The Small-Molecule Wnt Inhibitor ICG-001 Efficiently Inhibits Colorectal Cancer Stemness and Metastasis by Suppressing MEIS1 Expression

Recurrence and metastasis remain major obstacles in colorectal cancer (CRC) treatment. Recent studies suggest that a small subpopulation of cells with a self-renewal ability, called cancer stem-like cells (CSCs), promotes recurrence and metastasis in CRC. Unfortunately, no CSC inhibitor has been demonstrated to be more effective than existing chemotherapeutic drugs, resulting in a significant unmet need for effective CRC therapies. In this study, transcriptomic profiling of metastatic tumors from CRC patients revealed significant upregulation in the Wnt pathway and stemness genes. Thus, we examined the therapeutic effect of the small-molecule Wnt inhibitor ICG-001 on cancer stemness and metastasis. The ICG-001 treatment efficiently attenuated self-renewal activity and metastatic potential. Mechanistically, myeloid ecotropic viral insertion site 1 (MEIS1) was identified as a target gene of ICG-001 that is transcriptionally regulated by Wnt signaling. A series of functional analyses revealed that MEIS1 enhanced the CSC behavior and metastatic potential of the CRC cells. Collectively, our findings suggest that ICG-001 efficiently inhibits CRC stemness and metastasis by suppressing MEIS1 expression. These results provide a basis for the further clinical investigation of ICG-001 as a targeted therapy for CSCs, opening a new avenue for the development of novel Wnt inhibitors for the treatment of CRC metastasis.

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Polymethoxylated Flavones Target Cancer Stemness and Improve the Antiproliferative Effect of 5-Fluorouracil in a 3D Cell Model of Colorectal Cancer

Nutrients ◽

10.3390/nu11020326 ◽

2019 ◽

Vol 11 (2) ◽

pp. 326 ◽

Cited By ~ 6

Author(s):

Carolina Pereira ◽

Marlene Duarte ◽

Patrícia Silva ◽

Andreia Bento da Silva ◽

Catarina Duarte ◽

...

Keyword(s):

Colorectal Cancer ◽

Cell Proliferation ◽

Colony Formation ◽

Cell Model ◽

Ht29 Cell ◽

Cancer Stemness ◽

Self Renewal ◽

Cell Spheroids ◽

Polymethoxylated Flavones ◽

The Impact

Polymethoxylated flavones (PMFs) from citrus fruits are reported to present anticancer potential. However, there is a lack of information regarding their effect on cancer stem cell (CSC) populations, which has been recognized as responsible for tumor initiation, relapse, and chemoresistance. In this study, we evaluated the effect of an orange peel extract (OPE) and its main PMFs, namely, nobiletin, sinensetin, tangeretin, and scutellarein tetramethylether in targeting cell proliferation and stemness using a 3D cell model of colorectal cancer composed of HT29 cell spheroids cultured for 7 days in stirred conditions. Soft agar assay, ALDH1 activity, and relative quantitative gene expression analysis of specific biomarkers were carried out to characterize the stemness, self-renewal, and mesenchymal features of HT29 cell spheroids. Then, the impact of OPE and PMFs in reducing cell proliferation and modulating cancer stemness and self-renewal was assessed. Results showed that, when compared with monolayer cultures, HT29 cell spheroids presented higher ALDH1 activity (81.97% ± 5.27% compared to 63.55% ± 17.49% for 2D), upregulation of CD44, PROM1, SOX9, and SNAI1 genes (1.83 ± 0.34, 2.54 ± 0.51, 2.03 ± 0.15, and 6.12 ± 1.59 times) and high self-renewal capability (352 ± 55 colonies compared to 253 ± 42 for 2D). Incubation with OPE (1 mg/mL) significantly inhibited cell proliferation and modulated cancer stemness and self-renewal ability: colony formation, ALDH1 activity, and the expression of cancer stemness biomarkers PROM1 and LGR5 were significantly reduced (0.66 ± 0.15 and 0.51 ± 0.14 times, respectively). Among all PMFs, tangeretin was the most efficient in targeting the CSC population by decreasing colony formation and the expression of PROM1 and LGR5. Scutellarein tetramethylether was shown to modulate markers of mesenchymal/metastatic transition (increasing CDH1 and reducing ZEB1 and SNAI1) and nobiletin was capable of downregulating PROM1 and SNAI1 expression. Importantly, all PMFs and OPE were shown to synergistically interact with 5-fluorouracil, improving the antiproliferative response of this drug.

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Abstract 1215: Small molecule Prodigiosin-mediated p53 pathway restoration and inhibition of self-renewal in colorectal cancer involves c-Jun-mediated ΔNp73 inhibition and p73 activation

10.1158/1538-7445.am2015-1215 ◽

2015 ◽

Author(s):

Varun Vijay Prabhu ◽

Shengliang Zhang ◽

Bo Hong ◽

Joshua E. Allen ◽

Amriti Lulla ◽

...

Keyword(s):

Colorectal Cancer ◽

Small Molecule ◽

Self Renewal ◽

P53 Pathway

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Cancer stemness as a target for immunotherapy is shaped by pro-inflammatory stress.

Current Stem Cell Research & Therapy ◽

10.2174/1574888x15666200309145901 ◽

2020 ◽

Vol 15 ◽

Author(s):

Nese Unver

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Cancer Stem Cells ◽

Immune Cells ◽

Tumor Recurrence ◽

Inflammatory Factors ◽

Cancer Stemness ◽

Self Renewal ◽

Inflammatory Stress ◽

Factors Affecting

: Cancer stem cells represent a rare subpopulation of cancer cells carrying self-renewal and differentiation features in the multi-step tumorigenesis, tumor recurrence and metastasis. Pro-inflammatory stress is highly associated with cancer stemness via induction of cytokines, tumor-promoting immune cells and cancer stemness-related signaling pathways. This review summarizes the major pro-inflammatory factors affecting cancer stem cell characteristics and the critical immunotherapeutic strategies to eliminate cancer stem cells.

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Impact of HuR inhibition by the small molecule MS-444 on colorectal cancer cell tumorigenesis

Oncotarget ◽

10.18632/oncotarget.12189 ◽

2016 ◽

Vol 7 (45) ◽

pp. 74043-74058 ◽

Cited By ~ 37

Author(s):

Fernando F. Blanco ◽

Ranjan Preet ◽

Andrea Aguado ◽

Vikalp Vishwakarma ◽

Laura E. Stevens ◽

...

Keyword(s):

Colorectal Cancer ◽

Cancer Cell ◽

Small Molecule ◽

Colorectal Cancer Cell

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B7-H4 induces epithelial–mesenchymal transition and promotes colorectal cancer stemness

Pathology - Research and Practice ◽

10.1016/j.prp.2020.153323 ◽

2021 ◽

pp. 153323

Author(s):

Ying Feng ◽

Zhaoting Yang ◽

Chengye Zhang ◽

Nan Che ◽

Xingzhe Liu ◽

...

Keyword(s):

Colorectal Cancer ◽

Epithelial Mesenchymal Transition ◽

Cancer Stemness ◽

Mesenchymal Transition

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Circulating let-7e-5p, miR-106a-5p, miR-28-3p, and miR-542-5p as a Promising microRNA Signature for the Detection of Colorectal Cancer

Cancers ◽

10.3390/cancers13071493 ◽

2021 ◽

Vol 13 (7) ◽

pp. 1493

Author(s):

Camila Meirelles S. Silva ◽

Mateus C. Barros-Filho ◽

Deysi Viviana T. Wong ◽

Julia Bette H. Mello ◽

Livia Maria S. Nobre ◽

...

Keyword(s):

Colorectal Cancer ◽

Unmet Need ◽

Area Under The Curve ◽

Discrimination Performance ◽

Colorectal Carcinogenesis ◽

The Cancer Genome Atlas ◽

Colon Perforation ◽

Data Series ◽

Predictive Tool ◽

Incidence And Mortality

Colorectal cancer (CRC) is a disease with high incidence and mortality. Colonoscopy is a gold standard among tests used for CRC traceability. However, serious complications, such as colon perforation, may occur. Non-invasive diagnostic procedures are an unmet need. We aimed to identify a plasma microRNA (miRNA) signature for CRC detection. Plasma samples were obtained from subjects (n = 109) at different stages of colorectal carcinogenesis. The patients were stratified into a non-cancer (27 healthy volunteers, 17 patients with hyperplastic polyps, 24 with adenomas), and a cancer group (20 CRC and 21 metastatic CRC). miRNAs (381) were screened by TaqMan Low-Density Array. A classifier based on four differentially expressed miRNAs (miR-28-3p, let-7e-5p, miR-106a-5p, and miR-542-5p) was able to discriminate cancer versus non-cancer cases. The overexpression of these miRNAs was confirmed by RT-qPCR, and a cross-study validation step was implemented using eight data series retrieved from Gene Expression Omnibus (GEO). In addition, another external data validation using CRC surgical specimens from The Cancer Genome Atlas (TCGA) was carried out. The predictive model’s performance in the validation set was 76.5% accuracy, 59.4% sensitivity, and 86.8% specificity (area under the curve, AUC = 0.716). The employment of our model in the independent publicly available datasets confirmed a good discrimination performance in five of eight datasets (median AUC = 0.823). Applying this algorithm to the TCGA cohort, we found 99.5% accuracy, 99.7% sensitivity, and 90.9% specificity (AUC = 0.998) when the model was applied to solid colorectal tissues. Overall, we suggest a novel signature of four circulating miRNAs, i.e., miR-28-3p, let-7e-5p, miR-106a-5p, and miR-542-5p, as a predictive tool for the detection of CRC.

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Metformin and Niclosamide Synergistically Suppress Wnt and YAP in APC-Mutated Colorectal Cancer

Cancers ◽

10.3390/cancers13143437 ◽

2021 ◽

Vol 13 (14) ◽

pp. 3437

Author(s):

Hee Eun Kang ◽

Yoojeong Seo ◽

Jun Seop Yun ◽

Sang Hyun Song ◽

Dawool Han ◽

...

Keyword(s):

Colorectal Cancer ◽

Cancer Progression ◽

Therapeutic Strategy ◽

Target Gene ◽

Advanced Colorectal Cancer ◽

Therapeutic Potential ◽

Cancer Stemness ◽

Reciprocal Regulation ◽

Canonical Wnt

The Wnt and Hippo pathways are tightly coordinated and understanding their reciprocal regulation may provide a novel therapeutic strategy for cancer. Anti-helminthic niclosamide is an effective inhibitor of Wnt and is now in a phase II trial for advanced colorectal cancer (CRC) patients. We found that Axin2, an authentic target gene of canonical Wnt, acts as aYAP phosphorylation activator in APC-mutated CRC. While niclosamide effectively suppresses Wnt, it also inhibits Hippo, limiting its therapeutic potential for CRC. To overcome this limitation, we utilized metformin, a clinically available AMPK activator. This combinatory approach not only suppresses canonical Wnt activity, but also inhibits YAP activity in CRC cancer cells and in patient-derived cancer organoid through the suppression of cancer stemness. Further, combinatory oral administration suppressed in vivo tumorigenesis and the cancer progression of APC-MIN mice models. Our observations provide not only a reciprocal link between Wnt and Hippo, but also clinically available novel therapeutics that are able to target Wnt and YAP in APC-mutated CRC.

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