The Varied Roles of Notch in Cancer

Abstract

Notch receptors influence cellular behavior by participating in a seemingly simple signaling pathway, but outcomes produced by Notch signaling are remarkably varied depending on signal dose and cell context. Here, after briefly reviewing new insights into physiologic mechanisms of Notch signaling in healthy tissues and defects in Notch signaling that contribute to congenital disorders and viral infection, we discuss the varied roles of Notch in cancer, focusing on cell autonomous activities that may be either oncogenic or tumor suppressive.

Keywords: Notch; cancer hallmarks; cellular transformation; oncogene; tumor suppressor.

Figure 1

Cancer hallmarks proposed to be influenced by Notch signaling. Positive (oncogenic) effects are shown in green, tumor suppressive effects are in red. T-ALL, T acute lymphoblastic leukemia; CLL, chronic lymphocytic leukemia, ACC, adenoid cystic carcinoma; SCCa, squamous cell carcinoma; breast Ca, breast carcinoma; TICs, tumor initiating cells.

Figure 2

Structure of human Notch receptors and ligands. NRR, negative regulatory region; LNR, Lin-12/Notch repeat; HD, heterodimerization domain; TM, transmembrane domain; ANK, ankyrin repeat domain; TAD, transcriptional activation domain; MNNL, N-terminal domain of Notch ligands; DSL, Delta-Serrate-Lag2 domain.

Figure 3

Notch signaling. See text for details.

Figure 4

Patterns of Notch mutations in various cancers. The red X in the negative regulatory region (NRR) corresponds to point substitutions, in-frame indels, and rare deletions that remove the 5′ coding exons of Notch receptors. The red X in the PEST domain corresponds to nonsense or frameshift mutations that lead to loss of the PEST domain.

Figure 5

H3K27 acetylation patterns in the 3′ Myc enhancer region predict response to Notch pathway inhibitors. T-ALL, T acute lymphoblastic leukemia; ETP-ALL, early T progenitor acute lymphoblastic leukemia; AML, acute myeloid leukemia; NDME, Notch dependent Myc enhancer; BDME, Brd4 dependent Myc enhancer.

Figure 6

Enforced expression of Myc, but not myristylated Akt, suppresses the selective drive for Notch1 mutations in murine T-ALL. Hematopoietic stem cells (HSCs) engineered to develop Kras-driven T-ALL were transduced with retroviruses expressing only GFP, myristylated Akt, or Myc and transplanted into recipient mice, which were monitored for T-ALL development.

Figure 7

Myb/p63/Notch1 transcriptional hierarchies in adenoid cystic carcinoma.

Figure 8

Detection of activated Notch in formalin-fixed paraffin-embedded tissues. A) Staining for activated Notch1 in a lymph node involved by chronic lymphocytic leukemia (CLL) associated with a Notch1 PEST domain mutation (85). Note that the staining is nuclear and is stronger in intranodal (IN) cells than in extranodal (EN) cells, presumably due to ligand-mediated Notch1 activation in the nodal microenvironment. C, lymph node capsule. B) Detection of activated Notch3 in human TALL1 cells, which carry a Notch3 allele an activating mutation in the Notch3 negative regulatory region (191). Strong nuclear staining is observed in the tumor cells using an antibody specific for activated Notch3 (191).