New Opportunities and Challenges to Defeat Cancer Stem Cells

Cancer stem cells (CSCs) are a subpopulation of cancer cells that are capable of self-renewal, proliferation, differentiation, plastic adaptation, and immune regulation, thereby mediating tumorigenesis, metastasis, and therapy resistance. CSCs are associated with cancer progression and clinical outcome in cancer patients. Successful targeting of CSCs will therefore be necessary to eradicate and cure cancer. Functional regulators of stem cell (stemness) signaling pathways in human cancers have brought new opportunities to target CSCs and reframe cancer-targeting strategies in clinical settings. However, challenges remain due to a lack of complete understanding of CSC plasticity/heterogeneity and the limited efficacy of individual stemness inhibitors in cancer treatment. In this article we review CSC signaling pathways and the current state of CSC-targeting therapeutics in combinatory treatments in clinical trials. CSCs mediate tumorigenesis, metastasis, and therapy resistance via their self-renewal, proliferation, differentiation, and immune evasion abilities. Many signaling pathways regulate CSCs, including but not limited to Notch, Hedgehog, FAK, Wnt, Nanog, and STAT, and many targeting strategies have been developed to inhibit such stemness signaling. In addition to conventional and targeted therapies, immunotherapy shows promising potential in killing CSCs. Super computation-based data sharing and artificial intelligence will assist the full understanding of CSC heterogeneity, evolution, plasticity, and motility for breakthrough discoveries and the eradication of CSCs and cancer.