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2010 ; 70
(1
): 338-46
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Elimination of human lung cancer stem cells through targeting of the stem cell
factor-c-kit autocrine signaling loop
#MMPMID20028869
Levina V
; Marrangoni A
; Wang T
; Parikh S
; Su Y
; Herberman R
; Lokshin A
; Gorelik E
Cancer Res
2010[Jan]; 70
(1
): 338-46
PMID20028869
show ga
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.