Clinical Implications of Colorectal Cancer Stem Cells in the Age of Single-Cell Omics and Targeted Therapies

Abstract

The cancer stem cell (CSC) concept emerged from the recognition of inherent tumor heterogeneity and suggests that within a given tumor, in analogy to normal tissues, there exists a cellular hierarchy composed of a minority of more primitive cells with enhanced longevity (ie, CSCs) that give rise to shorter-lived, more differentiated cells (ie, cancer bulk populations), which on their own are not capable of tumor perpetuation. CSCs can be responsible for cancer therapeutic resistance to conventional, targeted, and immunotherapeutic treatment modalities, and for cancer progression through CSC-intrinsic molecular mechanisms. The existence of CSCs in colorectal cancer (CRC) was first established through demonstration of enhanced clonogenicity and tumor-forming capacity of this cell subset in human-to-mouse tumor xenotransplantation experiments and subsequently confirmed through lineagetracing studies in mice. Surface markers for CRC CSC identification and their prospective isolation are now established. Therefore, the application of single-cell omics technologies to CSC characterization, including wholegenome sequencing, RNA sequencing, and epigenetic analyses, opens unprecedented opportunities to discover novel targetable molecular pathways and hence to develop novel strategies for CRC eradication. We review recent advances in this field and discuss the potential implications of next-generation CSC analyses for currently approved and experimental targeted CRC therapies.

Oxymatrine Synergistically Enhances Doxorubicin Anticancer Effects in Colorectal Cancer

“…Colorectal cancer (CRC) is the third most common malignancy worldwide ( Burnett-Hartman et al, 2021 ). Development of CRC is a multifactorial process with known risk factors including older age, male sex, family history, and unhealthy lifestyle including a dysregulated diet with low intake of fresh fruits and vegetables, obesity, smoking, and lack of exercise ( Frank et al, 2021 ; Sehgal et al, 2021 ). As clinical therapy, the first-line chemotherapy includes fluoropyrimidines (5-fluorouracil or capecitabine) alone or combined with leucovorin (LV) as well as other cytotoxic agents, such as oxaliplatin (5-Fu/LV/oxaliplatin FOLFOX) and capecitabine/LV/oxaliplatin [CAPOX]) or irinotecan (5-Fu/LV/irinotecan [FOLFIRI]).…”

Quantification of Fibrinogen-to-Pre-Albumin Ratio Provides an Integrating Parameter for Differential Diagnosis and Risk Stratification of Early-Stage Colorectal Cancer

“…Patients with low-grade FPR (≤15) showed complete response to CT; however, median-grade FPR (20≥FPR>15) and high-grade FPR (>20) implied chemosensitivity and chemoresistance in CRC patients [16]. In this study, we found that CT-treated FPR>20 patients harbored the highest recurrence and death rates, and similar highest recurrence and death rates were observed in non-CT-treated patients with FPR>20, indicating that the cases with FPR>20 might not bene t from CT, and that these patients may be treated with single-targeted therapy or onco-immunotherapy, combined CT after the surgery [34][35][36]. Moreover, the recurrence and death rates in non-CT treated patients with 20≥FPR>15 were approximately ve times higher than those of the CT-treated cases, suggesting that patients with 20≥FPR>15 were suitable to receive CT and could signi cantly bene t from the treatment.…”

Markers and Reporters to Reveal the Hierarchy in Heterogeneous Cancer Stem Cells

“…So the antibody recognizes only the glycosylated form of the molecule. A comparative study of this antibody and another antibody that recognizes the non-glycosylated form showed that only the glycosylation is negatively regulated with differentiation (Florek et al, 2005). In colon cancer, the reduction in population expressing the AC133 epitope and loss of clonogenicity upon differentiation of CSCs did not correspond to a reduction of CD133 promoter activity or its expression at mRNA or protein level (Kemper et al, 2010).…”

“…The significance of CD133 signaling was not unraveled for a long time. A report that showed CD133's interaction with cholesterol to act as an organizer for membrane topology was the first report that suggested its role in signaling (Florek et al, 2005). However, its relevance in stem cell biology was not unraveled until a physical interaction of CD133 to p85 subunit of PI3K was shown to activate its catalytic subunit p110 (Wei et al, 2013).…”

“…Additionally, this dormant population can acquire proliferative capacity to facilitate differentiation. Recent advances in the single-cell-based technologies, such as single-cell DNA/RNA-Sequencing, mass cytometry (CyTOF), next-generation fluorescence flow cytometry, and “imaging mass cytometry” platform, help us to understand how functional heterogeneity is reflected by phenotypic heterogeneity ( Akrap et al, 2016 ; Puram et al, 2017 ; Colacino et al, 2018 ; Sharma et al, 2018 ; Prieto-Vila et al, 2019 ; Taverna et al, 2020 ; Frank et al, 2021 ; Gonzalez Castro et al, 2021 ).…”