Lung cancer tumorigenicity and drug resistance are maintained through ALDH(hi)CD44(hi) tumor initiating cells.

Jing Liu, Zhijie Xiao, Sunny Kit Man Wong, Vicky Pui Chi Tin, Ka Yan Ho, Junwen Wang, Mai Har Sham, Maria Pik Wong

Research output: Contribution to journalArticle

Abstract

Limited improvement in long term survival of lung cancer patients has been achieved by conventional chemotherapy or targeted therapy. To explore the potentials of tumor initiating cells (TIC)-directed therapy, it is essential to identify the cell targets and understand their maintenance mechanisms. We have analyzed the performance of ALDH/CD44 co-expression as TIC markers and treatment targets of lung cancer using well-validated in vitro and in vivo analyses in multiple established and patient-derived lung cancer cells. The ALDH(hi)CD44(hi) subset showed the highest enhancement of stem cell phenotypic properties compared to ALDH(hi)CD44(lo), ALDH(lo)CD44(hi), ALDH(lo)CD44(lo) cells and unsorted controls. They showed higher invasion capacities, pluripotency genes and epithelial-mesenchymal transition transcription factors expression, lower intercellular adhesion protein expression and higher G2/M phase cell cycle fraction. In immunosuppressed mice, the ALDH(hi)CD44(hi)xenografts showed the highest tumor induction frequency, serial transplantability, shortest latency, largest volume and highest growth rates. Inhibition of sonic Hedgehog and Notch developmental pathways reduced ALDH+CD44+ compartment. Chemotherapy and targeted therapy resulted in higher AALDH(hi)CD44(hi) subset viability and ALDH(lo)CD44(lo) subset apoptosis fraction. ALDH inhibition and CD44 knockdown led to reduced stemness gene expression and sensitization to drug treatment. In accordance, clinical lung cancers containing a higher abundance of ALDH and CD44-coexpressing cells was associated with lower recurrence-free survival. Together, results suggested theALDH(hi)CD44(hi)compartment was the cellular mediator of tumorigenicity and drug resistance. Further investigation of the regulatory mechanisms underlying ALDH(hi)CD44(hi)TIC maintenance would be beneficial for the development of long term lung cancer control.

Original languageEnglish (US)
Pages (from-to)1698-1711
Number of pages14
JournalOncotarget
Volume4
Issue number10
StatePublished - Oct 2013
Externally publishedYes

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Neoplastic Stem Cells
Drug Resistance
Lung Neoplasms
Maintenance
Drug Therapy
Epithelial-Mesenchymal Transition
Survival
Hedgehogs
G2 Phase
Therapeutics
Cell- and Tissue-Based Therapy
Heterografts
Cell Division
Cell Cycle
Transcription Factors
Stem Cells
Apoptosis
Gene Expression
Recurrence
Growth

ASJC Scopus subject areas

  • Oncology

Cite this

Liu, J., Xiao, Z., Wong, S. K. M., Tin, V. P. C., Ho, K. Y., Wang, J., ... Wong, M. P. (2013). Lung cancer tumorigenicity and drug resistance are maintained through ALDH(hi)CD44(hi) tumor initiating cells. Oncotarget, 4(10), 1698-1711.

Lung cancer tumorigenicity and drug resistance are maintained through ALDH(hi)CD44(hi) tumor initiating cells. / Liu, Jing; Xiao, Zhijie; Wong, Sunny Kit Man; Tin, Vicky Pui Chi; Ho, Ka Yan; Wang, Junwen; Sham, Mai Har; Wong, Maria Pik.

In: Oncotarget, Vol. 4, No. 10, 10.2013, p. 1698-1711.

Research output: Contribution to journalArticle

Liu, J, Xiao, Z, Wong, SKM, Tin, VPC, Ho, KY, Wang, J, Sham, MH & Wong, MP 2013, 'Lung cancer tumorigenicity and drug resistance are maintained through ALDH(hi)CD44(hi) tumor initiating cells.', Oncotarget, vol. 4, no. 10, pp. 1698-1711.
Liu, Jing ; Xiao, Zhijie ; Wong, Sunny Kit Man ; Tin, Vicky Pui Chi ; Ho, Ka Yan ; Wang, Junwen ; Sham, Mai Har ; Wong, Maria Pik. / Lung cancer tumorigenicity and drug resistance are maintained through ALDH(hi)CD44(hi) tumor initiating cells. In: Oncotarget. 2013 ; Vol. 4, No. 10. pp. 1698-1711.
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abstract = "Limited improvement in long term survival of lung cancer patients has been achieved by conventional chemotherapy or targeted therapy. To explore the potentials of tumor initiating cells (TIC)-directed therapy, it is essential to identify the cell targets and understand their maintenance mechanisms. We have analyzed the performance of ALDH/CD44 co-expression as TIC markers and treatment targets of lung cancer using well-validated in vitro and in vivo analyses in multiple established and patient-derived lung cancer cells. The ALDH(hi)CD44(hi) subset showed the highest enhancement of stem cell phenotypic properties compared to ALDH(hi)CD44(lo), ALDH(lo)CD44(hi), ALDH(lo)CD44(lo) cells and unsorted controls. They showed higher invasion capacities, pluripotency genes and epithelial-mesenchymal transition transcription factors expression, lower intercellular adhesion protein expression and higher G2/M phase cell cycle fraction. In immunosuppressed mice, the ALDH(hi)CD44(hi)xenografts showed the highest tumor induction frequency, serial transplantability, shortest latency, largest volume and highest growth rates. Inhibition of sonic Hedgehog and Notch developmental pathways reduced ALDH+CD44+ compartment. Chemotherapy and targeted therapy resulted in higher AALDH(hi)CD44(hi) subset viability and ALDH(lo)CD44(lo) subset apoptosis fraction. ALDH inhibition and CD44 knockdown led to reduced stemness gene expression and sensitization to drug treatment. In accordance, clinical lung cancers containing a higher abundance of ALDH and CD44-coexpressing cells was associated with lower recurrence-free survival. Together, results suggested theALDH(hi)CD44(hi)compartment was the cellular mediator of tumorigenicity and drug resistance. Further investigation of the regulatory mechanisms underlying ALDH(hi)CD44(hi)TIC maintenance would be beneficial for the development of long term lung cancer control.",
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