The Relevance of Transcription Factors in Gastric and Colorectal Cancer Stem Cells Identification and Eradication

Abstract

Gastric and colorectal cancers have a high incidence and mortality worldwide. The presence of cancer stem cells (CSCs) within the tumor mass has been indicated as the main reason for tumor relapse, metastasis and therapy resistance, leading to poor overall survival. Thus, the elimination of CSCs became a crucial goal for cancer treatment. The identification of these cells has been performed by using cellsurface markers, a reliable approach, however it lacks specificity and usually differs among tumor type and in some cases even within the same type. In theory, the ideal CSC markers are those that are required to maintain their stemness features. The knowledge that CSCs exhibit characteristics comparable to normal stem cells that could be associated with the expression of similar transcription factors (TFs) including SOX2, OCT4, NANOG, KLF4 and c-Myc, and signaling pathways such as the Wnt/βcatenin, Hedgehog (Hh), Notch and PI3K/AKT/mTOR directed the attention to the use of these similarities to identify and target CSCs in different tumor types. Several studies have demonstrated that the abnormal expression of some TFs and the dysregulation of signaling pathways are associated with tumorigenesis and CSC phenotype. The disclosure of common and appropriate biomarkers for CSCs will provide an incredible tool for cancer prognosis and treatment. Therefore, this review aims to gather the new insights in gastric and colorectal CSC identification specially by using TFs as biomarkers and divulge promising drugs that have been found and tested for targeting these cells.

FOLFOX Therapy Induces Feedback Upregulation of CD44v6 through YB-1 to Maintain Stemness in Colon Initiating Cells

“…Although CICs and somatic stem cells exhibit similar transcription factors (TFs), including SOX2, OCT4, NANOG, KLF4, and c-Myc, several studies have demonstrated that the abnormal expression of some distinctive TFs [ 64 ] have a crucial role in the reprogramming of these cells [ 65 ]. In this case, overexpression of TFs results in dysregulation of associated signaling pathways that are linked with CIC lineage and differentiation phenotype [ 66 ].…”

“…In this case, overexpression of TFs results in dysregulation of associated signaling pathways that are linked with CIC lineage and differentiation phenotype [ 66 ]. Transcriptional regulation occurs when certain TFs bind to the DNA at binding sites of a promoter and affect the transcription of the regulated gene via interactions with their gene promoters [ 65 , 66 ]. In this circumstance, TFs may have a crucial role in the maintenance of CIC stemness.…”

“…Besides this, several genes that are frequently upregulated in tumors, such as STAT3 [ 80 , 81 ] and β-catenin [ 82 , 83 ], have been shown to contribute to the long-term maintenance of the stem cell traits. CRC CICs exhibit characteristics comparable to normal stem cells that could be associated with the expression of similar TFs including SOX2, OCT4, NANOG, KLF4, Lgr5, TWIST1, and c-Myc, and signaling pathways including WNT/β-catenin pathways directed for CRC propagation [ 65 , 84 , 85 ]. Many studies indicate that the Y-box-binding protein-1 (YB-1) transcription factor can function as an oncoprotein [ 86 , 87 , 88 ] to regulate stemness, drug-resistance and tumorigenic properties in various cancers [ 89 , 90 , 91 , 92 , 93 , 94 ] including CRC [ 95 ].…”

Roles of microRNAs in Gastrointestinal Cancer Stem Cell Resistance and Therapeutic Development

“…Due to this continuous proliferation and differentiation of cells, dysregulation in the proliferation and/or differentiation pathways within these cells can result in forming CRC CSCs [ 33 ]. Although the origin of CRC CSCs is still debated today, ultimately, among several other pathways, dysregulations within the Wnt [ 36 ], Notch, and TGF-β signaling pathways of the intestinal epithelial cells have all been found to contribute to the stemness of CRC CSCs [ 2 , 33 , 35 , 37 ]. As a result of these efforts, various genes associated with these pathways have been identified as potential biomarkers for CRC CSCs [ 2 , 34 , 38 ].…”

“…As a result of these efforts, various genes associated with these pathways have been identified as potential biomarkers for CRC CSCs [ 2 , 34 , 38 ]. In addition to biomarkers directly associated with these pathways, general markers found in several different types of stem cells and CSCs, such as NANOG, OCT-3/4 (also known as POU5F1), and SOX2, are highly expressed in CRC CSCs [ 2 , 33 , 34 , 37 , 38 ]. In addition to these general markers for stemness, it has been well-documented that CD24, CD44, CD133, LGR5, ALDH1, CXCR4, DCLK1, and EpCAM (also known as ESA) can also be used to identify CRC CSCs [ 2 , 19 , 20 , 33 , 34 , 38 , 39 , 40 , 41 ].…”