The strategies to cure cancer patients by eradicating cancer stem-like cells

Abstract

Cancer stem-like cells (CSCs), a subpopulation of cancer cells, possess remarkable capability in proliferation, self-renewal, and differentiation. Their presence is recognized as a crucial factor contributing to tumor progression and metastasis. CSCs have garnered significant attention as a therapeutic focus and an etiologic root of treatment-resistant cells. Increasing evidence indicated that specific biomarkers, aberrant activated pathways, immunosuppressive tumor microenvironment (TME), and immunoevasion are considered the culprits in the occurrence of CSCs and the maintenance of CSCs properties including multi-directional differentiation. Targeting CSC biomarkers, stemness-associated pathways, TME, immunoevasion and inducing CSCs differentiation improve CSCs eradication and, therefore, cancer treatment. This review comprehensively summarized these targeted therapies, along with their current status in clinical trials. By exploring and implementing strategies aimed at eradicating CSCs, researchers aim to improve cancer treatment outcomes and overcome the challenges posed by CSC-mediated therapy resistance.

Keywords: Cancer stem cells; Immune evasion; Targeted therapies; Tumor microenvironment.

Fig. 1

Specific biomarkers for CSCs in different types of cancer

Fig. 2

Contribution of aberrantly activated pathways in CSCs. Dysregulated pathways activate the transcriptional activity of target genes, thereby contributing to the maintenance of the proliferation/dormancy, survival, self-renewal, migration, and evasion properties of CSCs

Fig. 3

Illustration of abnormal pathways and potential targets in CSCs. FZD antagonists target either the Wnt proteins or FZD receptor complexes to inhibit the ligand-receptor interactions in both canonical and non-canonical Wnt pathway. DVL inhibitors block the DVL-PDZ interaction, resulting in subsequently inhibition of the signal transduction pathway. Tankyrase inhibitors stabilize Axin via inhibition of its proteasomal degradation, conversely resulting in increased degradation of β-catenin. CK1 agonists selectively potentiate CK1 kinase activity and stabilize the β-catenin destruction complex that decreasing Wnt signaling. β-catenin/TCF regulators inhibit Wnt-mediated transcriptional activity. LRP5/6 inhibitors competitively bind to the LRP5/6-sclerostin complex thus reverse the activation of Wnt/β-catenin signaling. ROR1-inhibitors ameliorate the access activated Wnt-signaling-mediated cancer cell proliferation, invasion, and therapy resistance. Potential anticancer therapeutic agents targeting the Notch pathway include targeting Notch ligands or receptors, inhibitors of the γ-secretase complex, and inhibitors of NICD-interacting transcriptional complex. SMO inhibitors block the Hh signaling by cyclopamine-competitively binding to SMO. GLI inhibitors prevent the transportation of GLI protein to nucleus thus decreased tumorigenesis gene expression. Inhibition of STAT3 and PI3K blocks their interactions with self-renewal pathways to facilitate CSCs eradication

Fig. 4

TME-induced immunosuppressive environment for the maintenance of CSC properties. Cytokines and growth factors from CAFs, Tregs, MDSCs and TAMs activate cancer-related EMT and suppress DC cell maturation, NK cell function, and TH1/TH2 differentiation. Additionally, TME-derived factors activate cancer-associated pathways including PI3K/Akt, JAK/STAT, and RAS

Fig. 5

DC and T cell mediated tumor immunology and immunotherapy. In MHC-I antigen presentation pathway, oligopeptides degraded from cytosolic and nuclear protein are taken up and translocated into ER by TAP and further trimmed by ERAPs. The modified peptides bind to MHC-I and are transported to the cell surface for exposure to CD8 + T cells [233]. DC produce CXCL9, CXCL10 and IL-2 to recruit effective T cells therefore increase immune response. Activation of CTLA-4 and PD1/PDL1 reprogrammed immune homeostasis and induced cancer cells to eliminate T cell function. Immunotherapies that inhibit CTLA-4 and PD1/PDL1 and enhance MHC-I expression can effectively modulate DC function and improve cancer immunotherapy