Identification of selective inhibitors of cancer stem cells by high-throughput screening

By Piyush B. Gupta, T. Onder, Guozhi Jiang, Kai Tao, Charlotte Kuperwasser, R. Weinberg, Eric S. Lander. Cell, 2009

2,391 citations recorded by the source corpus.

Summary Screens for agents that specifically kill epithelial cancer stem cells (CSCs) have not been possible due to the rarity of these cells within tumor cell populations and their relative instability in culture. We describe here a novel approach to screening for agents with epithelial CSC-specific toxicity. We have implemented this method in the context of a chemical screen and have discovered compounds showing selective toxicity for breast CSCs. In functional assays, one compound (salinomycin) reduced the proportion of CSCs by >100-fold relative to paclitaxel, a commonly used breast cancer chemotherapeutic drug. Treatment of mice with salinomycin inhibits mammary tumor growth in vivo and induces increased epithelial differentiation of tumor cells. In addition, global gene expression analyses show that salinomycin but not paclitaxel treatment results in the loss of expression of breast CSC genes previously identified by analyses of breast tissues isolated directly from patients. This study demonstrates that it is possible to identify agents with specific toxicity for epithelial CSCs as well as providing a practical approach for doing so.

Subfields: Cancer Research, Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/197e8ce4b6e08d14960a2adf8dca63b34497a36a

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Citations in the corpus

Targeting Epithelial–Mesenchymal Transition (EMT) to Overcome Drug Resistance in Cancer (2016, background): “Empirical evidence suggested that cells undergone EMT have a stem cell-like property, thus sharing key signaling pathways and drug resistance phenotypes with CSCs [43,44].”
EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer (2010, background): “However, whether CSCs are truly the only cells with de facto tumorigenic potential remains controversial (Quintana et al., 2008; Gupta et al., 2009a).”
Cancer heterogeneity—a multifaceted view (2013, positive): “It is generally assumed that these cells are more resistant to a variety of treatments [62,85].”
Nanomedicine therapeutic approaches to overcome cancer drug resistance (2013, neutral): “[132,147]”
Dynamic interplay between the collagen scaffold and tumor evolution (2010, background): “Furthermore, breast cancer cells with stem cell-like characteristics express increased levels of types I, IV and XVIII collagen, suggesting that an ECM autocrine circuit might promote tumor evolution [98].”
Dynamic EMT: a multi‐tool for tumor progression (2021, positive): “Experimentally transformed HMLER breast cancer cells with increased EMT features display about 10-fold increase in IC50 doses of many chemotherapeutics (Gupta et al , 2009; Singh et al , 2009; Singh & Settleman, 2010; Tulchinsky et al , 2019).”
The therapeutic promise of the cancer stem cell concept. (2010, methodology): “Most recently, also in human breast cancer, Gupta et al. used a high-throughput screening approach to determine the anticancer activity of approximately 16,000 compounds and identified a potassium ionophore, salinomycin, that selectively targets CD24loCD44hi CSCs (122).”
Epithelial-Mesenchymal Transition in Cancer: Parallels Between Normal Development and Tumor Progression (2010, background): “Indeed, recent evidence shows that this is the case: therapies do select for more mesenchymal and cancer stem cell-like cancer cells, pointing to a need for chemotherapeutic agents that specifically target cells that have undergone EMTand display enhanced tumor-initiating capabilities [90, 91].”
Epithelial-Mesenchymal Plasticity: A central regulator of cancer progression (2015, background): “This resistance causes enrichment of the more mesenchymal, stem-like cancer cells after initial treatment, which can often give rise to clinical relapse (Gupta et al., 2009).”
Deconstructing the molecular portraits of breast cancer (2010, background): “Among the w20 genes that compose this cluster are claudin 3, 4, 7, cingulin and occludin that are involved in tight junctions, and E-cadherin that is a calcium dependent cell adhesion protein.”
Tumors as organs: complex tissues that interface with the entire organism (2010, positive): “Interestingly, breast cancer cells with stem cell-like characteristics express increased levels of type I, IV, and XVIII collagens, suggesting that cancer cells may contribute to the generation of their niche (Gupta et al., 2009).”
Epithelial–mesenchymal plasticity in carcinoma metastasis (2013, background): “Salinomycin was also identified as inducing selective killing of E-cadherin-null breast epithelial cells compared with E-cadherin-positive cells (Gupta et al. 2009), although its molecular action toward EMT is unknown.”
Stochastic state transitions give rise to phenotypic equilibrium in populations of cancer cells. (2011, positive): “Additionally, because anticancer therapies preferentially kill specific cancer cell states, treatment can result in selective changes in phenotypic proportions within tumors (Creighton et al., 2009; Gupta et al., 2009; Li et al., 2008; Woodward et al., 2007).”