Active TGF-β signaling and decreased expression of PTEN separates angiosarcoma of bone from its soft tissue counterpart

Sofie L J Verbeke, Franco Bertoni, Patrizia Bacchini, Jan Oosting, Raf Sciot, T. Krenács, Judith V M G Bovée

Research output: Article

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Abstract

Angiosarcomas constitute a heterogeneous group of highly malignant vascular tumors. Angiosarcoma of bone is rare and poorly characterized. For angiosarcoma of soft tissue, some pathways seem to be involved in tumor development. Our aim was to evaluate the role of these pathways in angiosarcoma of bone. We collected 37 primary angiosarcomas of bone and used 20 angiosarcomas of soft tissue for comparison. Immunohistochemistry was performed on constructed tissue microarrays to evaluate expression of CDKN2A, TP53, PTEN, BCL2, CDK4, MDM2, cyclin D1, β-catenin, transforming growth factor-β (TGF-β), CD105, phospho-Smad1, phospho-Smad2, hypoxia-inducible factor-1α, plasminogen activator inhibitor type 1 (PAI-1), VEGF, CD117 and glucose transporter - 1. PIK3CA was screened for hotspot mutations in 19 angiosarcomas. In nearly 55% of the angiosarcoma of bone, the retinoblastoma (Rb) pathway was affected. Loss of CDKN2A expression was associated with a significantly worse prognosis. No overexpression of TP53 or MDM2 was found, suggesting that the TP53 pathway is not important in angiosarcoma of bone. Angiosarcoma of bone showed highly active TGF-β signaling with immunoreactivity for phospho-Smad2 and PAI-1. Although the phosphatidylinositol 3-kinase (PI3K)/Akt pathway seems to be active in both tumor groups, different mechanisms were involved: 41% of angiosarcoma of bone showed a decrease in expression of PTEN, whereas in angiosarcoma of soft tissue overexpression of KIT was found (90%). PIK3CA hotspot mutations were absent. In conclusion, the Rb pathway is involved in tumorigenesis of angiosarcoma of bone. The PI3K/Akt pathway is activated in both angiosarcoma of bone and soft tissue, however, with a different cause; PTEN expression is decreased in angiosarcoma of bone, whereas angiosarcomas of soft tissue show overexpression of KIT. Our findings support that angiosarcomas are a heterogeneous group of vascular malignancies. Both angiosarcoma of bone and soft tissue may benefit from therapeutic strategies targeting the PI3K/Akt pathway. However, interference with TGF-β signaling may be specifically relevant in angiosarcoma of bone.

Original languageEnglish
Pages (from-to)1211-1221
Number of pages11
JournalModern Pathology
Volume26
Issue number9
DOIs
Publication statusPublished - szept. 2013

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Hemangiosarcoma
Transforming Growth Factors
Bone and Bones
Phosphatidylinositol 3-Kinase
Retinoblastoma
Plasminogen Activator Inhibitor 1
Blood Vessels
Neoplasms
Hypoxia-Inducible Factor 1
Catenins
Mutation
Facilitative Glucose Transport Proteins

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Active TGF-β signaling and decreased expression of PTEN separates angiosarcoma of bone from its soft tissue counterpart. / Verbeke, Sofie L J; Bertoni, Franco; Bacchini, Patrizia; Oosting, Jan; Sciot, Raf; Krenács, T.; Bovée, Judith V M G.

In: Modern Pathology, Vol. 26, No. 9, 09.2013, p. 1211-1221.

Research output: Article

Verbeke, Sofie L J ; Bertoni, Franco ; Bacchini, Patrizia ; Oosting, Jan ; Sciot, Raf ; Krenács, T. ; Bovée, Judith V M G. / Active TGF-β signaling and decreased expression of PTEN separates angiosarcoma of bone from its soft tissue counterpart. In: Modern Pathology. 2013 ; Vol. 26, No. 9. pp. 1211-1221.
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abstract = "Angiosarcomas constitute a heterogeneous group of highly malignant vascular tumors. Angiosarcoma of bone is rare and poorly characterized. For angiosarcoma of soft tissue, some pathways seem to be involved in tumor development. Our aim was to evaluate the role of these pathways in angiosarcoma of bone. We collected 37 primary angiosarcomas of bone and used 20 angiosarcomas of soft tissue for comparison. Immunohistochemistry was performed on constructed tissue microarrays to evaluate expression of CDKN2A, TP53, PTEN, BCL2, CDK4, MDM2, cyclin D1, β-catenin, transforming growth factor-β (TGF-β), CD105, phospho-Smad1, phospho-Smad2, hypoxia-inducible factor-1α, plasminogen activator inhibitor type 1 (PAI-1), VEGF, CD117 and glucose transporter - 1. PIK3CA was screened for hotspot mutations in 19 angiosarcomas. In nearly 55{\%} of the angiosarcoma of bone, the retinoblastoma (Rb) pathway was affected. Loss of CDKN2A expression was associated with a significantly worse prognosis. No overexpression of TP53 or MDM2 was found, suggesting that the TP53 pathway is not important in angiosarcoma of bone. Angiosarcoma of bone showed highly active TGF-β signaling with immunoreactivity for phospho-Smad2 and PAI-1. Although the phosphatidylinositol 3-kinase (PI3K)/Akt pathway seems to be active in both tumor groups, different mechanisms were involved: 41{\%} of angiosarcoma of bone showed a decrease in expression of PTEN, whereas in angiosarcoma of soft tissue overexpression of KIT was found (90{\%}). PIK3CA hotspot mutations were absent. In conclusion, the Rb pathway is involved in tumorigenesis of angiosarcoma of bone. The PI3K/Akt pathway is activated in both angiosarcoma of bone and soft tissue, however, with a different cause; PTEN expression is decreased in angiosarcoma of bone, whereas angiosarcomas of soft tissue show overexpression of KIT. Our findings support that angiosarcomas are a heterogeneous group of vascular malignancies. Both angiosarcoma of bone and soft tissue may benefit from therapeutic strategies targeting the PI3K/Akt pathway. However, interference with TGF-β signaling may be specifically relevant in angiosarcoma of bone.",
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