Elimination of human lung cancer stem cells through targeting of the stem cell factor–c-kit autocrine signaling loop
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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.
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20E treatment at doses of 0.1-100 μM significantly inhibited the expression of all CSC markers studied (ALDH, CD44, Oct4, c-Kit, Nestin).
“Figure 10 demonstrates that 20E treatment at doses of 0.1–100 µM significantly inhibited the expression of all of the CSC markers studied.”
From 20-Hydroxyecdysone Confers Antioxidant and Antineoplastic Properties in Human Non-Small Cell Lung Cancer Cells (2023) · cites this paper as [53]
For lung cancer, ALDH, CD44, Oct4, c-kit, and Nestin are among the most frequently observed CSCs markers that promote tumor development.
“For lung cancer, ALDH, CD44, Oct4, c-kit, and Nestin were shown to be some of the most frequently observed CSCs markers which promote tumor development [53,54,85,86,87].”
From 20-Hydroxyecdysone Confers Antioxidant and Antineoplastic Properties in Human Non-Small Cell Lung Cancer Cells (2023) · cites this paper as [53]
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- Authors
- Levina, V., Marrangoni, A., Wang, T., Parikh, S., Su, Y., Herberman, R., Lokshin, A., & Gorelik, E.
- Affiliations
- University of Pittsburgh (US)
- Corresponding author
- Levina, Vera
- Venue
- Cancer Research
- Published
- 2010-01-01
- Volume
- 70
- Issue
- 1
- Pages
- 338-346
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC4572892
- OpenAlex
- W2093146854
- Cited by
- 155
- References
- 48
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 3 · 2023: 6 · 2022: 8 · 2021: 13 · 2020: 5 · 2019: 7 · 2018: 10 · 2017: 9 · 2016: 9 · 2015: 9 · 2014: 16 · 2013: 18 · 2012: 17
- FWCI
- 6.00
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (R21CA143736, R01CA098642, U01CA117452, R03CA136019, R01CA108990)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Keywords
- lung cancer stem cells, non-small cell lung cancer, stem cell factor, CD117, autocrine signaling, imatinib, cisplatin, chemoresistance, tumor spheres, self-renewal, combination therapy
- MeSH terms
- Imatinib Mesylate, Antineoplastic Combined Chemotherapy Protocols, Benzamides, Carcinoma, Non-Small-Cell Lung, Cells, Cultured, Cisplatin, Flow Cytometry, Humans, Image Processing, Computer-Assisted, Lung Neoplasms, Piperazines, Pyrimidines, Neoplastic Stem Cells, Signal Transduction, Proto-Oncogene Proteins c-kit, Stem Cell Factor, Autocrine Communication
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