THE NOTCH TARGET HES4 PROMOTES OSTEOSARCOMA TUMOR GROWTH AND METASTASIS BY INHIBITING OSTEOGENIC DIFFERENTIATION, AND HAS POTENTIAL AS A PROGNOSTIC BIOMARKER FOR NEWLY DIAGNOSED PATIENTS WITH HIGH GRADE OSTEOSARCOMA.
Date of Graduation
Doctor of Philosophy (PhD)
Currently, there are no well-established prognostic biomarkers for osteosarcoma (OS) at the time of diagnosis. Although response to preoperative chemotherapy correlates with metastasis risk and overall survival, this information is obtained 3-4 months after the initial diagnosis. The major purpose of this study is to identify clinically relevant biomarkers that will allow for the stratification of patients into good or poor responders to chemotherapy at diagnosis. We also aim to understand the biology of these markers in OS pathogenesis. Because the development of OS is caused by genetic disruptions of osteogenic differentiation, we sought to identify pathways that are involved in normal bone development and homeostasis. One such pathway is the Notch signaling pathway. We hypothesized that the Notch downstream target Hairy/Enhancer of Split 4 (Hes4) is important in the pathogenesis of OS, and thus can be used as a biomarker for OS at the time of diagnosis.
The differentiation status of some cancers is linked with their metastatic behavior: the more immature the cell population, the more aggressive the disease. The Notch signaling pathway is a mediator of differentiation and a crucial component in normal bone development. In normal bone marrow stromal cells, Hes4 was shown to regulate commitment to the osteogenic pathway. By contrast, we demonstrated that in a tumorigenic context, human OS cells that overexpress Hes4 inhibited the progression of preosteoblasts to early and mature osteoblasts and increased the invasive capacity in vitro. This was not universal to all Notch effectors, as Hes1 overexpression induced opposing effects. When injected into NSG mice, Hes4 overexpressing OS cells produced significantly larger, more lytic tumors and significantly more metastases than did GFP expressing cells. In patients with high grade OS, high Hes4 mRNA expression in diagnostic primary tumor biopsies correlated with an increased incidence of metastasis and decreased overall survival. Therefore, Hes4 may allow for the stratification of patients into good or poor responders to chemotherapy at diagnosis. Early stratification and prognosis of OS would allow for modification of therapy and may serve as the basis for future clinical trials of OS treatment.
osteogenic differentiation, osteosarcoma, Hes4, Notch, biomarker