Breaking Down Barriers to Chemoresistance: Role of Chemotherapy-Induced Osteoblastic Jagged1  Khalid S. Mohammad, Theresa A. Guise  Cancer Cell  Volume 32, Issue 6, Pages 717-718 (December 2017) DOI: 10.1016/j.ccell.2017.11.016 Copyright © 2017 Elsevier Inc. Terms and Conditions

Figure 1 Osteoblast-Mediated Chemoresistance in the Setting of Bone Metastases: Role of Jagged1 Jagged1, expressed by tumor cells, activates Notch signaling in osteoblasts (OB) to result in secretion of factors such as IL-6 and CTGF, which can stimulate cancer cell proliferation and further osteoclastic bone destruction (left). When cancer cells are in physical contact with osteoblasts, resistance to chemotherapy is conferred, via induction of osteoblast Jagged1 expression by reactive oxygen species (ROS) (center). This results in significant upregulation of several Notch signaling genes including HES2, HEY1, and HEY2 and activation of Notch signaling in cancer cells. Increased expression of anti-apoptotic genes follows, with reduction in the expression of pro-apoptotic genes. This effect on apoptosis appears to be in part mediated by Notch activation and its effect on suppression of the p53-regulated apoptotic pathway. When the Jagged1 antibody 15D11 is used for treatment of bone metastases, in the presence of chemotherapy, it has a dual effect (right): (1) it reduces bone metastases through inhibition of osteoclast formation and (2) it enhances chemosensitivity of the cancer cells. Cancer Cell 2017 32, 717-718DOI: (10.1016/j.ccell.2017.11.016) Copyright © 2017 Elsevier Inc. Terms and Conditions