KSHV-Initiated Notch Activation Leads to Membrane-Type-1 Matrix Metalloproteinase-Dependent Lymphatic Endothelial-to Mesenchymal Transition.

Fang Cheng, et al.. 2011. Cell Host & Microbe 10, 577-590.

Speaker: Yu-Zhen Lu (呂瑜珍)                                     Time: 14:00~14:50, May. 30,2011

Commentator: Dr. Hsiao-Sheng Liu (劉校生博士)      Place: Room 601

Abstract

Kaposi’s sarcoma (KS), a major AIDS-associated cancer that presents as an angioproliferative spindle cell sarcoma of vascular origin. This disease is mainly caused by Kaposi sarcoma herpesvirus (KSHV) infection. The scientists previously discovered that the endothelial cells (ECs) are more susceptible to KSHV infection, expecting that KS is derived from ECs. To confirm this idea, the authors used ECs as an infected model system to study KSHV pathogenenesis. However, primary ECs infected with wild-type KSHV don’t acquire properties of transformed cell. To solve the problem, the authors assembled KSHV-infected primary lymphatic endothelial cell (LED) cultures into three-dimensional (3D) spheroids embedded in clotted-fibrin scaffolds to mimic cell-to-cell interactions occurring in vivo. In 3D spheroids, KSHV induced LEDs sprouting and expression ofmesenchymal markers similar to the KSHV-infected cells in KS lesions. This process is described endothelial- to- mesenchymal transition (EndMT) and that is thought to be an important source of invasion malignant stroma. Furthermore, the authors found that KSHV-induced EndMT was initiated by the viral proteins vFLIP and vGPCR through Notch pathway activation. Notch activates invasiveness by inducing PDGFβ signaling via the membrane- tethered matrix metalloproteinase MT1-MMP, which is also expressed at the invasive edge of KS lesion. Taken together, these findings established a very powerful method to understand the tumorigenesis of KS.

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