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Angiogenesis

, 8:339 | Cite as

Cyclooxygenase inhibition in early onset of tumor growth and related angiogenesis evaluated in EP1 and EP3 knockout tumor-bearing mice

  • Hans Axelsson
  • Christina Lönnroth
  • Wenhua Wang
  • Elisabeth Svanberg
  • Kent LundholmEmail author
Article

Abstract

It is well established that prostanoids are essential for local inflammation including cell proliferation and apoptosis. Accordingly, prostaglandin E2 (PGE2) is a critical factor in wound healing, tumor invasiveness and progression. Therefore, the aim of the present work was to evaluate effects by PGE2 on tumor vascular density at early onset of tumor growth where hypoxia is limited. Wild-type mice (C57Bl, C3H/HeN) bearing either MCG-101 tumors or a malignant melanoma (K1735-M2) with either high or insignificant PGE2 production and subsequently different in sensitivity to cyclooxygenase (COX) inhibition were used. Tumor angiogenesis was estimated by intravital microscopy and immune histochemical analysis in wild type and EP1 or EP3 subtype receptor knockout mice (C57Bl). Both MCG-101 and K1735-M2 tumor cells stimulated early outgrowth of tumor vessels in proportion to intrinsic growth rate of tumor cells. Indomethacin had no effects on tumor growth or tumor related vascular area in K1735-M2 bearing mice. By contrast, indomethacin decreased tumor cell proliferation and increased apoptosis in MCG-101 tumors with subsequent adaptation in tumor vascular density. Effects of indomethacin on early growth of MCG-101 tumors were not related to tumor content of bFGF protein, while our earlier studies on long-term tumor growth have shown decreased mRNA levels of bFGF during indomethacin treatment. Early onset of tumor growth was significantly promoted in EP3- but not in EP1-knockouts, although long-term tumor growth is attenuated in EP1-knockouts as reported elsewhere. Our results demonstrate that tumor production of PGE2 promotes primarily net growth of tumor cells with subsequent adaptations in development of the tumor vasculature. Therefore, it is likely that angiogenesis is not a limiting step at the early onset of tumor growth.

Keywords

angiogenesis COX EP-subtype receptor gene knockout 

Notes

Acknowledgements

This article was supported in parts by grants from the Swedish Cancer Society (2014, 4261), the Swedish Research Council (08712, 13268), Assar Gabrielsson Foundation (AB Volvo), Jubileumskliniken Foundation, IngaBritt & Arne Lundberg Research Foundation, Swedish and Göteborg Medical Societies and the Medical Faculty, Göteborg University.

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Copyright information

© Springer Science+Business Media, Inc. 2006

Authors and Affiliations

  • Hans Axelsson
    • 1
  • Christina Lönnroth
    • 1
  • Wenhua Wang
    • 1
  • Elisabeth Svanberg
    • 1
  • Kent Lundholm
    • 1
    • 2
    Email author
  1. 1.Department of Surgery, Surgical Metabolic Research Laboratory at Lundberg Laboratory for Cancer ResearchSahlgrenska University HospitalGöteborgSweden
  2. 2.Department of Surgery, Surgical Metabolic Research Laboratory, Lundberg Laboratory for Cancer ResearchSahlgrenska University HospitalGöteborgSweden

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