Active TGF-β Signalling and Decreased Expression of PTEN Separates Angiosarcoma of Bone from Its Soft Tissue Counterpart
Sofie LJ Verbeke, Franco Bertoni, Patrizia Bacchini, Jan Oosting, Raf Sciot, Tibor Krenacs, Peter ten Dijke, Judith VMG Bovee. Leiden University Medical Center, Leiden, Netherlands; Rizzoli Institute, Bologna, Italy; University Hospitals, Leuven, Belgium; Semmelweis University, Budapest, Hungary
Background: Angiosarcomas constitute a heterogeneous group of highly malignant vascular tumours. Moreover, angiosarcoma of bone is very rare and poorly characterized at the molecular level. Since for angiosarcoma of soft tissue the pathways involved in tumour development and progression are beginning to be explored, our aim is to evaluate the role of these pathways in angiosarcoma of bone.
Design: We collected 37 primary angiosarcoma of bone and used 20 angiosarcoma of soft tissue for comparison. Immunohistochemistry was performed on four TMA slides to evaluate expression of p16, p53, PTEN, BCL2, CDK4, MDM2, Cyclin D1, β-catenin, TGF-β, CD105, phospho-Smad1, phospho-Smad2, HIF-1α, PAI-1, VEGF, CD117 and GLUT-1. PIK3CA, was screened for hotspot mutations in 13 angiosarcoma of bone and 6 angiosarcoma of soft tissue.
Results: In nearly 55% of the angiosarcoma of bone the Rb pathway was affected, either through p16, Cyclin D1 or both. Loss of p16 expression was associated with a significantly worse prognosis. No overexpression of p53 or MDM2 was found, suggesting that the p53 pathway is not important in angiosarcoma of bone. Angiosarcoma of bone showed highly active TGF-β signalling; especially compared to angiosarcoma of soft tissue, with immunoreactivity for phospho-Smad2 and PAI-1. While the PI3K/Akt pathway seems to be active in both angiosarcoma of bone and soft tissue, different mechanisms were involved: 40.7% of angiosarcoma of bone showed a decrease in expression of PTEN, while in angiosarcoma of soft tissue overexpression of KIT was found in 89.5%. PIK3CA hotspot mutations were absent.
Conclusions: In conclusion, the Rb pathway is involved in tumourigenesis 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, while angiosarcoma of soft tissue show overexpression of KIT. Our findings support that angiosarcomas are a heterogeneous group of vascular malignancies, while both angiosarcoma of bone and soft tissue may benefit from therapeutic strategies targeting the PI3K/Akt pathway, interference with TGF-β signalling may be specifically relevant in angiosarcoma of bone.
Category: Bone & Soft Tissue
Monday, March 4, 2013 1:00 PM
Poster Session II # 3, Monday Afternoon