Inhibition of Notch Signaling Induces Neural Differentiation in Ewing Sarcoma

Abstract

Cells from Ewing sarcoma exhibit cellular features and express markers, suggesting that the tumor is of neuroectodermal origin. Because Notch signaling regulates the differentiation of neuroectodermal cells during development, we examined the role of Notch signaling in Ewing sarcomas. We found that Ewing sarcomas express Notch receptors, ligands, and the Notch target gene HES1. To determine the functional implications of Notch signaling, we expressed tetracycline-regulated constitutively active, dominant-negative (DN), or wild-type Notch-1 receptors in two Ewing sarcoma cell lines, or we treated the cell lines with a ␥-secretase inhibitor. Expression of the constitutively active Notch-1 reduced proliferation and expression of the DN Notch-1 reduced apoptosis in vitro. However, there was only a small difference in the volume of tumors that formed when the cell lines expressing these constructs were implanted in nude mice. Xenograft tumors derived from the cell lines expressing DN Notch-1 exhibited a neural phenotype. Treatment with a ␥-secretase inhibitor caused similar changes as expression of the DN construct. Notch signaling plays a role in cell differentiation, proliferation, and apoptosis in Ewing sarcoma, but its inhibition is only associated with a small change in tumor growth potential.

Osteosarcoma Cells Differentiate into Phenotypes from all Three Dermal Layers

“…Osteosarcomas are vascular, but the Finally, dexamethasone induced cells expressing markers unique to the endodermal phenotype, hepatocytes. Our results are consistent with those of other studies of nonosteoblast phenotypes, including some ectodermal phenotypes, in osteosarcomas in vivo [2,8,12,23,27,30,39,40,45,46,49]. However, no studies have reported the presence of staining in osteosarcomas in vivo for neurons, oligodendrocytes, skeletal muscle, or adipocytes.…”

The effect of simvastatin treatment on proliferation and differentiation of neural stem cells after traumatic brain injury

“…Several studies have shown that Notch-1 activation induced both radial glial phenotype and astrocyte differentiation (Baliko et al, 2007;Keilani and Sugaya, 2008), and γ-secretase inhibitor treatment after stroke decreased the number of proliferative GFAP-positive astrocytes and reactive astrocytes directly adjacent to the infarct core (Shimada et al, 2011). While our previous study has shown that simvastatin inhibits the activation of microglial cells and astrocytes after TBI and it can be increased by γ-secretase inhibitor.…”

BMI-1 Promotes Ewing Sarcoma Tumorigenicity Independent ofCDKN2ARepression

“…Our finding that developmental pathways are significantly affected by BMI-1 knockdown in ESFT cells suggests that the embryonic function of BMI-1 is being recapitulated in these undifferentiated tumor cells. It is particularly noteworthy that both WNT and NOTCH pathway genes are highly affected by BMI-1 knockdown as both of these developmental pathways have been previously implicated in ESFT growth and tumorigenicity (49, 50). Intriguingly, our data also show that among the affected developmental processes, BMI-1 loss has its most profound effect on genes that are involved in neural development with BMI-1 knockdown leading to increased expression of neural markers (Table 1 and Supplementary Table 1).…”