Cancer Stem Cells, the Cellular Signaling, and Potential Therapeutic Targets in Lung Cancer

Main Article Content

Nattamon Hongwiangchan
Pithi Chanvorachote
Sucharat Tungsukruthai


Recent studies in the field of cancer cell biology have pointed out that the cancer cells having stem cell property in tumor may contribute aggressive phenotypes of cancers. A limited population of cancer cells exhibiting high ability to generate new tumor named “cancer stem cells (CSCs)” has garnered significant attention in these years and was linked with the initiation of primary tumor and cancer cells as well as the successful establishment of metastatic tumors. Based on the theory that stem cells preserve their ability to generate the new clones with different cell lineages because of their pluripotency, CSCs similarly exert its tumorigenicity. Besides, CSCs were shown to highly resist to currently used anticancer drugs and have augmented ability to metastasis. It is worthy highlighted that the CSCs that survive after chemotherapeutic treatment are believed to be the cause of disease relapse. Taken together, these evidences have supported the development of CSC-based targeted therapy. This review aimed at describing the fundamental information regarding the role of CSCs in lung cancer and its cellular signaling that may benefit the understanding and support the development of CSC-targeting research.


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Review Articles
Author Biography

Pithi Chanvorachote, Department of Pharmacology and Physiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand

Research Publications
  1. Pithi Chanvorachote, Ubonthip Nimmannit, Liying Wang, Christian Stehlik, Bin Lu, Neelam Azad, and Yon Rojanasakul*. Nitric Oxide Negatively Regulates Fas CD95-induced Apoptosis through Inhibition of Ubiquitin-Proteasome-mediated Degradation of FLICE Inhibitory Protein. Journal of Biological Chemistry. (2005); 280: 42044-42050.
  2. Pithi Chanvorachote, Ubonthip Nimmannit, Christian Stehlik, Liying Wang,  Boonsri Ongpipatanakul,   and Yon Rojanasakul*.  Nitric Oxide Regulates Cell Sensitivity to Cisplatin-Induced Apoptosis through  S-nitrosylation and Inhibition of Bcl-2 Ubiquitination, Cancer Research. (2006); 66:6353-6360.
  3. Pithi Chanvorachote*, Ubonthip Nimmannit, Yongju Lu, Siera Talbott, Bing-Hua Jiang, and Yon Rojanasakul*. Nitric Oxide Regulates Lung Carcinoma Cell Anoikis through Inhibition of Ubiquitin-Proteasomal Degradation of Caveolin-1. Journal of Biological Chemistry. (2009); 284: 28476-28484.  
  4. Varisa Pongrakhananon, Ubonthip Nimmannit, Sudjit Luanpitpong, Yon Rojanasakul, and Pithi Chanvorachote*. Curcumin sensitizes non-small cell lung cancer cell anoikis through reactive oxygen species-mediated Bcl-2 downregulation. Apoptosis. (2010); 15:574–585
  5. Sudjit Luanpitpong, Siera Jo Talbott, Yon Rojanasakul, Ubonthip Nimmannit, Varisa Pongrakhananon, Liying Wang, and Pithi Chanvorachote*. Regulation of lung cancer cell migration and invasion by reactive oxygen species and Caveolin-1. Journal of Biological Chemistry.(2010); 285(50) : 38832- 38840.  
  6. Pithi Chanvorachote and Varisa Pongrakhananon*. Ouabain down-regulates Mcl-1 and sensitizes TRAIL-induced apoptosis in lung cancer cells. American Journal of Physiology-Cell Physiology. (2013); 304( 3): 263-272.
  7. Jirapan Muangjareon, Ubonthip Nimmannit, Patrick S Callery, Liying Wang, Neelam Azad, Vimolmas Lipipun, Pithi Chanvorachote and Yon Rojanasakul*. Reactive Oxygen species Mediate Caspase Activation and Apoptosis Induced by Lipoic Acid in Human Lung Epithelial Cancer Cells through Bcl-2 Downregulation. Journal of pharmacology and experimental therapeutics. (2006); 319 (3). 1062-1069.
  8. Liying Wang, Pithi Chanvorachote, David Toledo, Christian Stehlik, Robert R. Mercer, Vincent Castranova, and Yon Rojanasakul*. Peroxide is a key mediator of Bcl-2 down-regulation and apoptosis induction by cisplatin in human lung cancer cells. Molecular Pharmacology (2007); 73(1): 119-127. 
  9. Sumalee Wannachaiyasit, Pithi  Chanvorachote, and Ubonthip Nimmannit*. A Novel Anti-HIV Dextrin-Zidovudine Conjugate Improving the Pharmacokinetics of Zidovudine in Rats. AAPS PharmSci Tech. (2008); 9(3): 840-850.
  10. Pithi Chanvorachote*, Varisa Pongrakhananon, Sumalee Wannachaiyasit, Sudjit Luanpitpong, Yon Rojanasakul, Ubonthip Nimmannit. Curcumin sensitized lung cancer cells to cisplatin-induced apoptosis through superoxide anion induction and Bcl-1 degradation. Cancer Investigation. (2009); 27(6) : 624 – 635.
  11. Sudjit Luanpitpong, Varisa Pongrakhananon, Ubonthip Nimmannit, and Pithi Chanvorachote*. Emblica extract prevents cisplatin-induced apoptosis in dermal papilla fibroblasts. Songklanakarin Journal of Science and Technology. (2008); 30(5) : 627-633.
  12. Pithi Chanvorachote*, Varisa Pongrakhananon, Sudjit Luanpitpong, Boontarika Chanvorachote, Sumalee Wannachaiyasit, and Ubonthip Nimmannit*. Type I Pro-collagen Promoting and Anti-collagenase Activities of Phyllanthus emblica Extract in Mouse Fibroblast. Journal of Cosmetic Science. (2009); 60 : 395-403.
  13. Boonchu Sritularak, Aungkana Tantituvanont, Pithi Chanvorachote, Kulwara Meksawan, Tomofumi Miyamoto, Yuhki Kohno, and Kitisak Likhitwitayawuid. Flavonoids with free radical scavenging activity and nitric oxide inhibitory effect from the stem bark of Artocarpus gomezianus. Journal of Medicinal Plant Research. (2010); 4(5): 387-392.
  14. Sudjit Luanpitpong, Ubonthip Nimmannit, Varisa Pongrakhananon, and Pithi Chanvorachote*. Emblica (Phyllanthus emblica Linn.) Fruit Extract Promotes Proliferation in Dermal Papilla Cells of Human Hair Follicle. Journal of Medicinal Plants Research.(2011); 5(1):95-100
  15. Hasseri Halim, Preedakorn Chunhacha, Khanit Suwanborirux, and Pithi Chanvorachote*. Anti-cancer and antimetastatic activities of renieramycin M, a marine tetrahydroisoquinoline alkaloid, in human non-small cell lung cancer cells.  Anticancer Res. (2011); 31: 193-201.
  16. Pimuma Rungtabnapa, Ubonthip Nimmannit, Hasseri Halim, Yon Rojanasakul, and Pithi Chanvorachote*. Hydrogen peroxide inhibits non-small cell lung cancer cell anoikis through the inhibition of caveolin-1 degradation. American Journal of Physiology-Cell Physiology.(2011) ;  300 : C235-C245.
  17. Kanittha Pongjit, Chaunpit Ninsontia, Chatchai Chaotham, and Pithi Chanvorachote*. Protective Effect of Glycine max and Chrysanthemum indicum Extracts Against Cisplatin-Induced Renal Epithelial Cell Death. Human & Experimental Toxicology. (2011); 30(12):1931-44.
  18. Chuanpit Ninsontia, Kanittha Pongjit, Chatchai Chaotham, and Pithi Chanvorachote*. Silymarin selectively protects human renal cells from cisplatin-induced cell death. Pharmaceutical Biology. (2011); 49(10):1082-90.
  19. Sudjit Luanpitpong, Ubonthip Nimmannit, Pithi Chanvorachote, Stephen S. Leonard, Varisa Pongrakhananon, Liying Wang, and Yon Rojanasakul. Hydroxyl radical mediates cisplatin-induced apoptosis in human hair follicle dermal papilla cells and keratinocytes through Bcl-2-dependent mechanism. Apoptosis. (2011) 16(8):769-82.
  20. Kanittha Pongjit and Pithi Chanvorachote*. Caveolin-1 sensitizes cisplatin-induced lung cancer cell apoptosis via superoxide anion-dependent mechanism. Molecular and Cellular Biochemistry. (2011); 358(1-2):365-73.
  21. Supim Wongtongtair, Pithi Chanvorachote, Pilaiwanwadee Hutamekalin, Chaiyo Chaichantipyuth, Vimolmas Lipipun, Pornthep Tiensiwakul, and Duangdeun Meksuriyen. Barakol-induced apoptosis in P19 cells through generation of reactive oxygen species and activation of caspase-9. Journal of ethnopharmacology. (2011); 137(2):971-8.
  22. Buntitabhon Sirichanchuen, Thitima Pengsuparp*, and Pithi Chanvorachote*. Long-term cisplatin exposure impairs autophagy and causes cisplatin resistance in human lung cancer cells. Molecular and cellular biochemistry. (2012); 364: 11-18.
  23. Wongsakorn Suchaoin and Pithi Chanvorachote*. Caveolin-1 Attenuates Hydrogen Peroxide-Induced Oxidative Damage to Lung Carcinoma Cells. Anticancer Research. (2012); 32 (2): 483-490
  24. Preedakorn Chunhacha, Varisa Pongrakhananon, Yon Rojanasakul, and Pithi Chanvorachote*. Caveolin-1 Regulates Mcl-1 Stability and Anoikis in Lung Carcinoma Cells. American Journal of Physiology-Cell Physiology. (2012) ; 302: C1284–C1292.
  25. Pithi Chanvorachote*, Sudjit Luanpitpong, Preedakorn Chunhacha, Worrawat Promden, and Virote Sriuranpong. Expression of CA125 and cisplatin susceptibility of pleural effusion-derived human lung cancer cells of a Thai patient. Oncology letters.(2012); 4: 252-256.   
  26. Thitiporn Songserm, Varisa Pongrakhananon, and Pithi Chanvorachote*. Sub-toxic cisapltin mediates anoikis resistance through hydrogen peroxide-induced Caveolin-1 up-regulation in non-small cell lung cancer cells. Anticancer research. (2012); 32(5): 1659-1669.
  27. Sudjit Luanpitpong, Pithi Chanvorachote, Ubonthip Nimmannit, Stephen S Leonard, Christian Stehlik, Liying Wang, Yon Rojanasakul*. Mitochondrial superoxide mediates doxorubicin-induced keratinocyte apoptosis through oxidative modification of ERK and Bcl-2 ubiquitination. Biochemical pharmacology. (2012); 83(12): 1643-54.           
  28. Hasseri Halim, Sudjit Luanpitpong, Pithi Chanvorachote*. Acquisition of anoikis Resistance up-regulates caveolin-1 expression in human non-small cell lung cancer Cells. Anticancer research. (2012); 32 : 1649- 1658.
  29. Chatchai Chaotham, Wanchai De-Eknamkul, and Pithi Chanvorachote*.  Protective effect of plaunotol against doxorubicin-induced renal cell death. Journal of Natural Medicines. (2012); 67(2):311-319.
  30. Preedakorn Chunhacha and Pithi Chanvorachote*. Roles of Caveolin-1 on anoikis resistance in Non Small Cell Lung Cancer. International Journal of Physiology, Pathophysiology and Pharmacology. (2012); 4(3):149-155.
  31. Hasseri Halim and Pithi Chanvorachote*. Long-term hydrogen peroxide exposure potentiates anoikis resistance and anchorage-independent growth in lung carcinoma cells. Cell Biology International. (2012); 36: 1055–1066.
  32. Apiriya Dhumrongvaraporn and Pithi Chanvorachote*. Kinetics of Ultraviolet B Irradiation-Mediated Reactive Oxygen Species Generation in Human Keratinocytes. Journal of Cosmetic Science. (2013); 64: 1-11.
  33. Kanuengnit Choochuay, Preedakorn Chunhacha, Varisa Pongrakhananon, Rataya Luechapudiporn, and Pithi Chanvorachote*. Imperatorin sensitizes anoikis and inhibits anchorage-independent growth of lung cancer cells. Journal of Natural Medicines. (2012) 67(3):599-606
  34. Porntipa Chairuangkitti, Somsong Lawanprasert, Sittiruk Roytrakul, Sasitorn Aueviriyavit, Duangkamol Phummiratch, Kornphimol Kulthong, Pithi Chanvorachote, and Rawiwan Maniratanachote. Silver nanoparticles induce toxicity in A549 cells via ROS-dependent and ROS-independent pathways. Toxicology in Vitro. (2013); 27(1):330-8.
  35. Ekkarat Wongpankam, Preedakorn Chunhacha, Varisa Pongrakhananon, Boonchoo Sritulalak, and Pithi Chanvorachote*. Artonin E Mediates MCL1 Down-regulation and Sensitizes Lung Cancer Cells to Anoikis. Anticancer Research. (2013); 32: 5345-5352
  36. Preedakorn Chunhacha,Virote Sriuranpong, and Pithi Chanvorachote. Epithelial-mesenchymal transition mediates anoikis resistance and enhances invasion in pleural effusion-derived human lung cancer cells of a Thai patient. Oncology Letters. (2013): 5: 1043-1047.
  37. Phattrakorn Powan, Naoki Saito, Khanit Suwanborirux, and Pithi Chanvorachote*. Ecteinascidin 770, A Tetrahydroisoquinoline Alkaloid, Sensitizes Human Lung Cancer Cells to Anoikis. Anticancer Research. (2013). 33:505-512.          
  38. Pithi Chanvorachote, Akkarawut Kowitdamrong , Thidarat Ruanghirun, , Boonchoo Sritularak*, Chutichot Mungmee and Kittisak Likhitwitayawuid. Anti-metastatic activities of Bibenzyls from Dendrobium pulchellum. Natural Product Communications. (2013); 8(1):115-8
  39. Sudjit Luanpitpong, Pithi Chanvorachote, Christian Stehlik, William Wei Ning Tse, Patrick S Callery, Liying Wang, Yon Rojanasakul. Regulation of Apoptosis by Bcl-2 Cysteine Oxidation in Human Lung Epithelial Cells. Molecular Biology of the Cell. (2013); 24(6):858-69.
  40. Pithi Chanvorachote and Preedakorn Chunhacha*. Caveolin-1 regulates endothelial adhesion of lung cancer cells via reactive oxygen species-dependent mechanism. Plos One. (2013) 8(2) : e57466
  41. Akkarawut Kowitdamrong, Pithi Chanvorachote*, Boonchoo Sritularak and Varisa Pongrakhananon. Moscatilin inhibits lung cancer cell motility and invasion via suppression of endogenous reactive oxygen species. Biomed Research International. In press.
  42. Pithi Chanvorachote*, Preedakorn Chunhacha, and Varisa Pongrakhananon. Editorial: Anoikis: a potential target to prevent lung cancer metastasis. Lung cancer manage. (2013) 2(3):169-171.
  43. Kanok Plaibua, Varisa Pongrakhananon, Preedakorn Chunhacha, Boonchoo Sritularak, and Pithi Chanvorachote*. Effects of Artonin E on Migration and Invasion Capabilities of Human Lung Cancer Cells. Anticancer Research. (2013) 33: 3079-3088.
  44. Varisa Pongrakhananon, Preedakorn Chunhacha, and Pithi Chanvorachote* Ouabain suppresses migratory behavior of lung cancer cells. PLOS ONE. (2013) 8(7): e68623. 
  45. Arpasinee Sanuphan, Preedakorn Chunhacha, Varisa Pongrakhananon, and Pithi Chanvorachote*. Long-Term Nitric Oxide Exposure Enhances Lung Cancer Cell Migration. Biomed Research International. 2013;2013:186972. doi: 10.1155/2013/186972
  46. Thaniwan Cheun-Arom, Pithi Chanvorachote*, Natchanun Sirimangkalakitti, Taksina Chuanasa, Naoki Saito, Ikuro Abe, and Khanit Suwanborirux. Replacement of Quinone by 5-O-Acetylhydroquinone Abolishes Accidental Necrosis Inducing Effect while Preserving Apoptosis-Inducing Effect of Renieramycin M on Lung Cancer Cells. (2013). Journal of Natural Products. 76(8):1468-74.
  47. Oraphan Wanakhachornkrai, Varisa Pongrakhananon, Preedakorn Chunhacha, Aree Wanasuntronwong, Anusara Vattanajun, Boonyong Tantisira, Pithi Chanvorachote* and Mayuree H Tantisira*. Neuritogenic effect of standardized extract of Centella asiatica ECa233 on human neuroblastoma cells. BMC Complementary and Alternative Medicine 2013, 13:204.
  48. Varisa Pongrakhananon, Todd A Stueckle, Hua-Yu Leo Wang, George A O'Doherty, Cerasela Zoica Dinu, Pithi Chanvorachote, Yon Rojanasakul Monosaccharide digitoxin derivative sensitize human non-small cell lung cancer cells to anoikis through Mcl-1 proteasomal degradation. Biochemical pharmacology. In press
  49. Kulwara Meksawan, Urairut Sermsri, and Pithi Chanvorachote*. Zinc Supplementation Improves Anticancer Activity of Monocytes in Type 2 Diabetic Patients with Metabolic Syndrome. Anticancer Research. In press.
  50. Piyaparisorn Wongvaranon, Varisa Pongrakhananon, Preedakorn Chunhacha, and Pithi Chanvorachote*. Acquired Chemotherapeutic Resistance in Lung Cancer Cells Mediated by Prolonged Nitric Oxide Exposure. Anticancer Research. 2013 ;33(12):5433-44.
  51. Piyaparisorn Wongvaranon, Varisa Pongrakhananon and Pithi Chanvorachote*. Molecular mechanisms of chemotherapeutic resistance in lung cancer. Thai journal of Pharmaceutical Sciences 2014, 38 (1): 1-4.
  52. Chatchai Chaotham,Varisa Pongrakhananon, Boonchoo Sritularak, and Pithi Chanvorachote*. A Bibenzyl from Dendrobium ellipsophyllum inhibits epithelial to Mesenchymal Transition and Sensitizes Lung Cancer Cells to Anoikis. Anticancer Research 2014, 34: 1931-1938.
  53. Thidarat ruanghirun, Varisa Pongrakhananon, and Pithi Chanvorachote*. Ouabain Enhances Lung Cancer Cell Detachment. Anticancer Research, 2014 May;34(5):2231-8. 
  54. Phattrakorn Powan, Pithi Chanvorachote*. Nitric oxide mediates cell aggregation and mesenchymal to epithelial transition in anoikis-resistant lung cancer cells. Mol Cell Biochem. In press. DOI 10.1007/s11010-014-2066-7
  55. Thitita Unahabhokha , Apirada Sucontphunt, Ubonthip Nimmannit, Pithi Chanvorachote, Nuttida Yongsangguanchai, Varisa Pongrakhananon*. Molecular signaling in Keloid disease and current therapeutic approaches from natural based compounds. Pharmaceutical Biology. In press
  56. Pithi Chanvorachote*, Varisa Pongrakhananon, and Preedakorn Chunhacha*. Prolonged Nitric Oxide Exposure Enhances enhanced anoikis resistance and migration through Epithelial-Mesenchymal Transition and Caveolin-1 Up-regulation. Biomed Research International. In press
  57. Sopinya Charoenrungruang, Pithi Chanvorachote, Boonchoo Sritularak, and Varisa Pongrakhananon*. Gigantol, a Bibenzyl from Dendrobium draconis, Inhibits the Migratory Behavior of Non-Small-Cell Lung Cancer Cells. Journal of Natural Products. In press.
  58. Pithi Chanvorachote, Varisa Pongrakhananon*, and Preedakorn Chunhacha*. Caveolin-1 induces lamellipodia formation via an Akt-dependent pathway. Cancer Cell International 2014, 14:52.
  59. Sopanya Charoenrungruang, Pithi Chanvorachote, Boonchoo Sritularak, and Varisa Pongrakhananon*. Gigantol-induced apoptosis in lung cancer cell through mitochondrial-dependent pathway.  Thai journal of Pharmaceutical Sciences 2014, 38 (2): 67-73.
  60. Boonchoo Sritularak, Angkana Tantituvanont1, Pithi Chanvorachote, Kulwara Meksawan, T. Miyamoto, Y. Kohno, and Kitisak Likhitwitayawuid. Flavonoids with free radical scavenging activity and nitric oxide inhibitory effect from the stem bark of Artocarpus gomezianus. Journal of Medicinal Plants Research 4(5): 387-392.
  61. Vititda Awaiwanont, Angkana Tantituvanont*, Waraporn Suwakul, Kulwara Meksawan, and Pithi Chanvorachote*. Scavenging Activity of Whey Protein Hydrolysates in HaCaT Cells. Chiang Mai Journal of Science. In press.
  62. Chuanpit Ninsontia and Pithi Chanvorachote*.Ouabain Mediates Integrin Switch in Human Lung Cancer Cells. Anticancer research. 34(10):5495-502.
  63. Arnatchai Maiuthed and Pithi Chanvorachote*. Cisplatin at Sub-toxic Levels Mediates Integrin Switch in Lung Cancer Cells. Anticancer research. In press.
  64. Premkamol Pengpang, Boonchoo Sritularak, and Pithi Chanvorachote*. Dendrofalconerol A Suppresses Migrating Cancer Cells via EMT and Integrin Proteins. Anticancer research. In press.
  65. Thidarat Winitthana, Somsong Lawanprasert, Pithi Chanvorachote*. Triclosan potentiates epithelial-to-mesenchymal transition in anoikis-resistant human lung cancer cells. Plos One.  October 16, 2014, DOI: 10.1371/journal.pone.0110851
  66. Kasinee Tanagornmeatar, Chatchai Chaotham, Boonchoo Sritularak, Kitisak Likhitwitayawuid and Pithi Chanvorachote. Cytotoxic and Anti-metastatic Activities of Phenolic Compounds from Dendrobium ellipsophyllum. Anticancer Research. In press.
  67. Pithi Chanvorachote, Varisa Pongrakhananon, and Hasseri Halim. Caveolin-1 Regulates Metastatic Behaviors of Anoikis Resistant Lung Cancer Cells. Molecular and Cellular Biochemistry. In press.
  68. Premkamol Pengpang, Boonchoo Sritularak, Pithi Chanvorachote. Dendrofalconerol A sensitizes anoikis and inhibits migration in lung cancer cells. Journal of Natural Medicines. In press. 
  69. Nuttida Yongsanguanchai, Varisa Pongrakhananon, Apiwat Mutirangura, Yon Rojanasakul, and Pithi Chanvorachote*. Nitric Oxide induces Cancer Stem Cell-like Phenotypes in Human Lung Cancer Cells. American Journal of Physiology-Cell Physiology. In press.
  70. Sukhontha Hasatsri, Rungnapha Yamdech, Pithi Chanvorachote, and Pornanong Aramwit*. Physical and biological assessments of the innovative bilayered wound dressing made of silk and gelatin for clinical applications. Journal of  Biomaterials Applications. 2014 Nov 12. pii: 0885328214559138. In press.
  71. Tanagornmeatar K, Chaotham C, Sritularak B, Likhitwitayawuid K, Chanvorachote P. Cytotoxic and Anti-metastatic Activities of Phenolic Compounds from Dendrobium ellipsophyllum. Anticancer research. In press.


Huang T, Song X, Xu D, Tiek D, Goenka A, Wu B, et al. Stem cell programs in cancer initiation, progression, and therapy resistance. Theranostics. 2020;10(19): 8721-43.

Sowa T, Menju T, Sonobe M, Nakanishi T, Shikuma K, Imamura N, et al. Association between epithelial‐mesenchymal transition and cancer stemness and their effect on the prognosis of lung adenocarcinoma. Cancer med. 2015 Dec;4(12):1853-62.

Zhang HF, Wu C, Alshareef A, Gupta N, Zhao Q, Xu XE, et al. The PI3K/ AKT/c‐MYC axis promotes the acquisition of cancer stem‐like features in esophageal squamous cell carcinoma. Stem Cells. 2016 Aug;34(8):2040-51.

Xia P, Xu XY. PI3K/Akt/mTOR signaling pathway in cancer stem cells: from basic research to clinical application. Am J Cancer Res. 2015 Apr 15;5(5):1602-9.

Dubrovska A, Kim S, Salamone RJ, Walker JR, Maira SM, García-Echeverría C, et al. The role of PTEN/Akt/PI3K signaling in the maintenance and viability of prostate cancer stem-like cell populations. Proc Natl Acad Sci USA. 2009 Jan 6; 106(1):268-73.

Srinual S, Chanvorachote P, Pongrakhananon V. Suppression of cancer stem-like phenotypes in NCI-H460 lung cancer cells by vanillin through an Akt-dependent pathway. Int J Oncol. 2017 Apr;50(4):1341-51.

Murphy MJ, Wilson A, Trumpp A. More than just proliferation: Myc function in stem cells. Trends Cell Biol. 2005 Mar;15(3):128-37.

Elbadawy M, Usui T, Yamawaki H, Sasaki K. Emerging roles of c-Myc in cancer stem cell-related signaling and resistance to cancer chemotherapy: a potential therapeutic target against colorectal cancer. Int J Mol. Sci. 2019 May 11; 20(9):2340.

Deb TB, Coticchia CM, Dickson RB. Calmodulin-mediated activation of Akt regulates survival of c-Myc-overexpressing mouse mammary carcinoma cells. J Biol Chem. 2004 Sep 10;279(37):38903-11.

Swords RT, Schenk T, Stengel S, Gil VS, Petrie KR, Perez A, et al. Inhibition of the PI3K/AKT/mTOR pathway leads to down-regulation of c-Myc and overcomes resistance to ATRA in acute myeloid leukemia. Blood. 2015 Dec 3;126(23):1363.

Chanvorachote P, Sriratanasak N, Nonpanya N. C-myc contributes to malignancy of lung cancer: a potential anticancer drug target. Anticancer Res. 2020 Feb; 40(2):609-18.

Zhu J, Blenis J, Yuan J. Activation of PI3K/Akt and MAPK pathways regulates Myc-mediated transcription by phosphorylating and promoting the degradation of Mad1. Proc Natl Acad Sci USA. 2008 May 6;105(18):6584-9.

Sarode P, Mansouri S, Karger A, Schaefer MB, Grimminger F, Seeger W, et al. Epithelial cell plasticity defines heterogeneity in lung cancer. Cell Signal. 2020 Jan;65:109463.

Sears CR, Mazzone PJ. Biomarkers in lung cancer. Clin Chest Med. 2020 Mar; 41(1):115-27.

Bade BC, Cruz CSD. Lung cancer 2020: epidemiology, etiology, and prevention. Clin Chest Med. 2020 Mar;41(1):1-24.

Ahmad AS, Mayya AM. A new tool to predict lung cancer based on risk factors. Heliyon. 2020 Feb26;6(2):e03402.

Ning J, Li P, Zhang B, Han B, Su X, Wang Q, et al. miRNAs deregulation in serum of mice is associated with lung cancer related pathway deregulation induced by PM2.5. Environ Pollut. 2019 Nov;254(Pt A):112875.

Shahadin MS, Mutalib NSA, Latif MT, Greene CM, Hassan T. Challenges and future direction of molecular research in air pollution-related lung cancers. Lung Cancer. 2018 Apr;118:69-75.

Tseng CH, Tsuang BJ, Chiang CJ, Ku KC, Tseng JS, Yang TY, et al. The relationship between air pollution and lung cancer in nonsmokers in Taiwan. J Thorac Oncol. 2019 May;14(5):784-92.

Wang Y, Broderick P, Matakidou A, Eisen T, Houlston RS. Role of 5p15.33 (TERT-CLPTM1L), 6p21.33 and 15q25.1 (CHRNA5-CHRNA3) variation and lung cancer risk in never-smokers. Carcinogenesis. 2010 Feb;31(2):234-8.

Jin K, Wu M, Zhou JY, Yang J, Han RQ, Jin ZY, et al. Tobacco smoking modifies the association between hormonal factors and lung cancer occurrence among post-menopausal chinese women. Transl Oncol. 2019 Jun;12(6):819-27.

Hanagiri T, Sugio K, Mizukami M, Ichiki Y, Sugaya M, Yasuda M, et al. Significance of smoking as a postoperative prognostic factor in patients with non-small cell lung cancer. J Thorac Oncol. 2008 Oct;3(10):1127-32.

Steliga MA, Dresler CM. Epidemiology of lung cancer: smoking, secondhand smoke, and genetics. Surg Oncol Clin N Am. 2011 Oct;20(4):605-18.

Salehi-Rad R, Li R, Paul MK, Dubinett SM, Liu B. The biology of lung cancer: development of more effective methods for prevention, diagnosis, and treatment. Clin Chest Med. 2020 Mar;41(1):25-38.

Zappa C, Mousa SA. Non-small cell lung cancer: current treatment and future advances. Transl Lung Cancer Res. 2016 Jun;5(3):288-300.

Ginsberg RJ, Rubinstein LV, Group LCS. Randomized trial of lobectomy versus limited resection for T1 N0 non-small cell lung cancer. Ann Thorac Surg. 1995 Sep;60(3):615-22.

Benveniste MF, Welsh J, Viswanathan C, Shroff GS, Cuellar SLB, Carter BW, et al. Lung cancer: posttreatment imaging: radiation therapy and imaging findings. Radiol Clin North Am. 2018 May;56(3):471-83.

Codony-Servat J, Verlicchi A, Rosell R. Cancer stem cells in small cell lung cancer. Transl Lung Cancer Res. 2016 Feb;5(1):16-25.

Eide CA, Druker BJ. Understanding cancer from the stem cells up. Nat Med. 2017 Jun 6;23(6):656-7.

Yang L, Shi P, Zhao G, Xu J, Peng W, Zhang J, et al. Targeting cancer stem cell pathways for cancer therapy. Signal Transduct Target Ther. 2020 Feb 7;5(1):8.

Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer stem cells. Nature. 2001 Nov 1;414(6859):105-11.

Bao B, Ahmad A, Li Y, Azmi AS, Ali S, Banerjee S, et al. Targeting CSCs within the tumor microenvironment for cancer therapy: a potential role of mesenchymal stem cells. Expert Opin Ther Targets. 2012 Oct;16(10):1041-54.

Zakaria N, Satar NA, Abu Halim NH, Ngalim SH, Yusoff NM, Lin J, et al. Targeting lung cancer stem cells: research and clinical impacts. Front Oncol. 2017 May 5;7:80.

Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin. 2012 Jan-Feb;62(1):10-29.

Wu X, Chen H, Wang X. Can lung cancer stem cells be targeted for therapies? Cancer Treat Rev. 2012 Oct;38(6):580-8.

Eramo A, Haas T, De Maria R. Lung cancer stem cells: tools and targets to fight lung cancer. Oncogene. 2010 Aug 19;29(33):4625-35.

Kitamura H, Okudela K, Yazawa T, Sato H, Shimoyamada H. Cancer stem cell: implications in cancer biology and therapy with special reference to lung cancer. Lung Cancer. 2009 Dec;66(3):275-81.

Sullivan JP, Minna JD, Shay JW. Evidence for self-renewing lung cancer stem cells and their implications in tumor initiation, progression, and targeted therapy. Cancer Metastasis Rev. 2010 Mar;29(1):61-72.

Suresh R, Ali S, Ahmad A, Philip PA, Sarkar FH. The role of cancer stem cells in recurrent and drug-resistant lung cancer. Adv Exp Med Biol. 2016;890:57-74.

Mizugaki H, Sakakibara-Konishi J, Kikuchi J, Moriya J, Hatanaka KC, Kikuchi E, et al. CD133 expression: a potential prognostic marker for non-small cell lung cancers. Int J Clin Oncol. 2014 Apr;19(2):254-9.

Hu Y, Fu L. Targeting cancer stem cells: a new therapy to cure cancer patients. Am J Cancer Res. 2012;2(3):340.

Chen YC, Hsu HS, Chen YW, Tsai TH, How CK, Wang CY, et al. Oct-4 expression maintained cancer stem-like properties in lung cancer-derived CD133-positive cells. PloS one. 2008 Jul 9;3(7):e2637.

Singh S, Chellappan S. Lung cancer stem cells: molecular features and therapeutic targets. Mol Aspects Med. 2014 Oct;39:50-60.

Russo JE, Hilton J. Characterization of cytosolic aldehyde dehydrogenase from cyclophosphamide resistant L1210 cells. Cancer Res. 1988 Jun 1;48(11):2963-8.

Moreb J, Schweder M, Suresh A, Zucali JR. Overexpression of the human aldehyde dehydrogenase class I results in increased resistance to 4-hydroperoxy-cyclophosphamide. Cancer Gene Ther. 1996 Jan-Feb;3(1):24.

Sullivan JP, Spinola M, Dodge M, Raso MG, Behrens C, Gao B, et al. Aldehyde dehydrogenase activity selects for lung adenocarcinoma stem cells dependent on notch signaling. Cancer Res. 2010 Dec 1;70(23):9937-48.

Huang CP, Tsai MF, Chang TH, Tang WC, Chen SY, Lai HH, et al. ALDH-positive lung cancer stem cells confer resistance to epidermal growth factor receptor tyrosine kinase inhibitors. Cancer Lett. 2013 Jan 1;328(1):144-51.

Liu A, Yu X, Liu S. Pluripotency transcription factors and cancer stem cells: small genes make a big difference. Chin J Cancer. 2013 Sep;32(9):483-7.

Wang ML, Chiou SH, Wu CW. Targeting cancer stem cells: emerging role of Nanog transcription factor. Onco Targets Ther. 2013 Sep 4;6:1207-20.

Chiou SH, Wang ML, Chou YT, Chen CJ, Hong CF, Hsieh WJ, et al. Coexpression of Oct4 and Nanog enhances malignancy in lung adenocarcinoma by inducing cancer stem cell–like properties and epithelial–mesenchymal transdifferentiation. Cancer Res. 2010 Dec 15;70(24):10433-44.

Boyer LA, Lee TI, Cole MF, Johnstone SE, Levine SS, Zucker JP, et al. Core transcriptional regulatory circuitry in human embryonic stem cells. Cell. 2005 Sep 23;122(6):947-56.

Karachaliou N, Rosell R, Viteri S. The role of SOX2 in small cell lung cancer, lung adenocarcinoma and squamous cell carcinoma of the lung. Transl Lung Cancer Res. 2013 Jun;2(3):172-9.

Pan G, Thomson JA. Nanog and transcriptional networks in embryonic stem cell pluripotency. Cell Res. 2007 Jan;17(1):42-9.

Du Y, Ma C, Wang Z, Liu Z, Liu H, Wang T. Nanog, a novel prognostic marker for lung cancer. Surg Oncol. 2013 Dec;22(4):224-9.

Zhang W, Sui Y, Ni J, Yang T. Insights into the Nanog gene: A propeller for stemness in primitive stem cells. Int J Biol Sci. 2016 Oct 25;12(11):1372-81.

Zhang X, Neganova I, Przyborski S, Yang C, Cooke M, Atkinson SP, et al. A role for NANOG in G1 to S transition in human embryonic stem cells through direct binding of CDK6 and CDC25A. J Cell Biol. 2009 Jan 12;184(1):67-82.

Cao J, Li L, Chen C, Lv C, Meng F, Zeng L, et al. RNA interference-mediated silencing of NANOG leads to reduced proliferation and self-renewal, cell cycle arrest and apoptosis in T-cell acute lymphoblastic leukemia cells via the p53 signaling pathway. Leuk Res. 2013 Sep;37(9):1170-7.

Han J, Zhang F, Yu M, Zhao P, Ji W, Zhang H, et al. RNA interference-mediated silencing of NANOG reduces cell proliferation and induces G0/G1 cell cycle arrest in breast cancer cells. Cancer Lett. 2012 Aug 1;321(1):80-8.

Tian T, Zhang Y, Wang S, Zhou J, Xu S. Sox2 enhances the tumorigenicity and chemoresistance of cancer stem-like cells derived from gastric cancer. J Biomed Res. 2012 Sep;26(5):336-45.

Schaefer T, Lengerke C. SOX2 protein biochemistry in stemness, reprogramming, and cancer: the PI3K/AKT/SOX2 axis and beyond. Oncogene. 2020 Jan;39(2): 278-92.

Chang CC, Shieh GS, Wu P, Lin CC, Shiau AL, Wu CL. Oct-3/4 expression reflects tumor progression and regulates motility of bladder cancer cells. Cancer Res. 2008 Aug 1;68(15):6281-91.

Nichols J, Zevnik B, Anastassiadis K, Niwa H, Klewe-Nebenius D, Chambers I, et al. Formation of pluripotent stem cells in the mammalian embryo depends on the POU transcription factor Oct4. Cell. 1998 Oct 30;95(3):379-91.

Phi LTH, Sari IN, Yang YG, Lee SH, Jun N, Kim KS, et al. Cancer stem cells (CSCs) in drug resistance and their therapeutic implications in cancer treatment. Stem Cells Int. 2018 Feb 28;2018:5416923.

Takebe N, Miele L, Harris PJ, Jeong W, Bando H, Kahn M, et al. Targeting Notch, Hedgehog, and Wnt pathways in cancer stem cells: clinical update. Nat Rev Clin Oncol. 2015 Aug;12(8):445-64.

Kurth I, Peitzsch C, Baumann M, Dubrovska A. The role of cancer stem cells in tumor radioresistance. In: Rajasekhar VK, editor. Cancer stem cells. Hoboken: John Wiley & Sons; 2014. p. 473-91.

MacDonald BT, Tamai K, He X. Wnt/β-catenin signaling: components, mechanisms, and diseases. Dev Cell. 2009 Jul;17(1):9-26.

Kühl SJ, Kühl M. On the role of Wnt/β-catenin signaling in stem cells. Biochim Biophys Acta 2013 Feb;1830(2):2297-306.

Noda T, Nagano H, Takemasa I, Yoshioka S, Murakami M, Wada H, et al. Activation of Wnt/β-catenin signalling pathway induces chemoresistance to interferon-α/5-fluorouracil combination therapy for hepatocellular carcinoma. Br J Cancer. 2009 May 19;100(10):1647-58.

Zhong Z, Virshup DM. Wnt signaling and drug resistance in cancer. Mol Pharmacol. 2020 Feb;97(2):72-89.

Artavanis-Tsakonas S, Rand MD, Lake RJ. Notch signaling: cell fate control and signal integration in development. Science. 1999 Apr 30;284(5415):770-6.

Wang Z, Ahmad A, Li Y, Azmi AS, Miele L, Sarkar FH. Targeting notch to eradicate pancreatic cancer stem cells for cancer therapy. Anticancer Res. 2011 Apr;31(4):1105-13.

Koury J, Zhong L, Hao J. Targeting signaling pathways in cancer stem cells for cancer treatment. Stem Cells Int. 2017;2017:2925869.

Merchant AA, Matsui W. Targeting Hedgehog—a cancer stem cell pathway. Clin Cancer Res. 2010 Jun 15;16(12):3130-40.

Petrova R, Joyner AL. Roles for Hedgehog signaling in adult organ homeostasis and repair. Development. 2014 Sep;141(18):3445-57.

Matsui WH. Cancer stem cell signaling pathways. Medicine (Baltimore). 2016 Sep;95(1 Suppl 1):S8-S19.

Clement V, Sanchez P, de Tribolet N, Radovanovic I, Ruiz i Altaba A. HEDGEHOG-GLI1 signaling regulates human glioma growth, cancer stem cell self-renewal, and tumorigenicity. Curr Biol. 2007 Jan 23;17(2):165-72.

Van De Wetering M, Sancho E, Verweij C, De Lau W, Oving I, Hurlstone A, et al. The β-catenin/TCF-4 complex imposes a crypt progenitor phenotype on colorectal cancer cells. Cell. 2002 Oct 18;111(2):241-50.

Parsons DW, Wang TL, Samuels Y, Bardelli A, Cummins JM, DeLong L, et al. Mutations in a signalling pathway. Nature. 2005 Aug 11;436(7052):792.

Alves-Guerra MC, Ronchini C, Capobianco AJ. Mastermind-like 1 is a specific coactivator of β-catenin transcription activation and is essential for colon carcinoma cell survival. Cancer Res. 2007 Sep 15;67(18):8690-8.

Meng RD, Shelton CC, Li YM, Qin LX, Notterman D, Paty PB, et al.

γ-Secretase inhibitors abrogate oxaliplatin-induced activation of the Notch-1 signaling pathway in colon cancer cells resulting in enhanced chemosensitivity. Cancer Res. 2000 Jan 15;69(2):573-82.

Yao J, Duan L, Fan M, Yuan J, Wu X. Notch1 induces cell cycle arrest and apoptosis in human cervical cancer cells: involvement of nuclear factor kappa B inhibition. Int J Gynecol Cancer. 2007 Mar-Apr;17(2):502-10.

Qi R, An H, Yu Y, Zhang M, Liu S, Xu H, et al. Notch1 signaling inhibits growth of human hepatocellular carcinoma through induction of cell cycle arrest and apoptosis. Cancer Res. 2003 Dec 1;63(23):8323-9.

Varnat F, Duquet A, Malerba M, Zbinden M, Mas C, Gervaz P, et al. Human colon cancer epithelial cells harbour active HEDGEHOG‐GLI signalling that is essential for tumour growth, recurrence, metastasis and stem cell survival and expansion. EMBO Mol Med. 2009 Sep;1(6‐7):338-51.

Akiyoshi T, Nakamura M, Koga K, Nakashima H, Yao T, Tsuneyoshi M, et al. Gli1, downregulated in colorectal cancers, inhibits proliferation of colon cancer cells involving Wnt signalling activation. Gut. 2006 Jul;55(7):991-9.

Neiman P, Kimmel R, Icreverzi A, Elsaesser K, Bowers S, Burnside J, et al. Genomic instability during Myc-induced lymphomagenesis in the bursa of Fabricius. Oncogene. 2006 Oct 12;25(47):6325-35.

Prochownik EV. c-Myc: linking transformation and genomic instability. Curr Mol Med. 2008 Sep;8(6):446-58.

Kuzyk A, Mai S. c-MYC-induced genomic instability. Cold Spring Harb Perspect Med. 2014 Apr 1;4(4):a014373.

Felsher DW, Bishop JM. Transient excess of MYC activity can elicit genomic instability and tumorigenesis. Proc Natl Acad Sci USA.1999 Mar 30;96(7):3940-4.

Rockwood LD, Torrey TA, Kim JS, Coleman AE, Kovalchuk AL, Xiang S, et al. Genomic instability in mouse Burkitt lymphoma is dominated by illegitimate genetic recombinations, not point mutations. Oncogene. 2002 Oct 17; 21(47): 7235-40.

Silva AG, Graves HA, Guffei A, Ricca TI, Mortara RA, Jasiulionis MG, et al. Telomere-centromere-driven genomic instability contributes to karyotype evolution in a mouse model of melanoma. Neoplasia. 2010 Jan;12(1):11-9.

Aguilera A, Gómez-González B. Genome instability: a mechanistic view of its causes and consequences. Nat Rev Genet. 2008 Mar;9(3):204-17.

Rebucci M, Michiels C. Molecular aspects of cancer cell resistance to chemo-therapy. Biochem Pharmacol. 2013 May 1;85(9):1219-26.

Porta C, Paglino C, Mosca A. Targeting PI3K/Akt/mTOR signaling in cancer. Front Oncol. 2014 Apr 14;4:64.

Chang L, Graham P, Hao J, Ni J, Bucci J, Cozzi P, et al. Acquisition of

epithelial-mesenchymal transition and cancer stem cell phenotypes is associated with activation of the PI3K/Akt/mTOR pathway in prostate cancer radioresistance. Cell Death Dis. 2013 Oct 24;4(10):e875.

Zhang X, Ai Z, Chen J, Yi J, Liu Z, Zhao H, et al. Glycometabolic adaptation mediates the insensitivity of drug-resistant K562/ADM leukaemia cells to adriamycin via the AKT-mTOR/c-Myc signalling pathway. Mol Med Rep. 2017 Apr;15(4):1869-76.