Table 2.

NOTCH Signaling in Cancers

Cancer type	Involved NOTCH components	Relevant evidence	Ref.
NOTCH signaling pathway plays an oncogenic role
T-cell acute lymphoblastic leukemia	NOTCH1, NOTCH3	More than 50% of T-ALL patients have NOTCH1 somatic activating mutations; Transplanted hematopoietic progenitor cells with activation of Notch1 signaling in murine models can develop T-ALL; Activating mutations of NOTCH3 without NOTCH1 has also been found in several T-ALLs.	344,345,350
Splenic marginal zone lymphoma	NOTCH1, NOTCH2	Activating mutations of NOTCH signaling appeared in 58% of SMZLs, related to inferior survival.	351
B-chronic lymphocytic leukemia	NOTCH1-2, JAG1-2	Constitutively expression of NOTCH1, NOTCH2 proteins and their ligands JAG1 and JAG2 were detected in B-CLL; Dysfunction of NOTCH signaling reduces the morbidity of B-CLL, while activation of NOTCH signaling increases its survival.	352,664
Lung adenocarcinoma	NOTCH1, NOTCH3	NOTCH1 and NOTCH3 were detected highly expressed, suggesting poor prognosis and intensive invasion; Notch1-3 were confirmed contributing to the initiation and progression of LUAD in vivo and in vitro.	355,356,358
Breast cancer	NOTCH1, NOTCH4, JAG1	Upregulation of non-mutated NOTCH1 and JAG1 is associated with poor prognosis of BC; The mutations of Notch1 and Notch4 mediated by the mouse mammary tumor virus can promote epithelial mammary tumorigenesis; BC cell lines with functionally recurrent rearrangements of NOTCH genes are sensitive to NOTCH inhibitors.	379,380,382
Colorectal cancer	NOTCH1	Upregulation of NOTCH ligands (DLL1, DLL3, DLL4, JAG1 and JAG2) and aberrant activation of NOTCH1 were detected; Active Notch1 signaling induces the proliferation and activation of colon cancer hepatocytes, promoting cell invasion and metastasis.	365,367
Ovarian cancer	NOTCH1, NOTCH3	Ntch1 and Notch3 promote the occurrence and development of ovarian cancer; Overexpression of Notch3 is related to cell hyperproliferation and anti-apoptosis.	389–393
Adenoid cystic carcinoma	NOTCH1-2	Activated mutations of NOTCH1 and NOTCH2 were frequently detected in ACC; NOTCH1 inhibitors have significant antitumor efficacy in both ACC patients and PDX models.	415–420
Clear cell renal cell carcinoma	NOTCH1	Overexpression of NOTCH ligands and receptors were observed in CCRCC tissues, and activated NOTCH1 led to dysplastic hyperproliferation of tubular epithelial cells.	422
Hepatocellular carcinoma*	NOTCH1	Approximately 30% of human HCC samples have activated NOTCH signaling, promoting the formation of liver tumors in mice; NOTCH activation facilitates EMT progression and metastasis in HCC; Mutations in the NOTCH target gene HES5 in HCC samples can present both protumorigenic and antitumorigenic functions.	400,402,404
Glioma*	NOTCH1-2	Inhibiting NOTCH signaling with a γ-secretase inhibitor in glioma constrains tumor growth both in vivo and in vitro. NOTCH1 has oncogenic potential in the brain associating other oncogenic hotspots, such as p53 loss. Positive feedback of NOTCH1-SOX2 enhances glioma stem cell invasion along white matter tracts. Inactivation of Rbpj, Notch1 or Notch2 accelerates tumor growth in a mouse model.	407–410
NOTCH signaling pathway palys a tumor suppressing role
Squamous cell cancers	NOTCH1-3	Inactivated NOTCH1-3 were detected in SCC specimens; The genomic aberrations in NOTCH1 induced by mutagenic agent could cause an increasing tumor burden in SCCs; DNMAML1, an inhibitor to canonical NOTCH transcription, promotes de novo SCC formation.	438–440,449,451
Neuroendocrine tumors	NOTCH1, DLL3	Nearly 25% of human SCLC cases present inactivation of NOTCH target genes; DLL3, an inhibitory NOTCH signaling components, was detected highly expressed in SCLC and lung carcinoid tumors; Gastroenteropancreatic and lung neuroendocrine tumors exhibit decreased NOTCH expression and mutated NOTCH components; Activating NOTCH1 could inhibit the growth of thyroid neuroendocrine cancer cells in vitro.	425,426,431,432
Pancreatic ductal adenocarcinomaa	NOTCH1	Notch1 could inhibit the formation of pancreatic intraepithelial neoplasia in a PDAC mouse model; Notch1 loss is required for progression in a Kras-induced PDAC model.	454–456

T-ALL T-cell acute lymphoblastic leukemia, SMZL splenic marginal zone lymphoma, B-CLL B-cell chronic lymphocytic leukemia, LUAD lung adenocarcinoma, BC breast cancer, ACC adenoid cystic carcinoma, PDX patient-derived xenograft; CCRCC clear cell renal cell carcinoma, HCC hepatocellular carcinoma, EMT epithelial–mesenchymal transition, SCC, squamous cell cancer; SCLC small-cell lung cancer, DANMAML1 Dominant-Negative Mastermind Like1, PDAC pancreatic ductal adenocarcinoma

^aNOTCH might act as a tumor suppressor in oncogenic-oriented HCC⁴⁰⁵ and GBM⁴¹³, while as an oncogene in tumorsuppressive-oriented PDAC^454–456