Therapeutic strategies targeting Wnt/β‑catenin signaling for colorectal cancer (Review)

Ji, Yong; Lv, Jian; Sun, Di; Huang, Yu‐Feng

doi:10.3892/ijmm.2021.5056

Cited by 32 publications

(22 citation statements)

References 176 publications

(357 reference statements)

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“…Furthermore, all five patients with APC mutations had other concurrent gene mutations ( TP53 or KRAS ). CTNNB1 mutations have been shown to closely associate with activation of the Wnt pathway as well as APC mutations [ 28 ]. The CTNNB1 mutation rates were 13.6% in SBA in this study.…”

Section: Discussionmentioning

confidence: 99%

Genetic analysis of Japanese patients with small bowel adenocarcinoma using next-generation sequencing

et al. 2022

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Background Small bowel adenocarcinomas (SBAs) are rare and there is little comprehensive data on SBA genomic alterations for Asian patients. This study aimed to profile genomic alterations of SBA in Japanese patients using targeted next-generation sequencing (NGS). Methods We examined 22 surgical resections from patients with primary SBA. SBA genomic alterations were analyzed by NGS. Mismatch repair (MMR) status was determined by immunohistochemical analysis. Mucin phenotypes were classified as gastric (G), intestinal (I), gastrointestinal (GI), and null (N) types on MUC2, MUC5AC, MUC6, and CD10 immunostaining. Results The most common genomic alterations found in SBA tumors were TP53 (n = 16), followed by KRAS (n = 6), APC (n = 5), PIK3CA (n = 4), CTNNB1 (n = 3), KIT (n = 2), BRAF (n = 2), CDKN2A (n = 2), and PTEN (n = 2). Deficient MMR tumors were observed in 6 out of 22 patients. Tumor mucin phenotypes included 2 in G-type, 12 in I-type, 3 in GI-type, and 5 in N-type. APC and CTNNB1 mutations were not found in G-type and GI-type tumors. KRAS mutations were found in all tumor types except for G-type tumors. TP53 mutations were found in all tumor types. Although no single gene mutation was associated with overall survival (OS), we found that KRAS mutations were associated with significant worse OS in patients with proficient MMR tumors. Conclusions SBA genomic alterations in Japanese patients do not differ significantly from those reports in Western countries. Tumor localization, mucin phenotype, and MMR status all appear to impact SBA gene mutations.

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Section: Discussionmentioning

confidence: 99%

Genetic analysis of Japanese patients with small bowel adenocarcinoma using next-generation sequencing

et al. 2022

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“…Regarding regulatory function, previous literature reported that the WNT signaling pathway is the main pathway that promotes CRC stemness (39). Tang et al revealed that TM4SF1 is a key gene in CRC recurrence and metastasis and promotes CRC stemness through the WNT signaling pathway (40).…”

Section: Discussionmentioning

confidence: 99%

Establishment of a circular RNA regulatory stemness-related gene pair signature for predicting prognosis and therapeutic response in colorectal cancer

et al. 2022

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BackgroundColorectal cancer (CRC) is a common malignant tumor of the digestive tract with a poor prognosis. Cancer stem cells (CSCs) affect disease outcomes and treatment responses in CRC. We developed a circular RNA (circRNA) regulatory stemness-related gene pair (CRSRGP) signature to predict CRC patient prognosis and treatment effects.MethodsThe circRNA, miRNA, and mRNA expression profiles and clinical information of CRC patients were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. CRSRGPs were established based on stemness-related genes in the competing endogenous RNA (ceRNA) network. A CRSRGP signature was generated using the least absolute shrinkage and selection operator (Lasso) and Cox regression analysis of TCGA training set. The prognosis was predicted by generating a nomogram integrating the CRSRGP signature and clinicopathologic features. The model was validated in an external validation set (GSE17536). The antitumor drug sensitivity and immunotherapy responses of CRC patients in the high-risk group (HRG) and low-risk group (LRG) were evaluated by the pRRophetic algorithm and immune checkpoint analysis.ResultsWe established an 18-CRSRGP signature to predict the prognosis and treatment responses of CRC patients. In the training and external validation sets, risk scores were used to categorize CRC patients into the HRG and LRG. The Kaplan–Meier analysis showed a poor prognosis for patients in the HRG and that subgroups with different clinical characteristics had significantly different prognoses. A multivariate Cox analysis revealed that the CRSRGP signature was an independent prognostic factor. The nomogram integrating clinical features and the CRSRGP signature efficiently predicted CRC patient prognosis, outperformed the current TNM staging system, and had improved practical clinical value. Anticancer drug sensitivity predictions revealed that the tumors of patients in the HRG were more sensitive to pazopanib, sunitinib, gemcitabine, lapatinib, and cyclopamine. Analysis of immune checkpoint markers demonstrated that patients in the HRG were more likely to benefit from immunotherapy.ConclusionAn efficient, reliable tool for evaluating CRC patient prognosis and treatment response was established based on the 18-CRSRGP signature and nomogram.

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“…In addition, recent investigations on cancer stem cells are focused on examining the molecular mechanisms responsible for Wnt signaling in Apc and β-catenin mutated colorectal cancer cell organoids [ 61 , 62 , 63 , 64 , 65 ], the role of DNA repair in stem cell renewal [ 66 ], mechanisms for regulation of CD44 in stem cell proliferation [ 67 ], the role of one-carbon metabolism in cancer stem cells [ 68 ], and the role of ER-β in mammary carcinogenesis [ 69 ]. The Wnt/β-catenin signaling pathway plays important roles in colon cancer metastasis, cancer stem cell biology and epithelial-mesenchymal transition process, and therefore, a valuable therapeutic target [ 70 , 71 ]. Retinoic acid receptor agonists may function as novel inhibitors of colon cancer progression [ 72 ].…”

Section: Future Prospectsmentioning

confidence: 99%

Drug-Resistant Stem Cells: Novel Approach for Colon Cancer Therapy

Telang¹

2022

IJMS

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Background: Next to breast cancer, advanced stage metastatic colon cancer represents a major cause for mortality in women. Germline or somatic mutations in tumor suppressor genes or in DNA mismatch repair genes represent risk factors for genetic predisposition of colon cancer that are also detectable in sporadic colon cancer. Conventional chemotherapy for colon cancer includes combination of 5-fluoro-uracil with oxaliplatin and irinotecan or targeted therapy with non-steroid anti-inflammatory drugs and selective cyclooxygenase-2 inhibitors. Major limitations of these therapeutic interventions are associated with systemic toxicity, acquired tumor resistance and the emergence of drug resistant stem cells that favor initiation, progression and metastasis of therapy-resistant disease. These limitations emphasize an unmet need to identify tumor stem cell selective testable alternatives. Drug-resistant stem cell models facilitate the identification of new testable alternatives from natural phytochemicals and herbal formulations. The goal of this review is to provide an overview relevant to the current status of conventional/targeted therapy, the role of cancer stem cells and the status of testable alternatives for therapy-resistant colon cancer. Experimental models: Hyper-proliferative and tumorigenic cell lines from genetically predisposed colonic tissues of female mice represent experimental models. Chemotherapeutic agents select drug-resistant phenotypes that exhibit upregulated expressions of cellular and molecular stem cell markers. Mechanistically distinct natural phytochemicals effectively inhibit stem cell growth and downregulate the expressions of stem cell markers. Conclusions: The present review discusses the status of colon cancer therapy and inherent limitations, cancer stem cell biology, potential lead compounds and their advantages over chemotherapy. The present experimental approaches will facilitate the identification of pharmacological and naturally-occurring agents as lead compounds for stem cell targeted therapy of colon cancer.

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Therapeutic strategies targeting Wnt/β‑catenin signaling for colorectal cancer (Review)

Cited by 32 publications

References 176 publications

Genetic analysis of Japanese patients with small bowel adenocarcinoma using next-generation sequencing

Genetic analysis of Japanese patients with small bowel adenocarcinoma using next-generation sequencing

Establishment of a circular RNA regulatory stemness-related gene pair signature for predicting prognosis and therapeutic response in colorectal cancer

Drug-Resistant Stem Cells: Novel Approach for Colon Cancer Therapy

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