Bone morphogenetic protein signaling promotes tumorigenesis in a murine model of high-grade glioma

Laura D. Hover, Philip Owens, Alexander L. Munden, Jialiang Wang, Lola B. Chambless, Corey R. Hopkins, Charles C. Hong, Harold L. Moses, Ty W. Abel

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Background Improved therapies for high-grade glioma (HGG) are urgently needed as the median survival for grade IV gliomas is only 15 months. Bone morphogenetic protein (BMP) signaling plays critical and complex roles in many types of cancer, including glioma, with most of the recently published work focusing on BMP-mediated regulation of glioma stem cells (GSCs). We hypothesized that BMP signaling may be an important modulator of tumorigenic properties in glioma cells outside of the GSC compartment. Methods We used a human HGG tissue microarray and performed immunohistochemistry for phospho-Smads1,5,8. To examine the role of BMP signaling in tumorigenic astrocytes, transgenic mice were used to delete the BMP type IA receptor (Bmpr1a) and generate astrocytes transformed with oncogenic Ras and homozygous deletion of p53. The cells were transplanted orthotopically into immunocompetent adult host mice. Results First we established that BMP signaling is active within the vast majority of HGG tumor cells. Mice implanted with BMPR1a-knockout transformed astrocytes showed an increase in median survival compared with mice that received BMPR1a-intact transformed astrocytes (52.5 vs 16 days). In vitro analysis showed that deletion of BMPR1a in oncogenic astrocytes resulted in decreased proliferation, decreased invasion, decreased migration, and increased expression of stemness markers. In addition, inhibition of BMP signaling in murine cells and astrocytoma cells with a small molecule BMP receptor kinase inhibitor resulted in similar tumor suppressive effects in vitro. Conclusion BMP inhibition may represent a viable therapeutic approach in adult HGG.

Original languageEnglish (US)
Pages (from-to)928-938
Number of pages11
JournalNeuro-Oncology
Volume18
Issue number7
DOIs
StatePublished - Jul 1 2016

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Bone Morphogenetic Proteins
Glioma
Carcinogenesis
Astrocytes
Type I Bone Morphogenetic Protein Receptors
Stem Cells
Bone Morphogenetic Protein Receptors
Neoplasms
Survival
Astrocytoma
Protein Kinase Inhibitors
Transgenic Mice
Immunohistochemistry

Keywords

  • BMP
  • BMPR1a
  • DMH1
  • genetically engineered mice
  • high-grade glioma

ASJC Scopus subject areas

  • Oncology
  • Clinical Neurology
  • Cancer Research

Cite this

Hover, L. D., Owens, P., Munden, A. L., Wang, J., Chambless, L. B., Hopkins, C. R., ... Abel, T. W. (2016). Bone morphogenetic protein signaling promotes tumorigenesis in a murine model of high-grade glioma. Neuro-Oncology, 18(7), 928-938. https://doi.org/10.1093/neuonc/nov310

Bone morphogenetic protein signaling promotes tumorigenesis in a murine model of high-grade glioma. / Hover, Laura D.; Owens, Philip; Munden, Alexander L.; Wang, Jialiang; Chambless, Lola B.; Hopkins, Corey R.; Hong, Charles C.; Moses, Harold L.; Abel, Ty W.

In: Neuro-Oncology, Vol. 18, No. 7, 01.07.2016, p. 928-938.

Research output: Contribution to journalArticle

Hover, LD, Owens, P, Munden, AL, Wang, J, Chambless, LB, Hopkins, CR, Hong, CC, Moses, HL & Abel, TW 2016, 'Bone morphogenetic protein signaling promotes tumorigenesis in a murine model of high-grade glioma', Neuro-Oncology, vol. 18, no. 7, pp. 928-938. https://doi.org/10.1093/neuonc/nov310
Hover, Laura D. ; Owens, Philip ; Munden, Alexander L. ; Wang, Jialiang ; Chambless, Lola B. ; Hopkins, Corey R. ; Hong, Charles C. ; Moses, Harold L. ; Abel, Ty W. / Bone morphogenetic protein signaling promotes tumorigenesis in a murine model of high-grade glioma. In: Neuro-Oncology. 2016 ; Vol. 18, No. 7. pp. 928-938.
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AB - Background Improved therapies for high-grade glioma (HGG) are urgently needed as the median survival for grade IV gliomas is only 15 months. Bone morphogenetic protein (BMP) signaling plays critical and complex roles in many types of cancer, including glioma, with most of the recently published work focusing on BMP-mediated regulation of glioma stem cells (GSCs). We hypothesized that BMP signaling may be an important modulator of tumorigenic properties in glioma cells outside of the GSC compartment. Methods We used a human HGG tissue microarray and performed immunohistochemistry for phospho-Smads1,5,8. To examine the role of BMP signaling in tumorigenic astrocytes, transgenic mice were used to delete the BMP type IA receptor (Bmpr1a) and generate astrocytes transformed with oncogenic Ras and homozygous deletion of p53. The cells were transplanted orthotopically into immunocompetent adult host mice. Results First we established that BMP signaling is active within the vast majority of HGG tumor cells. Mice implanted with BMPR1a-knockout transformed astrocytes showed an increase in median survival compared with mice that received BMPR1a-intact transformed astrocytes (52.5 vs 16 days). In vitro analysis showed that deletion of BMPR1a in oncogenic astrocytes resulted in decreased proliferation, decreased invasion, decreased migration, and increased expression of stemness markers. In addition, inhibition of BMP signaling in murine cells and astrocytoma cells with a small molecule BMP receptor kinase inhibitor resulted in similar tumor suppressive effects in vitro. Conclusion BMP inhibition may represent a viable therapeutic approach in adult HGG.

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