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of insulin-secreting pancreatic cells of inner ear suggesting a role for Notch2 as a tumor suppressor gene
[28]
hair cells, and intestinal crypt and goblet cells. in these cancers. In agreement with this observation,
[29]
[30]
Accordingly, the important role of the Notch pathway for active Notch2 induces reduction in tumor take and
normal tissues development has been proven by the increased apoptosis in human MDA-MB-231 (ERα, Her2
identification of Notch mutations in human inherited negative cell line) xenograft tumor growth. The Notch
[50]
diseases. Indeed, Notch alterations have been detected in: pathway is a major determinant of breast cancer stem
(1) Cerebral autosomal dominant arteriopathy, with sub- cells survival, and Notch activation in these cells has been
cortical infarcts and leukoencephalopathy (a heritable linked to resistance to tamoxifen. [51,52] Consistently, Notch
arteriopathy that leads to damaged small blood vessels activation plays a role in tamoxifen resistance observed
and irreversible dementia); (2) spondylocostal dysostosis in protein kinase C-α overexpressing estrogen-responsive
(characterized by abnormal development of bones in the breast cancers and in ErbB-2-positive breast tumors. [54]
[53]
spine and ribs); (3) Alagille syndrome affecting the liver,
heart, kidney, and other systems of the body; (4) Dysregulated expression of Notch proteins, ligands,
[31]
congenital heart diseases. Similarly, in the last decade, and targets has been described in a multitude of solid
[32]
it has been demonstrated that the Notch signaling pathway tumors, including cervical, head and neck, endometrial,
contributes to the regulation of the immune system by renal, lung, pancreatic, ovarian, prostate, esophageal,
playing a role in multiple lineage decisions of developing oral, hepatocellular and gastric carcinomas, osteosarcoma,
lymphoid and myeloid cells. Recent work has shown mesothelioma melanoma, gliomas, medulloblastomas, and
[33]
[8]
that Notch, through macrophage-dependent delta-like rhabdomyosarcoma. Dysregulation of Notch signaling
ligand 1 and 4 signaling, is critical in providing an anti- has been reported in some hematological malignancies,
viral response by linking innate and acquired immunity other than T-ALL, including Hodgkin lymphomas,
during influenza and dengue viral infections. anaplastic large-cell non-Hodgkin lymphomas, acute
[34]
[35]
myeloid leukemias, and B-cell chronic lymphoid leukemias
Notch has emerged as a potent oncogene when it was multiple myeloma (for the original articles on the subject
first shown that a subset of T-cell acute lymphoblastic the reader is referred to). [8]
leukemias (T-ALL) contained a chromosomal translocation,
t(7;9), leading to abnormal expression of the Notch1 intra- Tumor angiogenesis is crucial for cancer growth and
cellular domain, which was later shown to be able to progression. The Notch pathway promotes cancer
[55]
[36]
cause T-cell neoplasm in mice. Later studies confirmed growth not only by enhancing the survival of cancer
[37]
the existence of Notch1 mutation in 60% of human cells and their progenitors but also by controlling tumor
T-ALL. In T-cell neoplasms, Notch1 represses p53, vascularization. Dll4/Notch1-mediated signaling modulates
[38]
[38]
induces c-myc, and inhibits phosphatase and tensin VEGF-A-driven angiogenesis by affecting the number of
[39]
homolog, a downregulator of the phosphatidylinositol sprouts (new branches) on endothelial cells. This interplay
3 kinase (PI3K)-AKT pathway involved in promoting between Dll4/Notch1/VEGFR determines the balance
cancer cell survival. Recent work has shed light on between the number of tip cells (leading and guiding the
[40]
the role of Notch in T-ALL showing that in these tumors blood vessel sprout) and stalk cells (proliferating cells
aberrant Notch activity counteracts the tumor suppression forming the vascular lumen). [24,56] Interference with tumor
function of the transcription factor IKZF1 (IKAROS). [41] angiogenesis by inhibition of Dll4-mediated signaling
has been effective in blocking cancer growth in animal
The major role played by Notch in breast cancer is also models. Recently, high levels of Jagged1 have also been
[57]
well established. Reports of an involvement of Notch in shown to promote tumor angiogenesis by destabilizing the
mammary gland development and neoplasia came from tip and stalk cell fates and by regulating levels of
[58]
the observation of the Notch4/int3 gene as a common VEGFR1, 2 and activate Notch3/Hey1 in tumor cells
[59]
provirus integration site in mammary tumors of mice thus promoting proliferation, survival, and epithelial to
infected with mouse mammary tumor virus (MMTV), mesenchymal transition. Consistently, inhibition of
[42]
[59]
followed by the report that transgenic female mice experimental tumors growth has been obtained by blocking
carrying Notch1 and 3 activating mutations (caused by Jagged1-dependent Notch signaling. [60]
the insertion of the MMTV) developed mammary gland
tumors. Notch has been found activated in ERα Notch inhibitors are currently under clinical investigation,
[43]
positive-, negative-, triple negative-breast cancer cell lines in combination with existing therapies for the treatment
and breast cancer cell lines overexpressing the oncogene of several types of cancers. Considering the role of
[61]
Her2/neu. [18,19,44] Dysregulation of Notch has been shown in Notch in maintaining intestinal homeostasis, patients
human breast cancer biopsies [45-47] in which overexpression treated with Notch inhibitors require clinical monitoring
of Notch1 and one of its ligands, Jagged1 has been linked of the gastrointestinal tract. Furthermore, due to the
[62]
to poor prognosis and overall diminished survival. [48,49] Of effect of Notch in promoting angiogenesis and survival of
interest, Notch2 overexpression was instead associated cardiac progenitor cells, cancer patients with preexisting
with increased survival in breast cancer patients, ischemic diseases should also be monitored for possible
[49]

Journal of Cancer Metastasis and Treatment ¦ Volume 2 ¦ Issue 1 ¦ January 15, 2016 ¦ 13