Lung Cancer Stem Cell Markers as Therapeutic Targets: An Update on Signaling Pathways and Therapies

Cancer stem cells, a relatively small group of self-renewing cancer cells, were first isolated from acute myeloid leukemia. These cells can play a crucial role in tumor metastasis, relapse, and therapy resistance. The cancer stem cell theory may be applied to lung cancer and explain the inefficiency of traditional treatments and eventual recurrence. However, because of the unclear accuracy and illusive biological function of cancer stem cells, some researchers remain cautious about this theory. Despite the ongoing controversy, cancer stem cells are still being investigated, and their biomarkers are being discovered for application in cancer diagnosis, targeted therapy, and prognosis prediction. Potential lung cancer stem cell markers mainly include surface biomarkers such as CD44, CD133, epithelial cell adhesion molecule, and ATP-binding cassette subfamily G member 2, along with intracellular biomarkers such as aldehyde dehydrogenase, sex-determining region Y-box 2, NANOG, and octamer-binding transcription factor 4. These markers have different structures and functions but are closely associated with the stem potential and uncontrollable proliferation of tumor cells. The aberrant activation of major signaling pathways, such as Notch, Hedgehog, and Wnt, may be associated with the expression and regulation of certain lung cancer stem cell markers, thus leading to lung cancer stem cell maintenance, chemotherapy resistance, and cancer promotion. Treatments targeting lung cancer stem cell markers, including antibody drugs, nanoparticle drugs, chimeric antigen receptor T-cell therapy, and other natural or synthetic specific inhibitors, may provide new hope for patients who are resistant to conventional lung cancer therapies. This review provides comprehensive and updated data on lung cancer stem cell markers with regard to their structures, functions, signaling pathways, and promising therapeutic target approaches, aiming to elucidate potential new therapies for lung cancer.