Hypoxia-induced TIMAP Upregulation Promotes Tumor Angiogenesis

• Author / Creator

  Aburahess, Salah

• Angiogenesis, the process of forming new blood vessels from a pre-exciting vasculature, is an essential component of embryonic development, tissue remodelling, wound healing, and tumor growth. This process is strictly regulated by a vast array of cellular signalling pathways involving kinases, phosphatases, growth factors and cytokines. Hypoxia, which is a hallmark of tumor growth, is a key trigger of angiogenesis. During tumorigenesis, neovascularization is a critical element for the tumor to promote its growth and progression. In rapidly expanding solid tumors, cancer cells in the center of the tumor become hypoxic as they grow further away from the original organ’s vasculature. In these hypoxic cancer cells, hypoxia induces several signalling cascades and stimulates release of pro-angiogenic factors which promote angiogenesis to overcome the hypoxic microenvironment and continue to survive. Several anti-angiogenic drugs that target specific angiogenic signalling pathways have proven clinically useful, although tumors frequently develop resistance to this approach. This is due to the substantial complexity and redundancy of the signalling pathways that regulate tumor angiogenesis. Therefore, thoroughly understanding these mechanisms may help to develop better anti-angiogenic approaches that more effectively inhibit tumor growth and progression by interfering with the disordered angiogenesis.
  TIMAP (TGF-β-Inhibited Membrane-Associated Protein) is an endothelial cell (EC)-predominant pro-angiogenic protein that promotes EC proliferation and enhances in vitro angiogenic sprout formation. However, its angiogenic role in the in vivo setting remains unknown. Here we demonstrate that TIMAP is necessary for mouse tumor growth and angiogenesis and elucidate the mechanisms that regulate TIMAP expression in EC. We found that hypoxia, the principal stimulus of tumor angiogenesis, raises TIMAP levels in mouse lung tissues and in cultured EC. We found that repression of TIMAP expression is mediated through activation of the EC-specific Activin Receptor-Like Kinase-1 (ALK1) SMAD1/5/8 pathway and that hypoxia stimulates TIMAP expression by attenuating BMP-9-induced ALK1-mediated TIMAP inhibition. The TGF-β signalling molecule Bone Morphogenetic Protein-9 (BMP-9) potently and selectively activates the EC ALK1 SMAD1/5/8 pathway and significantly reduces TIMAP abundance. HIF-α activation and ALK1 inhibition both impede BMP-9-stimulated SMAD1/5/8 phosphorylation, and both increase EC TIMAP levels. Furthermore, we also found that the angiogenic growth factors VEGF and IGF-1 induced by HIF-α activation in hypoxic tumor cells, also enhance EC TIMAP expression by attenuating the ALK1 pathway signalling, although they also induced EC TIMAP expression through ALK1 pathway independent effects. These findings indicate that TIMAP has critical pro-angiogenic effects in EC, which may point to a new potential target for inhibition of tumor angiogenesis.

• Subjects / Keywords

  • Endothelial cells
  • ALK1
  • BMP-9
  • HIF
  • E0771
  • Breast cancer

• Graduation date

  Fall 2023

• Type of Item

  Thesis

• Degree

  Doctor of Philosophy

• DOI

  https://doi.org/10.7939/r3-cpfh-sk29

• License

  This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.