Peter Vu

Introduction. Colorectal cancer (CRC) is the third most commonly diagnosed malignancy and the fourth leading cause of cancer-related mortality worldwide⁶. Colorectal stem cells (CSCs) are responsible for the progression, metastasis, relapse, and treatment resistance of CRC, and use similar signaling pathways found in normal intestine stem cells⁷. The Wnt pathway plays a crucial role in intestinal tissue maintenance by regulating proliferation and differentiation of stem cells^4,5. The aberrant activation of Wnt pathway, such as the gain-of-function mutations of Wnt signaling mediator β-catenin, is responsible for proliferation of human CRC⁵. The Wnt pathway has been extensively characterized in CRC but its interactions with other cellular pathways, such as downstream Notch pathway Jagged1 and Jagged2 signaling, remains relatively unknown. These findings could suggest other therapeutic targets for CRC. Methods. Immunohistochemical assays of Notch1 intracellular domain (NICD1) and β-catenin localization in CRC lines and 189 colon cancer tissue samples were evaluated and analyzed for the correlation between the nuclear localization of NICD1 and the clinicopathological features of colon cancer patients^3,8. The utilization of short hairpin RNA (shRNA) on CRC regulated Jagged1 and Jagged2 in vivo treatments and allowed results examined via cell cycle analysis, cell migration and invasion assay, and xenograft tumorigenesis in nude mice^2,9. CRC explants were treated with PF-03084-14, a γ-secretase inhibitor, and evaluated for Notch and Wnt signaling via gene array and immunoblotting¹. Results. NICD1 and β-catenin exhibited a similar localization pattern within the nucleus in colon cancer tissues³. Knockdown of Jagged1 led to a significant inhibition of the migratory, invasive ability, and growth of CRC². Pharmacological inhibition or genetic knockdown of β-catenin in CRC cell lines suppressed Jagged2 expression, sensitizing CRC cells to chemotherapeutic treatments and suggesting Wnt/β-catenin regulation of Jagged2 expression⁹. Treatment with γ-secretase inhibitors resulted in a significant reduction in cleaved Notch, Wnt-dependent gene, and active β-catenin, resulting in increased apoptosis in CRC tumors¹.  Conclusions. Notch1 plays a key role in the Wnt pathway and activation of Notch1 is associated with the translocation of β-catenin to the nucleus³. These findings rationalize a mechanistic approach to CRC treatment based on Jagged1- and Jagged2-targeted therapeutic development^2,9. Inhibition of γ-secretase may be beneficial in a subset of CRC patients with elevated levels of the Wnt and Notch pathways¹. A pronounced comprehension of the critical steps in the crosstalk between Wnt and Notch pathways justify potential avenues in designing clinical trials that target and suppress CRC.

1. Arcaroli, J J, et al. “Tumours with Elevated Levels of the Notch and Wnt Pathways Exhibit Efficacy to PF-03084014, a γ-Secretase Inhibitor, in a Preclinical Colorectal Explant Model.” British Journal of Cancer, vol. 109, no. 3, 2013, pp. 667–675., doi:10.1038/bjc.2013.361.
2. Dai, Y, et al. “Silencing of Jagged1 Inhibits Cell Growth and Invasion in Colorectal Cancer.” Cell Death & Disease, vol. 5, no. 4, 2014, doi:10.1038/cddis.2014.137.
3. Ishiguro, Hideyuki, et al. “Notch1 Activates the Wnt/β-Catenin Signaling Pathway in Colon Cancer.” Oncotarget, vol. 8, no. 36, 2017, doi:10.18632/oncotarget.19534.
4. Ma, Huiying, et al. “Pathology and Genetics of Hereditary Colorectal Cancer.” The Journal of the Royal College of Pathologists of Australasia, vol. 50, no. 1, Jan. 2018, doi:https://doi.org/10.1016/j.pathol.2017.09.004.
5. Novellasdemunt, Laura, et al. “Targeting Wnt Signaling in Colorectal Cancer. A Review in the Theme: Cell Signaling: Proteins, Pathways and Mechanisms.” American Journal of Physiology: Cell Physiology, vol. 309, 19 Aug. 2015, doi:https://doi.org/10.1152/ajpcell.00117.2015.
6. PDQ® Screening and Prevention Editorial Board. PDQ Colorectal Cancer Prevention. Bethesda, MD: National Cancer Institute. Updated <03/09/2018>. Available at: https://www.cancer.gov/types/colorectal/patient/colorectal-prevention-pdq. Accessed <03/15/2018>. [PMID: 26389376]
7. Takebe, Naoko, et al. “Targeting Notch, Hedgehog, and Wnt Pathways in Cancer Stem Cells: Clinical Update.” Nature News, Nature Publishing Group, 7 Apr. 2015, www.nature.com/articles/nrclinonc.2015.61.
8. Tian, Hua, et al. “Opposing Activities of Notch and Wnt Signaling Regulate Intestinal Stem Cells and Gut Homeostasis.” Cell Reports, vol. 11, no. 1, 2015, pp. 33–42., doi:10.1016/j.celrep.2015.03.007.
9. Vaish, Vivek, et al. “Jagged-2 (Jagged2) Enhances Tumorigenicity and Chemoresistance of Colorectal Cancer Cells.” Oncotarget, vol. 8, no. 32, 2017, doi:10.18632/oncotarget.18391.