Informed by Cancer Stem Cells of Solid Tumors: Advances in Treatments Targeting Tumor-Promoting Factors and Pathways

Abstract

Cancer stem cells (CSCs) represent a subpopulation within tumors that promote cancer progression, metastasis, and recurrence due to their self-renewal capacity and resistance to conventional therapies. CSC-specific markers and signaling pathways highly active in CSCs have emerged as a promising strategy for improving patient outcomes. This review provides a comprehensive overview of the therapeutic targets associated with CSCs of solid tumors across various cancer types, including key molecular markers aldehyde dehydrogenases, CD44, epithelial cellular adhesion molecule, and CD133 and signaling pathways such as Wnt/β-catenin, Notch, and Sonic Hedgehog. We discuss a wide array of therapeutic modalities ranging from targeted antibodies, small molecule inhibitors, and near-infrared photoimmunotherapy to advanced genetic approaches like RNA interference, CRISPR/Cas9 technology, aptamers, antisense oligonucleotides, chimeric antigen receptor (CAR) T cells, CAR natural killer cells, bispecific T cell engagers, immunotoxins, drug-antibody conjugates, therapeutic peptides, and dendritic cell vaccines. This review spans developments from preclinical investigations to ongoing clinical trials, highlighting the innovative targeting strategies that have been informed by CSC-associated pathways and molecules to overcome therapeutic resistance. We aim to provide insights into the potential of these therapies to revolutionize cancer treatment, underscoring the critical need for a multi-faceted approach in the battle against cancer. This comprehensive analysis demonstrates how advances made in the CSC field have informed significant developments in novel targeted therapeutic approaches, with the ultimate goal of achieving more effective and durable responses in cancer patients.

Keywords: cancer stem cells; clinical trial; marker; target; therapeutic.

Figure 1

Cellular localization of CSC markers, pathways, and factors associated with CSCs in solid tumors as therapeutic targets. Schematic representation depicting the intracellular and membrane-bound distribution of key CSC markers, pathways, and factors associated with CSCs ALDH1A1, ALDH1A3, ALDH2, ALDH3A1, EpCAM, CD44, CD133, CD55, CXCR4, SOX2, Notch, Nanog, and SHH. Arrows depict signaling pathway intermediates.

Figure 2

Notch signaling pathway and therapeutic interventions. Schematic representation depicting the therapeutic targets of the Notch signaling pathway. Delta-like ligand binding to the Notch receptor results in proteolytic cleavage of the Notch receptor, catalyzed by ADAM metalloproteases and γ-secretase to release the Notch intracellular domain. DLL: Delta-like ligand, NICD: Notch intracellular domain, ADAM17: A disintegrin and metalloproteinase 17, MAML: mastermind-like, CSL: CFB1/RBPJκ/Su(H)/LAG-1.

Figure 3

Therapeutic targets of the Wnt/β-catenin signaling pathway. Wnt ligands are activated by porcupine-mediated lipid modification and bind to Frizzled receptors and LRP co-receptors. R-spondin binding to Lgr receptors enhances Wnt signaling by sequestering ZNRF3 and RNF43 to stabilize the Wnt/Fzd interaction. Activation of the Fzd/LRP receptor complex leads to the recruitment and activation of Disheveled. In turn, Disheveled inhibits the β-catenin destruction complex. β-catenin translocates to the nucleus, where it displaces TBL1-containing corepressor complexes from TCF/LEF transcription factors to allow the transcription of target genes. CBP is recruited to the promoter regions of Wnt target genes. PORCN: Porcupine, Wnt: wingless-related integration site, LRP: low-density lipoprotein receptor-related protein, ZNRF3: zinc and ring finger 3, RNF43: ring finger protein 43, Lgr: leucine-rich repeat-containing G protein-coupled receptor, RSPO: R-spondin, GSK-3β: glycogen synthase kinase-3β, Axin: axis inhibition protein, APC: adenomatous polyposis coli, CK1α: casein kinase 1 α, TBL1: transducin beta-like 1, TCF/LEF: T-cell factor/lymphoid enhancer factor, CBP: CREB-binding protein.

Figure 4

Therapeutic targets in the HH signaling pathway. Hedgehog ligands bind to Patched on the surface of target cells, relieving Patched-mediated inhibition of Smoothened. Activated Smoothened leads to activation of the Gli family of transcription factor, which promotes the expression of target genes. PTCH: Patched, SMO: smoothened, GLI1: Glioma-associated oncogene homolog 1.