Understanding the Role of Notch in Osteosarcoma

Abstract

The Notch pathway has been described as an oncogene in osteosarcoma, but the myriad functions of all the members of this complex signaling pathway, both in malignant cells and nonmalignant components of tumors, make it more difficult to define Notch as simply an oncogene or a tumor suppressor. The cell-autonomous behaviors caused by Notch pathway manipulation may vary between cell lines but can include changes in proliferation, migration, invasiveness, oxidative stress resistance, and expression of markers associated with stemness or tumor-initiating cells. Beyond these roles, Notch signaling also plays a vital role in regulating tumor angiogenesis and vasculogenesis, which are vital aspects of osteosarcoma growth and behavior in vivo. Further, osteosarcoma cells themselves express relatively low levels of Notch ligand, making it likely that nonmalignant cells, especially endothelial cells and pericytes, are the major source of Notch activation in osteosarcoma tumors in vivo and in patients. As a result, Notch pathway expression is not expected to be uniform across a tumor but likely to be highest in those areas immediately adjacent to blood vessels. Therapeutic targeting of the Notch pathway is likewise expected to be complicated. Most pharmacologic approaches thus far have focused on inhibition of gamma secretase, a protease of the presenilin complex. This enzyme, however, has numerous other target proteins that would be expected to affect osteosarcoma behavior, including CD44, the WNT/β-catenin pathway, and Her-4. In addition, Notch plays a vital role in tissue and organ homeostasis in numerous systems, and toxicities, especially GI intolerance, have limited the effectiveness of gamma secretase inhibitors. New approaches are in development, and the downstream targets of Notch pathway signaling also may turn out to be good targets for therapy. In summary, a full understanding of the complex functions of Notch in osteosarcoma is only now unfolding, and this deeper knowledge will help position the field to better utilize novel therapies as they are developed.

Doxorubicin activates the Notch signaling pathway in osteosarcoma

“…Although it is widely recognized that the agent intercalates into DNA and generates free radicals, the precise effect of doxorubicin on cancer cells requires further investigation (28). Dysregulated Notch activity has been reported to contribute to the carcinogenesis of osteosarcoma (22), with Notch1 activity appearing to be crucial for the invasion and metastasis of osteosarcoma (25). Furthermore, inhibition of the Notch signaling pathway suppressed osteosarcoma growth in vitro and in vivo (26).…”

“…Dysregulated Notch activity has been reported in an increasing number of malignancies, such as colon (17,18), pancreatic (19,20) and cervical (21) cancer. Additionally, dysregulated Notch activity has been reported to contribute to the carcinogenesis of osteosarcoma (22)(23)(24)(25)(26). However, the role of Notch in osteosarcoma chemoresistance remains unclear.…”

Deciphering signaling networks in osteosarcoma pathobiology

“…Therefore, Notch signaling in OS seems to be an outcome of paracrine induction from the tumor's microenvironment, mainly from pericytes and endothelial cells. 67 …”

Dual Mechanism of Action of Resveratrol in Notch Signaling Pathway Activation in Osteosarcoma

“…It is reported that Notch activity leads to the development of tumors in osteosarcoma cells [18]. The activity of Notch1 in osteosarcoma cells plays an important role in the process of tumor cell invasion and tissue metastasis [25].…”

“…Down-regulation of the activity of Notch genes has been detected in various malignancies like colon [12,13], pancreatic [14,15] and cervical [16] cancer. Furthermore, various studies have demonstrated reduced activity of Notch in osteosarcoma [17,18]. Therefore, the present study was designed to investigate the effect of resveratrol on the activity of the Notch signaling pathway in U2OS osteosarcoma cell lines.…”