Data from Critical Role of Notch Signaling in Osteosarcoma Invasion and Metastasis

Abstract

<div>Abstract<p><b>Purpose:</b> Notch signaling is an important mediator of growth and survival in several cancer types, with Notch pathway genes functioning as oncogenes or tumor suppressors in different cancers. However, the role of Notch in osteosarcoma is unknown.</p><p><b>Experimental Design:</b> We assessed the expression of Notch pathway genes in human osteosarcoma cell lines and patient samples. We then used pharmacologic and retroviral manipulation of the Notch pathway and studied the effect on osteosarcoma cell proliferation, survival, anchorage-independent growth, invasion, and metastasis <i>in vitro</i> and <i>in vivo</i>.</p><p><b>Results:</b> Notch pathway genes, including Notch ligand <i>DLL1, Notch1</i> and <i>Notch2</i>, and the Notch target gene <i>HES1</i>, were expressed in osteosarcoma cells, and expression of <i>HES1</i> was associated with invasive and metastatic potential. Blockade of Notch pathway signaling with a small molecule inhibitor of γ secretase eliminated invasion in Matrigel without affecting cell proliferation, survival, or anchorage-independent growth. Manipulation of Notch and HES1 signaling showed a crucial role for HES1 in osteosarcoma invasiveness and metastasis <i>in vivo</i>.</p><p><b>Conclusion:</b> These studies identify a new invasion and metastasis-regulating pathway in osteosarcoma and define a novel function for the Notch pathway: regulation of metastasis. Because the Notch pathway can be inhibited pharmacologically, these findings point toward possible new treatments to reduce invasion and metastasis in osteosarcoma.</p></div>