Lung cancer tumorigenicity and drug resistance are maintained through ALDHhiCD44hi tumor initiating cells

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 ALDHhiCD44hi subset showed the highest enhancement of stem cell phenotypic properties compared to ALDHhiCD44lo, ALDHloCD44hi, ALDHloCD44lo 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 ALDHhiCD44hi 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 ALDHhiCD44hi subset viability and ALDHloCD44lo 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 the ALDHhiCD44hi compartment was the cellular mediator of tumorigenicity and drug resistance. Further investigation of the regulatory mechanisms underlying ALDHhiCD44hi TIC maintenance would be beneficial for the development of long term lung cancer control.

Aldehyde dehydrogenases in cancer stem cells: potential as therapeutic targets

“…This is consistent with studies indicating that ALDH activity or expression of one or more ALDH protein correlate with tumor aggressiveness, treatment resistance, metastasis, and poor patient prognosis (6,25,44). ALDH has been proposed as a prognostic marker for many cancers including lung (45), breast (46), ovarian (47), pancreatic (24), and colon (48). There are many excellent recent reviews of ALDHs in cancer and CSCs (6,(49)(50)(51)(52) and these topics will not be discussed in detail here.…”

Sp1-mediated microRNA-182 expression regulates lung cancer progression

“…CD44, which localizes to the cell membrane, is reportedly involved in cell migration in various cancer types [44]. Recent studies also showed that tumor initiating cells with high CD44 expression maintained lung cancer tumorigenicity and drug resistance [45]. Another metastasis-related gene induced by miR-182 knockdown, ADAM9, cleaves membrane proteins such as E-cadherin [46].…”

Potential Anti-metastasis Natural Compounds for Lung Cancer

“…CSCs have the ability to self-renewal and can produce differentiated progeny through their pluripotency (69). It has been demonstrated that these CSCs in lung cancer resist to chemotherapeutic agents and have high tumorigenic potential (12,70). Also, the lung CSCs were shown to have augmented ability to move to other tissues (8,12,71).…”

“…Several CSC makers have been used to identify the CSC population in lung cancer, including cellular expression of CD44, CD133 and CD166 (67)(68)(69)(70)(71). Also aldehyde dehydrogenase (ALDH) activity and expression have been shown to indicate stemness in lung cancer (67)(68)(69)(70)(71).…”