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Overexpression of factor inhibiting HIF-1 enhances vessel maturation and tumor growth via platelet-derived growth factor-C.

Abstract
Recent studies have revealed that the maturation state of vessels in tumors, in addition to vascularity, is a critical determinant of tumor growth. The role of oxygen-dependent signaling pathways in hypoxia-stimulated angiogenesis is well established, however, little is known about their impact on vessel maturation in tumors. Here, we have studied the function of the cellular oxygen sensor, factor inhibiting HIF-1 (FIH), which controls the activity of hypoxia-inducible factor-1. FIH silencing in mouse LM8 osteosarcoma stimulated angiogenesis but did not influence tumor growth. In contrast, FIH overexpression led to increased pericyte coverage of the tumor vasculature, reduced vessel leakiness and enhanced tumor growth. Vessel maturation was paralleled by up-regulation of platelet-derived growth factor (PDGF)-C in tumors and expression of PDGF receptor-α on pericytes. Ablation of PDGF-C in FIH-overexpressing tumor cells reduced pericyte coverage and tumor growth. Our data suggest that FIH-mediated PDGF-C induction in LM8 osteosarcoma stimulates the recruitment of PDGFR-α positive pericytes to the tumor vasculature, leading to vessel maturation and enhanced tumor growth.
AuthorsAleksandar Kuzmanov, Ben Wielockx, Maryam Rezaei, Antje Kettelhake, Georg Breier
JournalInternational journal of cancer (Int J Cancer) Vol. 131 Issue 5 Pg. E603-13 (Sep 01 2012) ISSN: 1097-0215 [Electronic] United States
PMID22095574 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2011 UICC.
Chemical References
  • Angiogenesis Inducing Agents
  • Hypoxia-Inducible Factor 1
  • Lymphokines
  • Platelet-Derived Growth Factor
  • RNA, Messenger
  • RNA, Small Interfering
  • platelet-derived growth factor C
  • Mixed Function Oxygenases
  • factor inhibiting hypoxia-inducible factor 1, mouse
  • Receptor, Platelet-Derived Growth Factor alpha
Topics
  • Angiogenesis Inducing Agents
  • Animals
  • Apoptosis
  • Blotting, Western
  • Bone Neoplasms (blood supply, metabolism, pathology)
  • Cell Proliferation
  • Female
  • Hypoxia-Inducible Factor 1 (genetics, metabolism)
  • Immunoenzyme Techniques
  • Lymphokines (antagonists & inhibitors, genetics, metabolism)
  • Mice
  • Mice, Inbred C3H
  • Mixed Function Oxygenases (genetics, metabolism)
  • Neovascularization, Pathologic
  • Osteosarcoma (blood supply, metabolism, pathology)
  • Pericytes (metabolism, pathology)
  • Platelet-Derived Growth Factor (antagonists & inhibitors, genetics, metabolism)
  • RNA, Messenger (genetics)
  • RNA, Small Interfering (genetics)
  • Real-Time Polymerase Chain Reaction
  • Receptor, Platelet-Derived Growth Factor alpha (genetics, metabolism)
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction
  • Tumor Cells, Cultured

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