Lung Cancer Stem Cells: Relevance for Disease and Phytotherapeutic Opportunities

Lung cancer is presently the most diagnosed cancer after breast cancer with two million of reported new cases annually worldwide. Non-small cell lung cancer (NSCLC) forms the majority of these cases, whereas small cell lung cancer (SCLC) typically displays the lowest survival rate. Although treatment options are plentiful such as chemotherapy, targeted therapy and immunotherapy, new treatment strategies are needed to lower the number of deaths. This thesis aimed to investigate biological causes of therapy resistance and to identify alternative lung cancer treatments. Literature review suggested that lung cancer is initiated by a malignant mother cell, called cancer stem cell (CSC), which also drives disease progression including therapy resistance and metastasis. To better understand SCLC, the involvement of CSC in SCLC progression was further explored. A unique cell culture model consisting of three cell lines from one SCLC patient obtained during different cancer stages was used, representing untreated, treatment-relapsed and lethal progressive disease. It was found that CSC markers expression increased during disease progression. A corresponding increase in CSC activity, such as cell growth and radiotherapy resistance, was also demonstrated. Furthermore, the CSC inhibitory effect of natural phytochemicals directed against Wnt/β-catenin signaling, a CSC-supportive pathway, was examined in NSCLC. Chalcones, isothiocyanates and benzophenanthridine alkaloids could inhibit Wnt/β-catenin and NSCLC cell growth. In conclusion, we provided additional evidence that CSC play an important role in SCLC progression and identified phytochemicals that inhibit the Wnt/β-catenin pathway and thus NSCLC CSC at non-toxic concentrations, which may open up new therapeutic possibilities.