Elimination of Human Lung Cancer Stem Cells through Targeting of the Stem Cell Factor–c-kit Autocrine Signaling Loop

Abstract

Cancer stem cells (CSC) are thought to be responsible for tumor initiation and tumor regeneration after chemotherapy. Previously, we showed that chemotherapy of non–small cell lung cancer (NSCLC) cells lines can select for outgrowth of highly tumorigenic and metastatic CSCs. The high malignancy of lung CSCs was associated with an efficient cytokine network. In this study, we provide evidence that blocking stem cell factor (SCF)–c-kit signaling is sufficient to inhibit CSC proliferation and survival promoted by chemotherapy. CSCs were isolated from NSCLC cell lines as tumor spheres under CSC-selective conditions and their stem properties were confirmed. In contrast to other tumor cells, CSCs expressed c-kit receptors and produced SCF. Proliferation of CSCs was inhibited by SCF-neutralizing antibodies or by imatinib (Gleevec), an inhibitor of c-kit. Although cisplatin treatment eliminated the majority of tumor cells, it did not eliminate CSCs, whereas imatinib or anti-SCF antibody destroyed CSCs. Significantly, combining cisplatin with imatinib or anti-SCF antibody prevented the growth of both tumor cell subpopulations. Our findings reveal an important role for the SCF–c-kit signaling axis in self-renewal and proliferation of lung CSCs, and they suggest that SCF–c-kit signaling blockade could improve the antitumor efficacy of chemotherapy of human NSCLC.

Understanding cancer stem cell heterogeneity and plasticity

“…Similarly, stem-like cancer cells have been reported in human cancers of the prostate [87][88][89][90][91][92][93][94][95][96][97][98][99][100], lung [101][102][103][104][105][106][107][108][109][110][111], and many other organs (liver, pancreas, kidney, bladder, ovary, etc). In prostate cancer, tumor-initiating cells have been identified in xenografts in CD44 + [90,96], CD44 + α2β1 + [91], TRA-1-60 + CD151 + CD166 + [99], and ALDH + [97,98] populations as well as in SP [87] and holoclones [94].…”

Moderating Effects and Maintenance of Lung Cancer Cellular Immune Functions by CIK Cell Therapy

“…The incidence and mortality rates of lung cancer are in the first place of malignancy in the world, of which more than 80% are NSCLC, characterized by high incidence, high mortality and low survival (Levina et al, 2010). Standardized radiotherapy could kill the majority of tumor cells in a certain extent, but because of such factors as severe toxicity, resistant cells, the existence of cancer stem cells and anti-radiation cell, low immunity of advanced tumors patients and other factors, the implementation and benefit of the treatment program are greatly hampered (Levina et al, 2010;Baas et al, 2011;Hsu et al, 2011).…”

“…Standardized radiotherapy could kill the majority of tumor cells in a certain extent, but because of such factors as severe toxicity, resistant cells, the existence of cancer stem cells and anti-radiation cell, low immunity of advanced tumors patients and other factors, the implementation and benefit of the treatment program are greatly hampered (Levina et al, 2010;Baas et al, 2011;Hsu et al, 2011). Therefore, it is received widespread attention to explore and research new methods of treatment.…”

Elimination of quiescent/slow-proliferating cancer stem cells by Bcl-XL inhibition in non-small cell lung cancer

“…3 Lung cancer stem cells (LCSCs) have been previously identified through different criteria including surface expression of CD133, c-kit or through functional properties such as selective drug survival, elevated aldehyde dehydrogenase (ALDH) activity, increased glycolysis and glycine/serine metabolism or low concentrations of reactive oxygen species and ATP. [4][5][6][7][8][9] Importantly, when inoculated into immunocompromised mice, LCSCs give rise to xenografts that histologically reproduce the tumor of origin, thus representing an improved model for in vivo testing of new targeted therapies. 10 Several tumors express elevated levels of anti-apoptotic Bcl-2 family proteins such as Bcl-2, Bcl-X L and Mcl-1, which affect the apoptotic threshold of neoplastic cells contributing to chemotherapy resistance.…”