The shifting paradigm of colorectal cancer treatment: a look into emerging cancer stem cell-directed therapeutics to lead the charge toward complete remission

Kopenhaver, Jessica; Crutcher, Madison; Snook, Adam E.

doi:10.1080/14712598.2021.1929167

Cited by 7 publications

(5 citation statements)

References 98 publications

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“…The application of neoadjuvant therapy prior to surgery can reduce tumor volume, lower tumor staging, and enhance the likelihood of completing treatment. However, significant survival benefits have not been consistently observed in previous clinical trials [27, 28]. Therefore, a model for predicting survival in colon cancer patients, particularly those with advanced-stage disease, holds significant value.…”

Section: Discussionmentioning

confidence: 99%

Identification of cuproptosis and ferroptosis-related subtypes and development of a prognostic signature in colon cancer

He,

Liu,

Jiang

2024

Preprint

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Colon cancer, as a highly prevalent malignant tumor globally, poses a significant threat to human health. In recent years, ferroptosis and cuproptosis, as two novel forms of cell death, have attracted widespread attention for their potential roles in the development and treatment of colon cancer. However, the investigation into the subtypes and their impact on the survival of colon cancer patients remains understudied. In this study, utilizing data from TCGA and GEO databases, we examined the expression differences of ferroptosis and cuproptosis-related genes in colon cancer and identified two subtypes. Through functional analysis and bioinformatics methods, we elucidated pathway differences and biological characteristics between these two subtypes. By leveraging differential genes between the two subtypes, we constructed a prognostic model using univariate Cox regression and multivariate Cox regression analysis as well as LASSO regression analysis. Further survival analysis and receiver operating characteristic curve analysis demonstrated the model’s high accuracy. To enhance its clinical utility, we evaluated the clinical significance of the model and constructed a nomogram, significantly improving the predictive ability of the model and providing a new tool for prognostic assessment of colon cancer patients. Subsequently, through immune-related analysis, we revealed differences in immune cell infiltration and immune function between high- and low-risk groups. Further analysis of the relationship between the model and immune cells and functions revealed potential therapeutic targets. Drug sensitivity analysis revealed associations between the expression of model-related genes and drug sensitivity, suggesting their involvement in tumor resistance through certain mechanisms. AZD8055_1059, Bortezomib_1191, Dihydrorotenone_1827, and MG-132_1862 were more sensitive in the high-risk group. Finally, we analyzed differential expression of model-related genes between tumor tissues and normal tissues, validated through real-time quantitative PCR. In summary, our study provides a relatively accurate prognostic tool for colon cancer patients, offering guidance for treatment selection and indicating the potential of immunotherapy in colon cancer.

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Section: Discussionmentioning

confidence: 99%

Identification of cuproptosis and ferroptosis-related subtypes and development of a prognostic signature in colon cancer

He,

Liu,

Jiang

2024

Preprint

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“…At present, the main treatment methods for colorectal cancer include surgical resection, radiotherapy and chemotherapy, and immunotherapy; however, patients often have tumor recurrence and metastasis and poor prognosis [ 2 , 3 ]. A large number of studies have shown that cancer stem cells (CSCs) are the core factor leading to postoperative recurrence, metastasis, and insensitivity to radiotherapy and chemotherapy in colorectal cancer patients [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

AT7867 Inhibits the Growth of Colorectal Cancer Stem-Like Cells and Stemness by Regulating the Stem Cell Maintenance Factor Ascl2 and Akt Signaling

Yuan

Yang

et al. 2023

Stem Cells International

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Cancer stem cells (CSCs) are the core factors leading to recurrence, insensitivity to radiotherapy and chemotherapy, and immunotherapy resistance in patients with colorectal cancer. AT7867, a potent oral AKT inhibitor, was found to have antitumor activity in colorectal cancer; however, the effect on colorectal cancer stem cells is still unclear. This study was conducted to clarify the molecular mechanism underlying the CSC growth inhibitory effects of AT7867. We cultured colorectal cancer cells (CRCs) in a serum-free medium and enriched colorectal cancer stem cells. Subsequently, the effects of AT7867 on CSCs were analyzed by CCK-8, colony formation, flow cytometry, and immunofluorescence assays. The results indicated that AT7867 induces G2/M phase arrest and cell apoptosis in cancer stem cells. Subsequently, we identified Ascl2 as the main gene affecting the stemness of colorectal cancer in AT7867 by RNA sequencing. The current study showed that Ascl2 is involved in the metastasis, invasion, and proliferation of CRCs. The next experiments demonstrated that overexpression of Ascl2 did affect the therapeutic effect of AT7867 on CRC stemness. Furthermore, compared with other Akt inhibitors, AT7867 could promote the differentiation of colorectal cancer stem cells. Thus, AT7867 might be a potential antitumor drug candidate to treat CRC by targeting CSCs.

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“…The primary causes of this are post-operative cancer recurrence or metastasis, as well as cancer cell drug resistance ( 4 ), which is related to CRC stem cells (CCSCs), a subpopulation of CRC cells with the capacity to self-renew, differentiate into multiple lineages, resist therapy and develop metastasis ( 5 ). Therefore, studies are currently underway to create novel CCSC-targeted therapeutics that will enhance the isolation and differentiation of CCSCs from other types of CSCs ( 6 , 7 ).…”

Section: Introductionmentioning

confidence: 99%

“…The most frequently employed markers in CCSC research are cell surface markers ( 7 ). For example, targeting CD133, CD166, CD44, aldehyde dehydrogenase 1 (ALDH1), leucine rich repeat containing G protein-coupled receptor 5 (Lgr5) and epithelial cell adhesion molecule, cell surface markers present on CCSCs, with monoclonal antibodies has the potential to shrink tumors and lessen metastasis ( 8 ).…”

Section: Introductionmentioning

confidence: 99%

“…For example, targeting CD133, CD166, CD44, aldehyde dehydrogenase 1 (ALDH1), leucine rich repeat containing G protein-coupled receptor 5 (Lgr5) and epithelial cell adhesion molecule, cell surface markers present on CCSCs, with monoclonal antibodies has the potential to shrink tumors and lessen metastasis ( 8 ). The lack of a consistent and reliable marker for CCSCs restricts their use in clinical practice ( 7 ), and they are also present in varying degrees in stem cells from normal tissues or other cancer types ( 9 , 10 ).…”

Section: Introductionmentioning

confidence: 99%

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Regulation of the migration of colorectal cancer stem cells via the TLR4/MyD88 signaling pathway by the novel surface marker CD14 following LPS stimulation

Li,

Shi,

Liu

et al. 2023

Oncol Lett

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Cell surface markers are most widely used in the study of cancer stem cells (CSCs). However, cell surface markers that are safely and stably expressed in CSCs have yet to be identified. Colonic CSCs express leukocyte CD14. CD14 binding to the ligand lipopolysaccharide (LPS) is involved in the inflammatory response via the Toll-like receptor 4 (TLR4)/myeloid differentiation factor 88 (MyD88) signaling pathway. TLR4 and MyD88 have been reported to promote the proliferation, metastasis and tumorigenicity of colon cancer cells, which is consistent with the characteristics of CSCs. In the present study, the proposed experimental method to detect cell proliferation, metastasis and tumorigenesis was used to confirm that, under LPS stimulation, CD14 promoted the proliferation, migration and tumorigenesis of colonic CSCs via the TLR4/MyD88 signaling pathway. Cell Counting Kit-8 and 5-ethynyl-2′-deoxyuridine assays were used to assess the proliferation and migration of the cells. Colony formation and nude mouse xenograft assays were used to assess the capacity of cells to form tumors. Using western blotting and reverse transcription-quantitative PCR, the mRNA and protein levels of CD14, TLR4 and MyD88 were examined. It was confirmed that CD14 promoted the proliferation, metastasis and tumorigenesis of colon CSCs in response to LPS stimulation via the TLR4/MyD88 signaling pathway, and CD14 + colon cancer cells were successfully isolated and sorted. According to the results of proliferation assay, it was determined that CD14 regulated the LPS-induced proliferation of colon CSCs. CD14, TLR4 and MyD88 protein and mRNA expression was upregulated in colon CSCs in response to LPS stimulation. This indicates a potential novel target for colon CSC-related studies.

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The shifting paradigm of colorectal cancer treatment: a look into emerging cancer stem cell-directed therapeutics to lead the charge toward complete remission

Cited by 7 publications

References 98 publications

Identification of cuproptosis and ferroptosis-related subtypes and development of a prognostic signature in colon cancer

Identification of cuproptosis and ferroptosis-related subtypes and development of a prognostic signature in colon cancer

AT7867 Inhibits the Growth of Colorectal Cancer Stem-Like Cells and Stemness by Regulating the Stem Cell Maintenance Factor Ascl2 and Akt Signaling

Regulation of the migration of colorectal cancer stem cells via the TLR4/MyD88 signaling pathway by the novel surface marker CD14 following LPS stimulation

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