Colorectal cancer (CRC) is the third leading cause of cancer death worldwide. It is also the third most common cancer diagnosis among men, and the second most common cancer diagnosis among women. Globally, CRC can account for nearly 694,000 annual deaths. It is widely appreciated that CRC is the result of dysregulated cellular pathways that promote an inappropriate stem-cell-like phenotype, apoptotic resistance, unchecked proliferation and metastatic spread. While no single pathway is responsible for all of these attributes, an array of recent studies suggests a pivotal role for abnormal Notch-1 signaling in CRC, in part due to interconnectivity of Notch with other pathways. This review will summarize recent evidence for a role of Notch signaling in CRC, will consider interconnectivity between Notch and other pathways involved in CRC and will discuss the possible utility of targeting Notch as a CRC therapeutic.Recent global statistics show that there are more than 1 million colorectal cancer (CRC) cases with about 694,000 deaths annually.1,2 Worldwide, CRC is the third and second most common cancer type found in men and women, respectively.
A role for cancer initiating cells (CIC) in tumor growth, drug resistance, relapse, and metastasis via epithelial to mesenchymal transition (EMT) has been supported by experimental evidence. It is well-documented that Notch-1 receptor signaling participates in stem cell maintenance and lineage commitment in various organs, including the colon, and can regulate EMT. The function of Notch signaling in colorectal cancer (CRC) is not clear. We have reported that Notch-1 activation in the human colon tumor cell line HCT-116 resulted in upregulation of Jagged-1, Smad-3, CD44, and Slug proteins. These changes were accompanied by acquisition of a mesenchymal cell phenotype that included increased anchorage independent growth and migratory activity. Experiments with a γ-secretase inhibitor (DAPT) and soluble Jagged1-Fc protein demonstrated that Notch-1 signaling activates CD44 and Slug via other Notch receptors. In subsequent experiments, we observed an increase in Notch-3 expression in the presence of activated Notch-1. Herein, we tested the hypothesis that the stem cell-like mesenchymal phenotype induced by Notch-1 signaling in colon cancer cells is mediated by the Notch-3 receptor and Smad-3. The human colon tumor cell line HCT-116 was transduced with constitutively active Notch-1, and a Notch-3 shRNA to produce a Notch-3 null cell line with activated Notch-1 (ICN1-shN3 cells). ICN1-shN3 cells exhibited a 2.5-fold lower plating efficiency than the HCT-116/ICN1 cell line (p<0.01) that expresses constitutively active Notch-1 in the presence of Notch-3. In addition, Notch-3 null cells with constitutively active Notch-1 (ICN1-shN3 cells) were slower by 29% in completing wound healing as compared with the HCT-116/ICN1 cell line (p<0.05). Consistent with the lower plating efficiency, a 37% decrease in colosphere formation was observed with ICN1-shN3 cells as compared with the HCT-116/ICN1 cell line (p<0.001). These data indicated that loss of Notch-3 abrogated the Notch-1 induced mesenchymal cell phenotype. Western blot analysis demonstrated that the HCT-116/ICN1 cells with intact Notch-3 exhibited increased levels of the EMT associated proteins Smad-3, CD44 and Slug as compared to the parental HCT-116 cell line. Expression of CD44 and Slug in Notch-3 receptor null ICN1-shN3 cells was highly reduced compared with HCT-116/ICN1 cells and was similar to that detected in the parental HCT-116 cells. Treatment of HCT-116/ICN1 cells with a Smad-3 inhibitor resulted in significant reduction of the CD44 and Slug proteins. Meanwhile, Notch-3 receptor null ICN1-shN3 cells were also more sensitive to chemotherapy treatment than the HCT-116/ICN1 cell line (p<0.05). Collectively, our data provide evidence for a novel pathway in which Notch-1 signaling in colon tumor cells promotes a mesenchymal phenotype via activation of Jagged-1, Notch-3 and Smad-3, followed by expression of CD44 and Slug. Citation Format: George Sigounas, Fred E. Bertrand, Douglas A. Weidner, Kaitlyn E. Vinson, Alexander G. Clark, Azeem Khan. Notch-1 promotes a mesenchymal phenotype in colon cancer cells via Notch-3 and Smad-3 activation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 856. doi:10.1158/1538-7445.AM2017-856
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