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

Abstract

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.

Keywords: cancer stem cell; lung cancer; marker; signaling pathway; targeted therapy.

Figure 1

Potential lung cancer stem cell with its markers and major signaling pathways. CSCs can live deep in the hypoxic center of tumor and hypoxia may induce CSCs phenotype and the expression of CSC markers, thus promoting chemoresistance, while specific targeted therapy towards CSCs may solve this problem. Potential markers of lung cancer stem cells mainly include surface biomarkers, such as CD44, CD133, EpCAM and ABCG2, along with intracellular biomarkers, such as ALDH, SOX2, NANOG and OCT4, and they may act as promising therapeutic targets. Signaling pathways such as Notch, Hedgehog, and Wnt may jointly induce the expression of certain lung cancer stem cell markers and stimulate EMT, thus allowing tumor cells to obtain stemness and chemoresistance.

Figure 2

Promising therapies targeting lung cancer stem cell markers. CSCs are resistant to conventional therapy and lead to cancer recurrence, unless being specifically targeted. Therapies targeting lung cancer stem cell markers mainly rely on the specific recognition and binding of antibodies to lung cancer stem cell surface markers, thus leading to a variety of antibody drugs including monoclonal antibody, antibody-drug conjugate, bispecific antibody, and emerging nanoparticle drugs. In addition, novel CAR-T cell immunotherapy as well as inhibitors also play an increasingly important role in the experiments and future clinical trials.