMP)9 signaling axis in various mouse models of cancer. ALK1-Fc, a soluble ALK1 receptor domain ligand trap for BMP9 and BMP10, was evaluated in preclinical models of pancreatic and breast cancer, showing a decrease in angiogenesis, tumor growth and number of metastases. These reductions were enhanced when combined with chemotherapy. In the adjuvant setting, ALK1-Fc had fewer metastases in orthotopic breast cancer cell models following tumor resection. Combined deficiency of the genes encoding ALK1 and endoglin synergistically decreased the volume of pancreatic neuroendocrine tumors, whereas BMP9 knockout mice display decrease in primary tumor burden, but an increase in vessel hypersprouting and hepatic micrometastases.
In papers III and IV we investigated the roles of ALK5 and TGFBR2 in pancreatic neuroendocrine tumor models with genetic modifications limited to endothelial cells (EC). Mice undergo EC-specific recombination prior to the tumor angiogenic switch for deletion of TGFBR2, ALK5, or expression of a constitutively active ALK5 mutant. EC deletion of ALK5 induced blood vessel hypersprouting in tumors and increased lymph node metastases, whereas constitutive activation of ALK5 in ECs increased hepatic metastases. TGFBR2 deletion in ECs strongly inhibits tumorigenesis, decreasing the number of tumors and tumor volume, and tumors presented with highly irregular vasculature.
Our studies emphasize the impact of TGF-β signaling on tumor angiogenesis and metastatic dissemination, and this pathway presents potential targets in the development of clinical therapies. However the mechanism of action following pathway inhibition remains unclear, and further investigation is warranted. (Less)
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author
supervisor
opponent
  • Principal investigator Graupera, Mariona, Institut d'Investigació Biomèdica de Bellvitge
organization
publishing date
type
Thesis
publication status
published
subject
pages
58 pages
publisher
Lund University, Faculty of Medicine
defense location
Föreläsningssalen, Medicon Village, Lund
defense date
2017-03-17 13:00
ISBN
978-91-7619-422-5
language
English
LU publication?
yes
id
95fd8af3-a666-4f1a-8c24-b5fb7ed35376
date added to LUP
2017-02-21 15:15:34
date last changed
2017-03-01 08:53:08
@phdthesis{95fd8af3-a666-4f1a-8c24-b5fb7ed35376,
  abstract     = {Angiogenesis provides growing tumors a source of nutrients and oxygen, and a route for metastatic dissemination. In recent years anti-angiogenic therapies that primarily target the vascular endothelial growth factor (VEGF) signaling cascade have entered the clinic. However in practice, these have encountered unexpected mechanisms of resistance in many solid tumors, highlighting the need for further understanding of the basic biology behind alternative signaling pathways that drive angiogenesis. The transforming growth factor (TGF)-β superfamily of ligands and receptors are critical for vascular development and are widely implicated in cancer. Here we investigate the TGF-β signaling activity through endothelial cells (EC), including their impact on tumor angiogenesis and metastatic dissemination, through genetic modification and therapeutic inhibition.<br/>In papers I, II and IV we investigated the in vivo activing receptor-like kinase (ALK)1/bone morphogenetic protein (BMP)9 signaling axis in various mouse models of cancer. ALK1-Fc, a soluble ALK1 receptor domain ligand trap for BMP9 and BMP10, was evaluated in preclinical models of pancreatic and breast cancer, showing a decrease in angiogenesis, tumor growth and number of metastases. These reductions were enhanced when combined with chemotherapy. In the adjuvant setting, ALK1-Fc had fewer metastases in orthotopic breast cancer cell models following tumor resection. Combined deficiency of the genes encoding ALK1 and endoglin synergistically decreased the volume of pancreatic neuroendocrine tumors, whereas BMP9 knockout mice display decrease in primary tumor burden, but an increase in vessel hypersprouting and hepatic micrometastases.<br/>In papers III and IV we investigated the roles of ALK5 and TGFBR2 in pancreatic neuroendocrine tumor models with genetic modifications limited to endothelial cells (EC). Mice undergo EC-specific recombination prior to the tumor angiogenic switch for deletion of TGFBR2, ALK5, or expression of a constitutively active ALK5 mutant. EC deletion of ALK5 induced blood vessel hypersprouting in tumors and increased lymph node metastases, whereas constitutive activation of ALK5 in ECs increased hepatic metastases. TGFBR2 deletion in ECs strongly inhibits tumorigenesis, decreasing the number of tumors and tumor volume, and tumors presented with highly irregular vasculature.<br/>Our studies emphasize the impact of TGF-β signaling on tumor angiogenesis and metastatic dissemination, and this pathway presents potential targets in the development of clinical therapies. However the mechanism of action following pathway inhibition remains unclear, and further investigation is warranted.},
  author       = {Eleftheriou, Nikolas},
  isbn         = {978-91-7619-422-5},
  language     = {eng},
  pages        = {58},
  publisher    = {Lund University, Faculty of Medicine},
  school       = {Lund University},
  title        = {TGF-β Family Signaling in Tumor Angiogenesis},
  year         = {2017},
}