TABLE 2.

Markers of lung cancer stem cells.

Marker	Localization, functions
CD133	Member of pentaspan transmembrane glycoproteins, which specifically localizes to cellular protrusions. CD133 is expressed in hematopoietic stem cells, endothelial progenitor cells, glioblastoma, neuronal and glial stem cells, various pediatric brain tumors, as well as in the adult kidney, lung, mammary glands, trachea, salivary glands, uterus, placenta, digestive tract, testes, and some other cell types. CD133 is the most commonly used marker for isolation of CSC population from different tumors, mainly from various gliomas and carcinomas (Eramo et al., 2008; Klonisch et al., 2008; Tirino et al., 2009; Rivera et al., 2011; Alamgeer et al., 2013; Sarvi et al., 2014; Huang et al., 2015; MacDonagh et al., 2017; Liou, 2019).
CD44 CD44v8–10	Cell-adhesion molecule. Expression in normal tissues is low. In addition, CD44 is expressed on endothelial and mesenchymal cells. CD44+ cells showed increased self-renewal ability and increased ability to initiate tumor in vivo compared to CD44− cells (Yamaguchi et al., 1995; Yamaguchi et al., 1996; Okamoto et al., 1998; Ponta et al., 2003; Olsson et al., 2011; Rivera et al., 2011; Zöller, 2011; Asselin-Labat and Filby, 2012; Roudi et al., 2015; Hiraga and Nakamura, 2016; Liou, 2019).
CD87	Participates in cell migration, regulates cell adhesion. High CD87 expression correlates with poor clinical outcome and significantly shorter overall survival in SCLC. CD87+ cell population demonstrated a high spherical ability, an increased tumor initiation potential, and significant resistance to traditional chemotherapeutic agents in SCLC therapy (Romer et al., 2004; Gutova et al., 2007; Almasi et al., 2013; Kubo et al., 2013; Codony-Servat et al., 2016; MacDonagh et al., 2017).
CD117	CD117 (c-KIT) is a type III receptor tyrosine kinase. c-KIT is activated (phosphorylated) by binding of its ligand with stem cell factor (SCF). This leads to activating of signal cascade which activation apoptosis, cell differentiation, proliferation, chemotaxis, and cell adhesion. Overexpression of SCF and CD117 is observed in lung cancer. High SCF expression in lung adenocarcinoma is associated with poor prognosis. Overexpression of CD117 in lung tumors is also associated with poor prognosis, lower survival, and chemoresistance (Romer et al., 2004; Miettinen and Lasota, 2005; Kubo et al., 2013; Liou, 2019; Walcher et al., 2020).
ALDH	High activity of aldehyde dehydrogenase (ALDH) has been found in stem and progenitor cells. High activity and/or overexpression of ALDH can be used as a marker of CSC in various types of cancers, including lung cancer. Overexpression of ALDH1 is associated with a poor prognosis in patients with lung cancer and more severe histological grade and stage of the disease (Jones et al., 1995; Ginestier et al., 2007; Huang et al., 2009; Jiang et al., 2009; Okudela et al., 2013; MacDonagh et al., 2017).
SOX2	There is a relationship between SOX2 expression and SCLC stage and overall survival. SOX2 expression is associated with more aggressive tumors. An increase in SOX2 activity enhances the proliferation of tumor cells. Overexpression of SOX2 is important for lung CSC function (Saigusa et al., 2009; Wang et al., 2009; Levina et al., 2010; Sholl et al., 2010; Wilbertz et al., 2011; Donnenberg et al., 2012; Perumal et al., 2014; Walcher et al., 2020).
CRIPTO-1	There is cell surface glycosylphosphatidylinositol (GPI)-linked glycoprotein which plays an important role in the regulation of stem cell differentiation, embryogenesis, growth and tissue remodeling. Aberrant Cripto expression can stimulate the development and progression of various types of tumors, including lung cancer. Cripto regulates Wnt and Notch signaling pathways. Cripto interacts with a variety of signaling pathways that play a key role in regulating normal tissue homeostasis and tumorigenesis. Cripto expression in adult tissues is low. Tumors show elevated levels of Cripto in situ or in the bloodstream. High resistance to chemotherapy and tumorigenicity are associated with Cripto and CSC (Du et al., 2011; Nakatsugawa et al., 2011; Xiang et al., 2011; Nagaoka et al., 2013; Klauzinska et al., 2014; Xu et al., 2017).