Table 1.

Functional characteristics and markers for human lung cancer-initiating cells

	CIC-related characteristics	Citation
Functional characteristic
Sphere growth in serum-free medium	Sphere growth from 7/19 patient lung tumor samples (SCLC and NSCLC) with varying frequency of CD133+ expression (0.6 % to 22.0 % of tumor cells that were capable of forming spheres). CD133+ lung cancer spheres demonstrated (1) expression of stemness genes such as OCT4 and NANOG, (2) self-renewal potential, (3) proliferation and differentiation ability (with subsequent loss of tumorigenic potential upon differentiation), (4) chemotherapy resistance, and (5) ability to recapitulate tumor heterogeneity in vivo	[14]
	Sphere growth from 10 NSCLC patient samples and five lung cancer cell lines sorted for CD133+ expression	[13]
	Sphere growth in 11 out of 15 lung adenocarcinoma malignant pleural effusion patient samples. Compared to adherent cells, sphere cells were associated with enhanced ALDH1 activity and Oct-4, Nanog, Notch3, and Stat3 mRNA expression	[19]
Chemoresistance	In the human lung cancer cell line H460, drug-selected cells (doxorubicin, cisplatin, or etoposide) demonstrated (1) spheroid formation; (2) self-renewal capacity and ability to differentiate; (3) expression of CD133; (4) enrichment for SP cells; (5) expression of embryonic stem cell markers, growth factor receptors, and chemokine receptors; and (6) high tumorigenic and metastatic potential	[18]
Cell surface marker
CD133 (AC133, Prominin 1)	From patient lung cancer tissue samples, compared to CD133− cells, CD133+ cells displayed (1) enhanced expression of OCT4, (2) enhanced self-renewal ability, (3) increased expression of ABCG2, (4) enhanced resistance to chemotherapy and radiotherapy, (5) increased invasive ability, (6) increased in vivo tumor-restoration and proliferative capacity, and (7) increased spheroid formation	[13]
	From patient lung cancer tissue samples, compared to CD133− cells, CD133+ cells displayed (1) enhanced tumorigenic potential in vivo and (2) enhanced expression of ABCG2, CXCR4, α-6 integrin (CD49f), OCT4, and NANOG. CD133+ cells demonstrated a self-renewal capacity in vitro, and cisplatin resistance in vitro and in vivo	[12]
CD44	Expression of CD44 (62 % to 96 % of tumor cells) in 6/10 human NSCLC lines examined. Compared to CD44− cells, CD44+ cells displayed (1) spheroid formation, (2) resistance to cisplatin treatment in vitro, (3) enhanced tumorigenicity in vivo, and (4) enhanced expression of stemness genes OCT4, NANOG, and SOX2	[17]
Phenotypic marker
ABCG2 activity (side population expression)	In human lung cancer cell lines (H460, H23, HTB-58, A549, H441, and H2170), compared to non-SP cells, SP cells demonstrated (1) enhanced invasiveness in vitro and tumorigenicity in vivo, (2) enhanced ABCG2 and human telomerase reverse transcriptase expression, and (3) resistance to multiple chemotherapy drugs	[15]
	In human SCLC cells (NCI-H82, H146, and H526), SP expression comprised <1 % of cells. Compared to non-SP cells, SP cells were associated with (1) higher proliferative capacity; (2) efficient self-renewal capacity; (3) decreased expression of differentiated cell markers; (4) enhanced tumorigenicity; and (5) expression of genes associated with CICs, including ABCG2, MYC, SOX1/2, WNT1, and Notch and Hedgehog pathway genes	[42]
Aldehyde dehydrogenase 1 (ALDH1) activity	In human lung cancer cell lines ALDH1 activity was associated with (1) capacity for proliferation; (2) self-renewal and differentiation; (3) resistance to chemotherapy; (4) expression of CD133; and (5) enhanced tumorigenicity, as well as ability to recapitulate the original tumor heterogeneity in vivo	[16]
	From 303 clinical patient specimens and controls, overexpression was positively correlated with stage and grade to tumor and associated with poorer prognosis for patients with early-stage lung cancer