Chemotherapy-induced Enrichment of Cancer Stem Cells in Lung Cancer

Abstract

Small cell lung cancer (SCLC) is a neuroendocrine tumor of the lung that is clinically characterized by early recurrence after initial complete response to combination chemotherapy, resulting in dismal prognosis. Cancer stem cells (CSCs) are suspected to survive the initial cycles of treatment and trigger relapse in form of a chemoresistant tumor. Whereas a profound amount of results reporting on CSCs exists for non-small cell lung cancers (NSCLC), far less data which are restricted to a few cancer cell lines and CD133-positive subpopulations of fresh tumor tissues are available for SCLC. Enrichment of CSCs in response to chemoradiotherapy and in recurrent tumors would prove their clinical relevance. The GLC14, GLC16 and GLC19 series of SCLC cell lines established from serial biopsies of one patient before, during and after therapy, respectively, provides an opportunity to investigate the phenotypical changes during chemoradiotherapy. We demonstrated by whole genome expression analysis that CSC markers such as CD44, CD133, CD47, ALDH1A1, AKR1C and members of the WNT and Notch pathways are increasingly expressed after chemoradiotherapy in GLC16 and GLC19, compared to the treatment-naive GLC14 SCLC cells. These findings in addition to the available literature suggest a role for CSCs in SCLC in tumor recurrence and in the resistant phenotype. Thus, targeting of CSCs may constitute a promising approach to delay or prevent recurrences that would eventually result in treatment failure and poor survival rates in SCLC patients.