Elimination of human lung cancer stem cells through targeting of the stem cell factor-c-kit autocrine signaling loop.
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.
Levina
Vera
V
University of Pittsburgh Cancer Institute and Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA. levinav@upmc.edu
Marrangoni
Adele
A
Wang
Tingting
T
Parikh
Simul
S
Su
Yunyun
Y
Herberman
Ronald
R
Lokshin
Anna
A
Gorelik
Elieser
E
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D019898:Autocrine Communication / Q000187:drug effects / Q000502:physiology; D001549:Benzamides; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism*; D002478:Cells, Cultured; D002945:Cisplatin / Q000008:administration & dosage; D005434:Flow Cytometry; D006801:Humans; D007091:Image Processing, Computer-Assisted; D000068877:Imatinib Mesylate; D008175:Lung Neoplasms / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism*; D010879:Piperazines / Q000008:administration & dosage; D019009:Proto-Oncogene Proteins c-kit / Q000187:drug effects / Q000378:metabolism*; D011743:Pyrimidines / Q000008:administration & dosage; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D019089:Stem Cell Factor / Q000187:drug effects / Q000378:metabolism*
D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D019089:Stem Cell Factor; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit; D002945:Cisplatin