scholarly journals A Review on Notch Signaling and Colorectal Cancer

Cells ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 1549
Author(s):  
Ashish Tyagi ◽  
Arun K. Sharma ◽  
Chendil Damodaran
Keyword(s):  
Colorectal Cancer ◽  
Monoclonal Antibodies ◽  
Notch Signaling ◽  
Regulatory Region ◽  
Severe Toxicity ◽  
Oncogenic Signaling ◽  
Notch1 Signaling ◽  
Notch Receptors ◽  
Notch1 Receptor

Colorectal cancer (CRC) has one of the highest mortality rates despite the advancement of treatment options. Aggressive CRC remains difficult to treat owing to the activation of oncogenic signaling pathways such as the Notch signaling pathway. The role of Notch receptors varies according to the difference in their structures; in particular, aberrant activation of Notch1 has been attributed to the severity of CRC. Notch1 activation in CRC is inhibited by small molecule inhibitors that target γ-secretase, an enzyme responsible for the third and last cleavage step of Notch receptors. γ-Secretase also produces the intracellular domain that finally carries out cellular functions by activating downstream effectors. However, most inhibitors block γ-secretase non-selectively and cause severe toxicity. Plant-source-derived small molecules, monoclonal antibodies, biological molecules (such as SiRNAs), and compounds targeting the Notch1 receptor itself or the downstream molecules such as HES1 are some of the options that are in advanced stages of clinical trials. The Negative Regulatory Region (NRR), which plays a central role in the transduction of Notch1 signaling in the event of ligand-dependent and ligand-independent Notch1 processing is also being targeted specifically by monoclonal antibodies (mAbs) to prevent aberrant Notch1 activation. In this review, we discuss the role of Notch1 in CRC, particularly its metastatic phenotype, and how mutations in Notch1, specifically in its NRR region, contribute to the aberrant activation of Notch1 signaling, which, in turn, contributes to CRC pathogenesis. We also discuss prevailing and emerging therapies that target the Notch1 receptor and the NRR region, and we highlight the potential of these therapies in abrogating Notch signaling and, thus, CRC development and progression.

scholarly journals Lunatic Fringe-mediated Notch signaling is required for lung alveogenesis

2010 ◽  
Vol 298 (1) ◽  
pp. L45-L56 ◽  
Author(s):  
Keli Xu ◽  
Erica Nieuwenhuis ◽  
Brenda L. Cohen ◽  
Wei Wang ◽  
Angelo J. Canty ◽  
...  
Keyword(s):  
Notch Signaling ◽  
Lung Development ◽  
Smooth Muscle Actin ◽  
Mutant Mice ◽  
Myofibroblast Differentiation ◽  
Lunatic Fringe ◽  
Notch Receptors ◽  
Distal Lung

Distal lung development occurs through coordinated induction of myofibroblasts, epithelial cells, and capillaries. Lunatic Fringe ( Lfng) is a β1–3 N-acetylglucosamine transferase that modifies Notch receptors to facilitate their activation by Delta-like (Dll1/4) ligands. Lfng is expressed in the distal lung during saccular development, and deletion of this gene impairs myofibroblast differentiation and alveogenesis in this context. A similar defect was observed in Notch2 β-geo/+ Notch3 β-geo/β-geo compound mutant mice but not in Notch2 β-geo/+ or Notch3 β-geo/β-geo single mutants. Finally, to directly test for the role of Notch signaling in myofibroblast differentiation in vivo, we used ROSA26-rtTA/+; tetO-CRE/+; RBPJκflox/flox inducible mutant mice to show that disruption of canonical Notch signaling during late embryonic development prevents induction of smooth muscle actin in mesenchymal cells of the distal lung. In sum, these results demonstrate that Lfng functions to enhance Notch signaling in myofibroblast precursor cells and thereby to coordinate differentiation and mobilization of myofibroblasts required for alveolar septation.

Reversal of Resistance to Doxifluridine and Fluorouracil in Metastatic Colorectal Cancer: The Role of High-Dose Folinic Acid

1992 ◽  
Vol 78 (4) ◽  
pp. 258-261 ◽  
Author(s):  
Marco Colleoni ◽  
Emilio Bajetta ◽  
Filippo de Braud ◽  
Nicoletta Zilembo ◽  
Franco Noiè ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Folinic Acid ◽  
Performance Status ◽  
Objective Response ◽  
High Dose ◽  
Severe Toxicity ◽  
First Line ◽  
First Line Therapy ◽  
Colon And Rectum

The benefits from medical treatment in colorectal cancer are limited. Fluorouracil remains the only recognized drug, and how to treat unresponsive patients is still debated. To evaluate the role of folinic acid (FA) in circumvence resistance in colorectal cancer, 28 patients pretreated with fluoropyrimidine were candidated to receive one of the following schedules: fluorouracil (600 mg/m2) associated with FA (500 mg/m2) weekly for 6 weeks (Regimen A: 21 cases), or fluorouracil (370 mg/m2) plus FA (200 mg/m2) dally for 5 days every 4 weeks (Regimen B: 7 cases). Fourteen patients were pretreated with doxifluridlne, a new fluoropyrimldine derivative with a peculiar mechanism of action, and the remaining 14 patients with fluorouracil. All but 2 patients were unresponsive to first-line treatments. When the treatment began, the median age of the patients was 60 years (range, 30-68). The performance status (ECOG) was 0/1 in 25 of them, and the primary tumor was in the colon and rectum in 19 and 9 patients, respectively. Sites of disease were liver (64 %), lung (35 %), local recurrence (10 %) and peritoneum (10 %). A median of 3 cycles (range, 1-7) was delivered, and no objective response was observed in the group of patients pretreated with doxlfluridine or in the group pretreated with fluorouracil. In 5 cases a significant decrease in baseline CEA values was observed. Therapy was well tolerated, and no grade 4 toxicity was encountered. Severe toxicity was limited and included diarrhea (7 patients), stomatitis (1 patient) and nausea/vomiting (1 patient). High-dose FA has no role in reversing resistance to fluoropyrimidine, and other mechanisms of refractoriness are surely involved. FA should be associated with fluoropyrimidine as first-line therapy together with other biochemical modulators. Further rescue therapies need to be developed.

scholarly journals Enhancement of Notch receptor maturation and signaling sensitivity by Cripto-1

2009 ◽  
Vol 187 (3) ◽  
pp. 343-353 ◽  
Author(s):  
Kazuhide Watanabe ◽  
Tadahiro Nagaoka ◽  
Joseph M. Lee ◽  
Caterina Bianco ◽  
Monica Gonzales ◽  
...  
Keyword(s):  
Notch Signaling ◽  
Notch Receptor ◽  
Carcinoma Cells ◽  
Vertebrate Development ◽  
Notch Receptors ◽  
Epidermal Growth ◽  
Signaling Activation ◽  
Lipid Raft Microdomains ◽  
Golgi Network

Nodal and Notch signaling pathways play essential roles in vertebrate development. Through a yeast two-hybrid screening, we identified Notch3 as a candidate binding partner of the Nodal coreceptor Cripto-1. Coimmunoprecipitation analysis confirmed the binding of Cripto-1 with all four mammalian Notch receptors. Deletion analyses revealed that the binding of Cripto-1 and Notch1 is mediated by the Cripto-1/FRL-1/Cryptic domain of Cripto-1 and the C-terminal region of epidermal growth factor–like repeats of Notch1. Binding of Cripto-1 to Notch1 occurred mainly in the endoplasmic reticulum–Golgi network. Cripto-1 expression resulted in the recruitment of Notch1 protein into lipid raft microdomains and enhancement of the furin-like protein convertase-mediated proteolytic maturation of Notch1 (S1 cleavage). Enhanced S1 cleavage resulted in the sensitization to ligand-induced activation of Notch signaling. In addition, knockdown of Cripto-1 expression in human and mouse embryonal carcinoma cells desensitized the ligand-induced Notch signaling activation. These results suggest a novel role of Cripto-1 in facilitating the posttranslational maturation of Notch receptors.

scholarly journals Role of Notch signaling in colorectal cancer

2009 ◽  
Vol 30 (12) ◽  
pp. 1979-1986 ◽  
Author(s):  
L. Qiao ◽  
B. C.Y. Wong
Keyword(s):  
Colorectal Cancer ◽  
Notch Signaling

NOTCH1 Signaling Defines a Leukemia Initiating Cell Population in T-Cell Acute Lymphoblastic Leukemia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1507-1507
Author(s):  
Wenxue Ma ◽  
Kristen M. Smith ◽  
Alejandro Gutierrez ◽  
Heather S. Leu ◽  
Qingfei Jiang ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Notch Signaling ◽  
Lymphoblastic Leukemia ◽  
Therapeutic Resistance ◽  
Self Renewal ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Notch1 Receptor

Abstract Abstract 1507 Leukemia initiating cells (LIC) contribute to therapeutic resistance as a result of their capacity to accumulate mutations in pathways, such as the NOTCH1 receptor signaling pathway, that promote self-renewal and survival within specific niches. Activating mutations in NOTCH1 occur commonly in T cell acute lymphoblastic leukemia (T-ALL) and have been implicated in driving therapeutic resistance. However, the role of NOTCH1 activation in human T-ALL LIC propagation and LIC sensitivity to selective NOTCH1 receptor inhibition has not been examined. The difficulties in maintaining primary cultures of leukemia cells have hampered investigations into the biology of T-ALL LIC and underscore the need for a direct transplantation model to characterize human LIC in vivo and as a paradigm for screening candidate drugs that inhibit self-renewal pathways active in T-ALL LIC. Pediatric T-ALL serially transplantable LIC were found to be enriched in the CD34+CD4− and CD34+CD7− fractions of newly diagnosed patient samples. More recently, a CD7+CD1a− glucocorticoid resistant LIC population, capable of engrafting leukemia in NOD/SCID IL2Rƒn gamma null (NSG) mice, was identified in primary adult T-ALL without an in vitro expansion. In this study, we identified and molecularly characterized potential LIC populations in pediatric T-ALL without preceding in vitro culture and examined the role of NOTCH1 activation in LIC propagation. To further define the T-ALL LIC, CD34+CD2+CD7+ or CD34+CD2+CD7− cells were isolated from T-ALL primary patients' blood by FACS sorting and transplanted into neonatal RAG2−/− gamma chain−/− mice to determine their leukemic engraftment potential. Limiting dilution experiments were performed with cells from six T-ALL patient samples. Mice transplanted with CD34+CD2+CD7+ or CD34+CD2+CD7− cells developed a T-ALL-like disease characterized by pale bone marrow and enlarged spleen, thymus and liver. Hematopoietic organs were analyzed by flow cytometry and showed engraftment of bone marrow, spleen, thymus and liver. Furthermore, the disease could be serially transplanted. LIC were uniquely susceptible to targeted inhibition in vivo with a therapeutic human NOTCH1 negative regulatory region selective monoclonal antibody (mAb) while normal human hematopoietic progenitors were spared thereby highlighting the cell type and context specific effects of NOTCH signaling. Both the NOTCH1 mAb treatment and lentiviral shRNA knockdown of NOTCH1 reduced NOTCH1, HES1 and c-MYC transcript levels, underscoring the selectivity of NOTCH1 mAb inhibition of NOTCH signaling. These results demonstrate that CD34+CD2+CD7+ and CD34+CD2+CD7− subpopulations are enriched for LIC activity in pediatric T-ALL. Moreover, inhibition of NOTCH signaling by either mAb or shRNA-mediated Notch1 knockdown might be another strategy to target the LIC in T-ALL. Disclosures: No relevant conflicts of interest to declare.

scholarly journals A computational guided, functional validation of a novel therapeutic antibody proposes Notch signaling as a clinical relevant and druggable target in glioma

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Dayana Herrera-Rios ◽  
Guanzhang Li ◽  
Dilaware Khan ◽  
Julia Tsiampali ◽  
Ann-Christin Nickel ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cell Signaling ◽  
Notch Signaling ◽  
Notch Pathway ◽  
Therapy Resistance ◽  
Drug Candidate ◽  
Severe Toxicity ◽  
Gamma Secretase ◽  
Signaling Activity ◽  
Notch1 Receptor

Abstract The Notch signaling network determines stemness in various tissues and targeting signaling activity in malignant brain cancers by gamma-secretase inhibitors (GSI) has shown promising preclinical success. However, the clinical translation remains challenging due to severe toxicity side effects and emergence of therapy resistance. Better anti-Notch directed therapies, specifically directed against the tumor promoting Notch receptor 1 signaling framework, and biomarkers predicting response to such therapy are of highest clinical need. We assessed multiple patient datasets to probe the clinical relevance Notch1 activation and possible differential distribution amongst molecular subtypes in brain cancers. We functionally assessed the biological effects of the first-in-human tested blocking antibody against Notch1 receptor (brontictuzumab, BRON) in a collection of glioma stem-like cell (GSC) models and compared its effects to genetic Notch1 inhibition as well as classical pharmacological Notch inhibitor treatment using gamma-secretase inhibitor MRK003. We also assess effects on Wingless (WNT) stem cell signaling activation, which includes the interrogation of genetic WNT inhibition models. Our computed transcriptional Notch pathway activation score is upregulated in neural stem cells, as compared to astrocytes; as well as in GSCs, as compared to differentiated glioblastoma cells. Moreover, the Notch signature is clinical predictive in our glioblastoma patient discovery and validation cohort. Notch signature is significantly increased in tumors with mutant IDH1 genome and tumors without 1p and 19q co-deletion. In GSCs with elevated Notch1 expression, BRON treatment blocks transcription of Notch pathway target genes Hes1/Hey1, significantly reduced the amount of cleaved Notch1 receptor protein and caused significantly impairment of cellular invasion. Benchmarking this phenotype to those observed with genetic Notch1 inhibition in corresponding cell models did result in higher reduction of cell invasion under chemotherapy. BRON treatment caused signs of upregulation of Wingless (WNT) stem cell signaling activity, and vice versa, blockage of WNT signaling caused induction of Notch target gene expression in our models. We extend the list of evidences that elevated Notch signal expression is a biomarker signature declaring stem cell prevalence and useful for predicting negative clinical course in glioblastoma. By using functional assays, we validated a first in man tested Notch1 receptor specific antibody as a promising drug candidate in the context of neuro oncology and propose biomarker panel to predict resistance and therapy success of this treatment option. We note that the observed phenotype seems only in part due to Notch1 blockage and the drug candidate leads to activation of off target signals. Further studies addressing a possible emergence of therapy resistance due to WNT activation need to be conducted. We further validated our 3D disease modeling technology to be of benefit for drug development projects.

scholarly journals The Prognostic Role of BRAF Mutation in Metastatic Colorectal Cancer Receiving Anti-EGFR Monoclonal Antibodies: A Meta-Analysis

PLoS ONE ◽  
2013 ◽  
Vol 8 (6) ◽  
pp. e65995 ◽  
Author(s):  
Zi-Xu Yuan ◽  
Xiao-Yan Wang ◽  
Qi-Yuan Qin ◽  
De-Feng Chen ◽  
Qing-Hua Zhong ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Monoclonal Antibodies ◽  
Metastatic Colorectal Cancer ◽  
Braf Mutation ◽  
Meta Analysis ◽  
Prognostic Role

scholarly journals The Role of Intracellular Trafficking of Notch Receptors in Ligand-Independent Notch Activation

Biomolecules ◽  
2021 ◽  
Vol 11 (9) ◽  
pp. 1369 ◽  
Author(s):  
Judith Hounjet ◽  
Marc Vooijs
Keyword(s):  
Notch Signaling ◽  
Intracellular Trafficking ◽  
Current Knowledge ◽  
Unmet Need ◽  
Receptor Activation ◽  
Notch Receptor ◽  
Comprehensive Overview ◽  
Normal Tissues ◽  
Notch Receptors

Aberrant Notch signaling has been found in a broad range of human malignancies. Consequently, small molecule inhibitors and antibodies targeting Notch signaling in human cancers have been developed and tested; however, these have failed due to limited anti-tumor efficacy because of dose-limiting toxicities in normal tissues. Therefore, there is an unmet need to discover novel regulators of malignant Notch signaling, which do not affect Notch signaling in healthy tissues. This review provides a comprehensive overview of the current knowledge on the role of intracellular trafficking in ligand-independent Notch receptor activation, the possible mechanisms involved, and possible therapeutic opportunities for inhibitors of intracellular trafficking in Notch targeting.

Activation of Notch1 Signaling Suppresses Granulocytic Differentiation and Maintains a Part of Myeloid Progenitor Cells At the Immature Stage

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2375-2375
Author(s):  
Makoto Nakamura ◽  
Lizi Wu ◽  
Satoru Kojika ◽  
James D. Griffin ◽  
Kanji Sugita
Keyword(s):  
Notch Signaling ◽  
Immature Stage ◽  
The Other ◽  
Granulocytic Differentiation ◽  
Notch1 Signaling ◽  
Differentiated Cells ◽  
Myeloid Progenitor ◽  
Myeloid Progenitor Cells ◽  
The Difference

Abstract Abstract 2375 The Notch signaling pathway is evolutionally conserved and has crucial roles in the control of fate decision and differentiation in numerous cell types. Although Notch1 is continuously expressed in differentiation myeloid cells, the role of Notch1 signaling in regulating differentiation remains controversial. Here, we enhanced and/or suppressed Notch signaling in myeloblasts and then determined the effects of Notch signaling modulation on granulocytic differentiation. Specifically, we first transduced myeloblastic 32D and HL60 cells with retroviruses that express the intracellular domain of Notch1 (ICN1; pMSCV-ICN1-IRES-GFP) to activate Notch1 signaling, or alternatively expressed a dominant-negative form of Mastermind-like 1 (DNMAML1; pMSCV-DNMAML1-GFP) to inhibit Notch signaling. Then the transduced (GFP+) and untransduced (GFP-) cells were induced into granulocytic differentiation using G-CSF for 32D cells and ATRA for HL60 cells. The degree of granulocytic differentiation was then assessed by flow cytometric analysis of surface expression of CD11b, a marker of granulocytic lineage. We found that the percentage of differentiated cells (CD11bhigh for 32D and CD11b+ for HL60) in the ICN1 expressing (GFP+) group was significantly (p < 0.05) lower than that in the control (GFP-) group for most time-points that we examined, whereas the difference in the proportion of differentiated cells between DNMAML1 expressing (GFP+) and control (GFP-) groups was not statistically significant. These data suggest that forced activation of Notch1 signaling inhibits granulocytic differentiation, whereas endogenous Notch1 signaling appears not to have a major role in granulocytic maturation in these cell lines. Next, We further studied the role of Notch1 signaling in granulopoiesis by first activating Notch1 signaling in 32D cells by stable expression of exogenous ICN1 followed by Notch inhibition via DNMAML1 expression within the same cells. The subsequent four sub-populations of 32D cells termed as Vec/GFP (control), Vec/DNMAML1 (cells with endogenous Notch signaling blocked by DNMAML1, ICN1/GFP (cells with activating Notch1), and ICN1/DNMAML1 (cells with activating Notch1 followed by Notch signaling inhibition) were then cultured with G-CSF and evaluated for differentiation by CD11b staining. We found that on days 6 and 8 after the induction of differentiation, the proportion of differentiated (CD11bhigh) cells in ICN1/GFP was significantly (p < 0.05) lower than those in the other sub-populations, supporting that ICN1 inhibits granulocytic differentiation of 32D cells. On the other hand, the difference in the proportion of differentiated cells between the other 3 sub-populations was not statistically significant at any time-points, suggesting that DNMAML1 reverses the phenotype induced by activated Notch1 and that endogenous Notch1 signaling may have no effect on granulocytic maturation. Real-time RT-PCR analysis of cytoplasmic expression of myeloperoxidase (MPO) indicated that the MPO expression reached maximal level by day 2 in control (Vec/GFP) cells, the peak was delayed until day 5 in ICN1/GFP cells. The peak expression was observed on day 3 in both Vec/DNMAML1 and ICN1/DNMAML1 cells, indicating that ICN1 represses or delays granulocytic differentiation and that DNMAML1 partially neutralizes such a phenotype. Furthermore, morphological analysis, viable cell count, and cell cycle analysis revealed that a subset of ICN1/GFP cells remained myeloblastic with proliferative capacity after the induction of granulocytic differentiation, supporting the idea that ICN1 inhibits granulocytic differentiation. Our data indicate that Notch1 signaling activation suppresses granulocytic differentiation, and maintains a part of myeloid progenitor cells at the immature stage. Therefore, it suggests that aberrant Notch1 signaling could support the granulocytic transformation and the maintenance of the malignant phenotype. Disclosures: Griffin: Novartis Pharmaceuticals: Consultancy, Research Funding.

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