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.
Highlights
Lung cancer is the most common malignancy but curative therapy for metastatic disease is limited
The Aldehyde dehydrogenase 1 (ALDH)/CD44 co-expression profiles of 11 lung cancer cell lines including patientderived lung cancer cell lines (PDCL) and drug-induced resistant cells were analyzed by flow cytometry
The employment of cell surface markers allows the in vitro isolation of a particular cell population but no single marker has been found to be universally applicable for all cancers and the specific scenario being investigated needs to be noted
Summary
Lung cancer is the most common malignancy but curative therapy for metastatic disease is limited. Tyrosine kinase inhibitor (TKI) therapy achieves a higher objective response rate and longer progression free survival in cancers with epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK)rearrangement, relapse is the rule after 10-14 months due to drug resistance [1,2,3,4,5]. Inhibition of morphogenesis regulatory pathways such the Hedgehog, Notch and Wnt/β-catenin pathways can retard tumor transplantability, further supporting TIC-targeting could be useful for lung cancer control [8,9,10,11]. A deeper understanding of the cell targets and maintenance mechanisms is essential for further therapy development. Lung cancer cells expressing various molecules such as CD133, CD166, ALDH, CXCR4, GLDC, etc. Lung cancer cells expressing various molecules such as CD133, CD166, ALDH, CXCR4, GLDC, etc. have been shown to demonstrate TIC phenotypic characteristics www.impactjournals.com/oncotarget
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