Lung cancer stem cells: origin, features, maintenance mechanisms and therapeutic targeting.

Lung cancer remains the leading cause of cancer-related deaths despite recent breakthroughs in immunotherapy. The widely embraced cancer stem cell (CSC) theory has also been applied for lung cancer, postulating that an often small proportion of tumor cells with stem cell properties are responsible for tumor growth, therapeutic resistance and metastasis. The identification of these CSCs and underlying molecular maintenance mechanisms is considered to be absolutely necessary for developing therapies for their riddance, hence achieving remission. In this review, we will critically address the CSC concept in lung cancer and its advancement thus far. We will describe both normal lung stem cells and their malignant counterparts in order to identify common aspects with respect to their emergence and regulation. Subsequently, the importance of CSCs and their molecular features in lung cancers will be discussed in a preclinical and clinical context. We will highlight some examples on how lung CSCs attain stemness through different molecular modifications and cellular assistance from the tumor microenvironment. The exploitation of these mechanistic features for the development of pharmacological therapy will also be discussed. In summary, the validity of the CSC concept has been evidenced by various studies. Ongoing research to identify molecular mechanisms driving lung CSC have revealed potential new cell intrinsic as well as tumor microenvironment-derived therapeutic targets. Although successfully demonstrated in preclinical models, the clinical benefit of lung CSC targeted therapies has thus far not been demonstrated. Therefore, further research to validate the therapeutic value of CSC concept is required.