Stemness and plasticity of lung cancer cells: paving the road for better therapy

Figures & data

Table 1 Stemness modulation of LCSCs by signaling pathways

Cell type	Signaling pathway	Effect on stemness	Reference
A549	Wnt/beta-catenin	↑	^Citation30,Citation51
A549, H1299	Hedgehog	↑	^Citation58,Citation59
HCC, H1339	Hedgehog	↑	^Citation60
Primary LSCC tumor cells	Hedgehog	↑	^Citation61
A549, H1299 and H1755	Notch-1	↑	^Citation62
H460 and H661	Notch-1	↑	^Citation9
A panel of primary NSCLC	Notch-3	↑	^Citation63
NSCLC cell lines: NCI-H1299, NCI-H358, NCI-H441, NCI-H460, and A549	Notch	↑	^Citation64
H1650, H1975, A549	EGFR/Src/Akt	↑	^Citation65
Several lung AD cell lines including H1975 and PC-3	Akt/Sox2	↑	^Citation66
A549	pAkt	↑	^Citation67
A549	IGF1R/PI3K/AKT/GSK3β	↑	^Citation68
Gefitinib-resistant A549 cells	CXCR4-medated STAT3 pathway	↑	^Citation69

Abbreviations: NSCLC, non-small-cell lung cancer; EGFR, epidermal growth factor receptor; AD, adenocarcinoma; LSCC, laryngeal squamous cell carcinoma; HCC, hepatocellular carcinoma.

Table 2 Microenvironmental factors implicated in stemness modulation of lung cancer cells

Cell type	Microenvironmental factor	Effect on stemness	Reference
H-146 (small-cell lung carcinoma)	Hypoxia	↑	^Citation70
NSCLC cell lines, PC9 and HCC827	Hypoxia	↑	^Citation71
A549, NCI-H358	CAF likely via (TGF)-β1	↑	^Citation72
A549, PC-14, and CRL-5807	VAF	↑	^Citation73
A549	TGF-β1	↑	^Citation74
A549	IL-8	↑	^Citation75
A549	VEGF	↑	^Citation75
A549 and HTB177	tMVs	↑	^Citation76
CMT167	Matrix metalloproteinase-10	↑	^Citation77

Abbreviations: CAF, cancer associated fibroblasts; VAF, vascular adventitial fibroblasts; TGF, transforming growth factor; IL-8, interleukin 8; VEGF, vascular endothelial growth factor; NSCLC, non-small-cell lung cancer; CAF, cancer-associated fibroblasts; VAF, vascular adventitial fibroblasts; tMVs, tumor microvesicles.

TengYWangXWangYMaDWnt/beta-catenin signaling regulates cancer stem cells in lung cancer A549 cellsBiochem Biophys Res Commun2010392337337920074550

 PubMed Web of Science ®Google Scholar

TerasakiTKameyaTNakajimaTInterconversion of biological characteristics of small cell lung cancer depending on culture conditionsGann19847512108910996098504

 PubMedGoogle Scholar

ZhangSWangYMaoJHInhibition of CK2α down-regulates Hedgehog/Gli signaling leading to a reduction of a stem-like side population in human lung cancer cellsPLoS One201276e3899622768056

 PubMed Web of Science ®Google Scholar

AhmadAMaitahMYGinnebaughKRInhibition of Hedgehog signaling sensitizes NSCLC cells to standard therapies through modulation of EMT-regulating miRNAsJ Hematol Oncol2013617724199791

 PubMed Web of Science ®Google Scholar

TianFMysliwietzJEllwartJGamarraFHuberRMBergnerAEffects of the Hedgehog pathway inhibitor GDC-0449 on lung cancer cell lines are mediated by side populationsClin Exp Med2012121253021519961

 PubMed Web of Science ®Google Scholar

JustilienVWalshMPAliSAThompsonEAMurrayNRFieldsAPThe PRKCI and SOX2 Oncogenes Are Coamplified and Cooperate to Activate Hedgehog Signaling in Lung Squamous Cell CarcinomaCancer Cell201425213915124525231

 PubMed Web of Science ®Google Scholar

EliaszSLiangSChenYNotch-1 stimulates survival of lung adenocarcinoma cells during hypoxia by activating the IGF-1R pathwayOncogene201029172488249820154720

 PubMed Web of Science ®Google Scholar

LiuYPYangCJHuangMSCisplatin selects for multidrug-resistant CD133+ cells in lung adenocarcinoma by activating Notch signalingCancer Res201373140641623135908

 PubMed Web of Science ®Google Scholar

SullivanJPSpinolaMDodgeMAldehyde dehydrogenase activity selects for lung adenocarcinoma stem cells dependent on notch signalingCancer Res201070239937994821118965

 PubMed Web of Science ®Google Scholar

HassanKAWangLKorkayaHNotch pathway activity identifies cells with cancer stem cell-like properties and correlates with worse survival in lung adenocarcinomaClin Cancer Res20131981972198023444212

 PubMed Web of Science ®Google Scholar

SinghSTrevinoJBora-SinghalNEGFR/Src/Akt signaling modulates Sox2 expression and self-renewal of stem-like side- population cells in non-small cell lung cancerMol Cancer2012117323009336

 PubMed Web of Science ®Google Scholar

NaritaKMatsudaYSeikeMNaitoZGemmaAIshiwataTNestin regulates proliferation, migration, invasion and stemness of lung adenocarcinomaInt J Oncol20144441118113024481417

 PubMed Web of Science ®Google Scholar

LiuFCaoXLiuZCasticin suppresses self-renewal and invasion of lung cancer stem-like cells from A549 cells through down-regulation of pAktActa Biochim Biophys Sin (Shanghai)2014461152124247269

 PubMed Web of Science ®Google Scholar

KimIGKimSYChoiSILeeJHKimKCChoEWFibulin-3-mediated inhibition of epithelial-to-mesenchymal transition and self-renewal of ALDH+ lung cancer stem cells through IGF1R signalingOncogene2013

 Google Scholar

JungMJRhoJKKimYMUpregulation of CXCR4 is functionally crucial for maintenance of stemness in drug-resistant non-small cell lung cancer cellsOncogene201332220922122370645

 PubMed Web of Science ®Google Scholar

DasBTsuchidaRMalkinDKorenGBaruchelSYegerHHypoxia enhances tumor stemness by increasing the invasive and tumorigenic side population fractionStem Cells20082671818183018467664

 PubMed Web of Science ®Google Scholar

MurakamiATakahashiFNurwidyaFHypoxia Increases Gefitinib-Resistant Lung Cancer Stem Cells through the Activation of Insulin-Like Growth Factor 1 ReceptorPLoS One201491e8645924489728

 PubMed Web of Science ®Google Scholar

ShintaniYAbulaitiAKimuraTPulmonary Fibroblasts Induce Epithelial Mesenchymal Transition and Some Characteristics of Stem Cells in Non-Small Cell Lung CancerAnn Thorac Surg201396242543323773734

 PubMed Web of Science ®Google Scholar

HoshinoAIshiiGItoTPodoplanin-positive fibroblasts enhance lung adenocarcinoma tumor formation: podoplanin in fibroblast functions for tumor progressionCancer Res201171144769467921610106

 PubMed Web of Science ®Google Scholar

TirinoVCamerlingoRBifulcoKTGF-β1 exposure induces epithelial to mesenchymal transition both in CSCs and non-CSCs of the A549 cell line, leading to an increase of migration ability in the CD133+ A549 cell fractionCell Death Dis20134e62023640462

 PubMed Web of Science ®Google Scholar

DesaiSLaskarSPandeyBNAutocrine IL-8 and VEGF mediate epithelial-mesenchymal transition and invasiveness via p38/JNK-ATF-2 signalling in A549 lung cancer cellsCell Signal20132591780179123714383

 PubMed Web of Science ®Google Scholar

WysoczynskiMRatajczakMZLung cancer secreted microvesicles: underappreciated modulators of microenvironment in expanding tumorsInt J Cancer200912571595160319462451

 PubMed Web of Science ®Google Scholar

JustilienVRegalaRPTsengICMatrix metalloproteinase-10 is required for lung cancer stem cell maintenance, tumor initiation and metastatic potentialPLoS One201274e3504022545096

 PubMed Web of Science ®Google Scholar