Abstract
The Notch pathway is increasingly attracting attention as a source of therapeutic targets for cancer. Ligand-induced Notch signaling has been implicated in various aspects of cancer biology; as a consequence, pan-Notch inhibitors and therapeutic antibodies targeting one or more of the Notch receptors have been investigated for cancer therapy. Alternatively, Notch ligands provide attractive options for therapy in cancer treatment due to their more restricted expression and better-defined functions, as well as their low rate of mutations in cancer. One of the Notch ligands, Jagged1 (JAG1), is overexpressed in many cancer types, and plays an important role in several aspects of tumor biology. In fact, JAG1-stimulated Notch activation is directly implicated in tumor growth through maintaining cancer stem cell populations, promoting cell survival, inhibiting apoptosis, and driving cell proliferation and metastasis. In addition, JAG1 can indirectly affect cancer by influencing tumor microenvironment components such as tumor vasculature and immune cell infiltration. This article gives an overview of JAG1 and its role in tumor biology, and its potential as a therapeutic target.
Highlights
Jagged1 (JAG1) is one of the five canonical ligands for Notch receptors expressed by mammalian cells
It is worth noting that Jag1 gene knockout in mice causes severe vascular defects that are lethal in early embryogenesis [15], and that JAG1 mutations in human beings are responsible for Alagille syndrome, an inherited multi-organ developmental disorder [16]
We summarize what has been discovered about the contribution of JAG1 to tumor biology to date, and discuss the evidence supporting JAG1 as a valid target for cancer therapy
Summary
The Notch pathway plays an important role in normal stem cell biology, and this resulted in unacceptable levels of gastrointestinal toxicity when pan-Notch ablation was attempted using γ-secretase inhibitors [40, 41]. High levels of JAG1 promote stem cell self-renewal and potentiate mammosphere formation in vitro [23] In this context, JAG1 seems to play a central role in linking various pathways, involving well-established cancer-related molecules such as Notch, interleukin-6 (IL-6), carbonic anhydrase IX (CAIX), and NF-κB [23, 26, 59, 60]. Soluble JAG1 produced by tumor-associated endothelial cells promoted the CSC phenotype in human colorectal cancer cells [14] Overall, these data indicate JAG1 as an important inducer of the stem cell phenotype in different cancer types and, importantly, demonstrates that both tumor and stromal JAG1 expression are relevant targets for CSCs. EPITHELIAL–MESENCHYMAL TRANSITION, INVASION, AND METASTASIS The ability of tumor cells to invade the surrounding tissues and the ability of tumor cells to colonize distant organs (metastatic process) are both key features of aggressive cancers of pivotal clinical relevance.
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