Abstract
Cancer stem cells (CSCs), also known as tumorinitiating cells (TICs), are a group of cells found within cancer cells. Like normal stem cells, CSCs can proliferate, engage in self-renewal, and are often implicated in the recurrence of tumors after therapy [1, 2]. The existence of CSCs in various types of cancer has been proven, such as in acute myeloid leukemia (AML) [3], breast [4], pancreatic [5], and lung cancers [6], to name a few. There are two theories regarding the origin of CSCs. First, CSCs may have arisen from normal stem/progenitor cells that experienced changes in their environment or genetic mutations. On the other hand, CSCs may also have originated from differentiated cells that underwent genetic and/or heterotypic modifications [7]. Either way, CSCs reprogram their metabolism in order to support tumorigenesis.
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References
- Dick, J. E. (2008). Stem cell concepts renew cancer research. Blood, 112(13), 4793–4807. doi: 10.1182/blood-2008-08-077941. [DOI] [PubMed]
- Reya, T., et al. (2001). Stem cells, cancer, and cancer stem cells. Nature, 414(6859), 105–111. doi: 10.1038/35102167. [DOI] [PubMed]
- Bonnet, D., & Dick, J. E. (1997). Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nature Medicine, 3(7), 730–737. doi: 10.1038/nm0797-730. [DOI] [PubMed]
- Crabtree, J. S., & Miele, L. (2018). Breast cancer stem cells. Biomedicine, 6, 3. doi: 10.3390/biomedicines6030077. [DOI] [PMC free article] [PubMed]
- Hermann, P. C., et al. (2007). Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer. Cell Stem Cell, 1(3), 313–323. doi: 10.1016/j.stem.2007.06.002. [DOI] [PubMed]
- Ho, M. M., et al. (2007). Side population in human lung cancer cell lines and tumors is enriched with stem-like cancer cells. Cancer Research, 67(10), 4827–4833. doi: 10.1158/0008-5472.CAN-06-3557. [DOI] [PubMed]
- Yu, Z., et al. (2012). Cancer stem cells. The International Journal of Biochemistry & Cell Biology, 44(12), 2144–2151. doi: 10.1016/j.biocel.2012.08.022. [DOI] [PMC free article] [PubMed]
- Sancho, P., Barneda, D., & Heeschen, C. (2016). Hallmarks of cancer stem cell metabolism. British Journal of Cancer, 114(12), 1305–1312. doi: 10.1038/bjc.2016.152. [DOI] [PMC free article] [PubMed]
- Bose, S., Zhang, C., & Le, A. (2021). Glucose metabolism in cancer: The Warburg effect and beyond. Advances in Experimental Medicine and Biology, 1311, https://doi.org/10.1007/978-3-030-65768-0_1 doi: 10.1007/978-3-030-65768-0_1. [DOI] [PMC free article] [PubMed]
- Aguilar, E., et al. (2016). Metabolic reprogramming and dependencies associated with epithelial cancer stem cells independent of the epithelial-mesenchymal transition program. Stem Cells, 34(5), 1163–1176. doi: 10.1002/stem.2286. [DOI] [PMC free article] [PubMed]
- Song, K., et al. (2015). Active glycolytic metabolism in CD133(+) hepatocellular cancer stem cells: Regulation by MIR-122. Oncotarget, 6(38), 40822–40835. doi: 10.18632/oncotarget.5812. [DOI] [PMC free article] [PubMed]
- Shen, Y. A., et al. (2015). Metabolic reprogramming orchestrates cancer stem cell properties in nasopharyngeal carcinoma. Cell Cycle, 14(1), 86–98. doi: 10.4161/15384101.2014.974419. [DOI] [PMC free article] [PubMed]
- Shibuya, K., et al. (2015). Targeting the facilitative glucose transporter GLUT1 inhibits the self-renewal and tumor-initiating capacity of cancer stem cells. Oncotarget, 6(2), 651–661. doi: 10.18632/oncotarget.2892. [DOI] [PMC free article] [PubMed]
- Ciavardelli, D., et al. (2014). Breast cancer stem cells rely on fermentative glycolysis and are sensitive to 2-deoxyglucose treatment. Cell Death & Disease, 5, e1336. doi: 10.1038/cddis.2014.285. [DOI] [PMC free article] [PubMed]
- Xie, H., et al. (2014). Targeting lactate dehydrogenase--a inhibits tumorigenesis and tumor progression in mouse models of lung cancer and impacts tumor-initiating cells. Cell Metabolism, 19(5), 795–809. doi: 10.1016/j.cmet.2014.03.003. [DOI] [PMC free article] [PubMed]
- Le, A., et al. (2010). Inhibition of lactate dehydrogenase A induces oxidative stress and inhibits tumor progression. Proceedings of the National Academy of Sciences of the United States of America, 107(5), 2037–2042. doi: 10.1073/pnas.0914433107. [DOI] [PMC free article] [PubMed]
- Rajeshkumar, N. V., et al. (2015). Therapeutic targeting of the Warburg effect in pancreatic cancer relies on an absence of p53 function. Cancer Research, 75(16), 3355–3364. doi: 10.1158/0008-5472.CAN-15-0108. [DOI] [PMC free article] [PubMed]
- Dutta, P., et al. (2013). Evaluation of LDH-A and glutaminase inhibition in vivo by hyperpolarized 13C-pyruvate magnetic resonance spectroscopy of tumors. Cancer Research, 73(14), 4190–4195. doi: 10.1158/0008-5472.CAN-13-0465. [DOI] [PMC free article] [PubMed]
- Li, T., Copeland, C., & Le, A. (2021). Glutamine metabolism in cancer. Advances in Experimental Medicine and Biology, 1311, https://doi.org/10.1007/978-3-030-65768-0_2 doi: 10.1007/978-3-030-65768-0_2. [DOI] [PMC free article] [PubMed]
- Le, A., et al. (2012). Glucose-independent glutamine metabolism via TCA cycling for proliferation and survival in B cells. Cell Metabolism, 15(1), 110–121. doi: 10.1016/j.cmet.2011.12.009. [DOI] [PMC free article] [PubMed]
- Kim, J. H., et al. (2018). Effects of metformin on colorectal cancer stem cells depend on alterations in glutamine metabolism. Scientific Reports, 8(1), 409. doi: 10.1038/s41598-017-18762-4. [DOI] [PMC free article] [PubMed]
- Zimmermann, S. C., et al. (2016). Allosteric glutaminase inhibitors based on a 1,4-di(5-amino-1,3,4-thiadiazol-2-yl)butane scaffold. ACS Medicinal Chemistry Letters, 7(5), 520–524. doi: 10.1021/acsmedchemlett.6b00060. [DOI] [PMC free article] [PubMed]
- Rais, R., et al. (2016). Discovery of 6-diazo-5-oxo-l-norleucine (DON) prodrugs with enhanced CSF delivery in monkeys: a potential treatment for glioblastoma. Journal of Medicinal Chemistry, 59(18), 8621–8633. doi: 10.1021/acs.jmedchem.6b01069. [DOI] [PubMed]
- Xiang, Y., et al. (2015). Targeted inhibition of tumor-specific glutaminase diminishes cell-autonomous tumorigenesis. The Journal of Clinical Investigation, 125(6), 2293–2306. doi: 10.1172/JCI75836. [DOI] [PMC free article] [PubMed]
- Dang, C. V., et al. (2011). Therapeutic targeting of cancer cell metabolism. Journal of Molecular Medicine (Berlin), 89(3), 205–212. doi: 10.1007/s00109-011-0730-x. [DOI] [PMC free article] [PubMed]
- Hirschey, M. D., et al. (2015). Dysregulated metabolism contributes to oncogenesis. Seminars in Cancer Biology, 35(Suppl), S129–S150. doi: 10.1016/j.semcancer.2015.10.002. [DOI] [PMC free article] [PubMed]
- Elgogary, A., et al. (2016). Combination therapy with BPTES nanoparticles and metformin targets the metabolic heterogeneity of pancreatic cancer. Proceedings of the National Academy of Sciences of the United States of America, 113(36), E5328–E5336. doi: 10.1073/pnas.1611406113. [DOI] [PMC free article] [PubMed]
- Udupa, S., et al. (2019). Upregulation of the glutaminase II pathway contributes to glutamate production upon glutaminase 1 inhibition in pancreatic cancer. Proteomics, 19(21–22), e1800451. doi: 10.1002/pmic.201800451. [DOI] [PMC free article] [PubMed]
- Nguyen, T., et al. (2019). Uncovering the role of N-acetyl-aspartyl-glutamate as a glutamate reservoir in cancer. Cell Reports, 27(2), 491–501. e6. doi: 10.1016/j.celrep.2019.03.036. [DOI] [PMC free article] [PubMed]
- Li, D., et al. (2015). Inhibition of glutamine metabolism counteracts pancreatic cancer stem cell features and sensitizes cells to radiotherapy. Oncotarget, 6(31), 31151–31163. doi: 10.18632/oncotarget.5150. [DOI] [PMC free article] [PubMed]
- Cuyas, E., et al. (2018). Mitostemness. Cell Cycle, 17(8), 918–926. doi: 10.1080/15384101.2018.1467679. [DOI] [PMC free article] [PubMed]
- Liu, P. P., et al. (2014). Metabolic regulation of cancer cell side population by glucose through activation of the Akt pathway. Cell Death and Differentiation, 21(1), 124–135. doi: 10.1038/cdd.2013.131. [DOI] [PMC free article] [PubMed]
- Peiris-Pages, M., et al. (2016). Cancer stem cell metabolism. Breast Cancer Research, 18(1), 55. doi: 10.1186/s13058-016-0712-6. [DOI] [PMC free article] [PubMed]
- Lonardo, E., et al. (2013). Metformin targets the metabolic Achilles heel of human pancreatic cancer stem cells. PLoS One, 8(10), e76518. doi: 10.1371/journal.pone.0076518. [DOI] [PMC free article] [PubMed]
- Sancho, P., et al. (2015). MYC/PGC-1alpha balance determines the metabolic phenotype and plasticity of pancreatic cancer stem cells. Cell Metabolism, 22(4), 590–605. doi: 10.1016/j.cmet.2015.08.015. [DOI] [PubMed]
- Reid, M. A., Dai, Z., & Locasale, J. W. (2017). The impact of cellular metabolism on chromatin dynamics and epigenetics. Nature Cell Biology, 19(11), 1298–1306. doi: 10.1038/ncb3629. [DOI] [PMC free article] [PubMed]
- Wainwright, E. N., & Scaffidi, P. (2017). Epigenetics and cancer stem cells: Unleashing, hijacking, and restricting cellular plasticity. Trends Cancer, 3(5), 372–386. doi: 10.1016/j.trecan.2017.04.004. [DOI] [PMC free article] [PubMed]
- Mitani, M., et al. (1976). Salinomycin effects on mitochondrial ion translocation and respiration. Antimicrobial Agents and Chemotherapy, 9(4), 655–660. doi: 10.1128/aac.9.4.655. [DOI] [PMC free article] [PubMed]
- Gupta, P. B., et al. (2009). Identification of selective inhibitors of cancer stem cells by high-throughput screening. Cell, 138(4), 645–659. doi: 10.1016/j.cell.2009.06.034. [DOI] [PMC free article] [PubMed]
- Zhi, Q. M., et al. (2011). Salinomycin can effectively kill ALDH (high) stem-like cells on gastric cancer. Biomedicine & Pharmacotherapy, 65(7), 509–515. doi: 10.1016/j.biopha.2011.06.006. [DOI] [PubMed]
- Zhang, G. N., et al. (2011). Combination of salinomycin and gemcitabine eliminates pancreatic cancer cells. Cancer Letters, 313(2), 137–144. doi: 10.1016/j.canlet.2011.05.030. [DOI] [PubMed]
- Lyakhovich, A., & Lleonart, M. E. (2016). Bypassing mechanisms of mitochondria-mediated cancer stem cells resistance to chemo- and radiotherapy. Oxidative Medicine and Cellular Longevity, 2016, 1716341. doi: 10.1155/2016/1716341. [DOI] [PMC free article] [PubMed]
- Garcia-Heredia, J. M., & Carnero, A. (2015). Decoding Warburg’s hypothesis: Tumor-related mutations in the mitochondrial respiratory chain. Oncotarget, 6(39), 41582–41599. doi: 10.18632/oncotarget.6057. [DOI] [PMC free article] [PubMed]
- Hirsch, H. A., et al. (2009). Metformin selectively targets cancer stem cells, and acts together with chemotherapy to block tumor growth and prolong remission. Cancer Research, 69(19), 7507–7511. doi: 10.1158/0008-5472.CAN-09-2994. [DOI] [PMC free article] [PubMed]
- Dattilo, R., et al. (2020). Pyrvinium pamoate induces death of triple-negative breast cancer stem-like cells and reduces metastases through effects on lipid anabolism. Cancer Research, 80(19), 4087–4102. doi: 10.1158/0008-5472.CAN-19-1184. [DOI] [PMC free article] [PubMed]
- Fiorillo, M., et al. (2016). Repurposing atovaquone: Targeting mitochondrial complex III and OXPHOS to eradicate cancer stem cells. Oncotarget, 7(23), 34084–34099. doi: 10.18632/oncotarget.9122. [DOI] [PMC free article] [PubMed]
- Fiorillo, M., et al. (2016). Bedaquiline, an FDA-approved antibiotic, inhibits mitochondrial function and potently blocks the proliferative expansion of stem-like cancer cells (CSCs). Aging (Albany NY), 8(8), 1593–1607. doi: 10.18632/aging.100983. [DOI] [PMC free article] [PubMed]
- Sosa, V., et al. (2013). Oxidative stress and cancer: An overview. Ageing Research Reviews, 12(1), 376–390. doi: 10.1016/j.arr.2012.10.004. [DOI] [PubMed]
- Redza-Dutordoir, M., & Averill-Bates, D. A. (2016). Activation of apoptosis signalling pathways by reactive oxygen species. Biochimica et Biophysica Acta, 1863(12), 2977–2992. doi: 10.1016/j.bbamcr.2016.09.012. [DOI] [PubMed]
- Fan, P. C., et al. (2019). Quantitative proteomics reveals mitochondrial respiratory chain as a dominant target for carbon ion radiation: Delayed reactive oxygen species generation caused DNA damage. Free Radical Biology & Medicine, 130, 436–445. doi: 10.1016/j.freeradbiomed.2018.10.449. [DOI] [PubMed]
- Yang, H., et al. (2018). The role of cellular reactive oxygen species in cancer chemotherapy. Journal of Experimental & Clinical Cancer Research, 37(1), 266. doi: 10.1186/s13046-018-0909-x. [DOI] [PMC free article] [PubMed]
- Piao, L. S., et al. (2012). CD133+ liver cancer stem cells modulate radioresistance in human hepatocellular carcinoma. Cancer Letters, 315(2), 129–137. doi: 10.1016/j.canlet.2011.10.012. [DOI] [PubMed]
- Gomez-Casal, R., et al. (2013). Non-small cell lung cancer cells survived ionizing radiation treatment display cancer stem cell and epithelial-mesenchymal transition phenotypes. Molecular Cancer, 12(1), 94. doi: 10.1186/1476-4598-12-94. [DOI] [PMC free article] [PubMed]
- Collins, A. T., et al. (2005). Prospective identification of tumorigenic prostate cancer stem cells. Cancer Research, 65(23), 10946–10951. doi: 10.1158/0008-5472.CAN-05-2018. [DOI] [PubMed]
- Al-Hajj, M., et al. (2003). Prospective identification of tumorigenic breast cancer cells. Proceedings of the National Academy of Sciences of the United States of America, 100(7), 3983–3988. doi: 10.1073/pnas.0530291100. [DOI] [PMC free article] [PubMed]
- Dalerba, P., et al. (2007). Phenotypic characterization of human colorectal cancer stem cells. Proceedings of the National Academy of Sciences of the United States of America, 104(24), 10158–10163. doi: 10.1073/pnas.0703478104. [DOI] [PMC free article] [PubMed]
- Ishimoto, T., et al. (2011). CD44 variant regulates redox status in cancer cells by stabilizing the xCT subunit of system xc(-) and thereby promotes tumor growth. Cancer Cell, 19(3), 387–400. doi: 10.1016/j.ccr.2011.01.038. [DOI] [PubMed]
- Diehn, M., et al. (2009). Association of reactive oxygen species levels and radioresistance in cancer stem cells. Nature, 458(7239), 780–783. doi: 10.1038/nature07733. [DOI] [PMC free article] [PubMed]
- Schulz, A., et al. (2019). Cancer stem cells and radioresistance: DNA repair and beyond. Cancers (Basel), 11, 6. doi: 10.3390/cancers11060862. [DOI] [PMC free article] [PubMed]
- Park, J. K., et al. (2021). The heterogeneity of lipid metabolism in cancer. Advances in Experimental Medicine and Biology, 1311, https://doi.org/10.1007/978-3-030-65768-0_3 doi: 10.1007/978-3-030-65768-0_3. [DOI] [PMC free article] [PubMed]
- Sun, M., & Yang, Z. (2019). Metabolomic studies of live single cancer stem cells using mass spectrometry. Analytical Chemistry, 91(3), 2384–2391. doi: 10.1021/acs.analchem.8b05166. [DOI] [PMC free article] [PubMed]
- Gouw, A. M., et al. (2019). The MYC oncogene cooperates with sterol-regulated element-binding protein to regulate lipogenesis essential for neoplastic growth. Cell Metabolism, 30(3), 556–572. e5. doi: 10.1016/j.cmet.2019.07.012. [DOI] [PMC free article] [PubMed]
- Foster, D. W. (2012). Malonyl-CoA: The regulator of fatty acid synthesis and oxidation. The Journal of Clinical Investigation, 122(6), 1958–1959. doi: 10.1172/JCI63967. [DOI] [PMC free article] [PubMed]
- Begicevic, R. R., Arfuso, F., & Falasca, M. (2019). Bioactive lipids in cancer stem cells. World Journal of Stem Cells, 11(9), 693–704. doi: 10.4252/wjsc.v11.i9.693. [DOI] [PMC free article] [PubMed]
- Dang, C. V., Le, A., & Gao, P. (2009). MYC-induced cancer cell energy metabolism and therapeutic opportunities. Clinical Cancer Research, 15(21), 6479–6483. doi: 10.1158/1078-0432.CCR-09-0889. [DOI] [PMC free article] [PubMed]
- Le, A., & Dang, C. V. (2013). Studying Myc’s role in metabolism regulation. Methods in Molecular Biology, 1012, 213–219. doi: 10.1007/978-1-62703-429-6_14. [DOI] [PMC free article] [PubMed]
- Hanai, J. I., et al. (2013). ATP citrate lyase knockdown impacts cancer stem cells in vitro. Cell Death & Disease, 4, e696. doi: 10.1038/cddis.2013.215. [DOI] [PMC free article] [PubMed]
- Rios Garcia, M., et al. (2017). Acetyl-CoA carboxylase 1-dependent protein acetylation controls breast cancer metastasis and recurrence. Cell Metabolism, 26(6), 842–855. e5. doi: 10.1016/j.cmet.2017.09.018. [DOI] [PubMed]
- Corominas-Faja, B., et al. (2014). Chemical inhibition of acetyl-CoA carboxylase suppresses self-renewal growth of cancer stem cells. Oncotarget, 5(18), 8306–8316. doi: 10.18632/oncotarget.2059. [DOI] [PMC free article] [PubMed]
- Yasumoto, Y., et al. (2016). Inhibition of fatty acid synthase decreases expression of stemness markers in glioma stem cells. PLoS One, 11(1), e0147717. doi: 10.1371/journal.pone.0147717. [DOI] [PMC free article] [PubMed]
- Tracz-Gaszewska, Z., & Dobrzyn, P. (2019). Stearoyl-CoA desaturase 1 as a therapeutic target for the treatment of cancer. Cancers (Basel), 11, 7. doi: 10.3390/cancers11070948. [DOI] [PMC free article] [PubMed]
- Gruenbacher, G., & Thurnher, M. (2018). Mevalonate metabolism in cancer stemness and trained immunity. Frontiers in Oncology, 8, 394. doi: 10.3389/fonc.2018.00394. [DOI] [PMC free article] [PubMed]
- Chen, C. L., et al. (2016). NANOG metabolically reprograms tumor-initiating stem-like cells through tumorigenic changes in oxidative phosphorylation and fatty acid metabolism. Cell Metabolism, 23(1), 206–219. doi: 10.1016/j.cmet.2015.12.004. [DOI] [PMC free article] [PubMed]
- Kuo, C. Y., & Ann, D. K. (2018). When fats commit crimes: Fatty acid metabolism, cancer stemness and therapeutic resistance. Cancer Communications (Lond), 38(1), 47. doi: 10.1186/s40880-018-0317-9. [DOI] [PMC free article] [PubMed]
- Hoang, G., Udupa, S., & Le, A. (2019). Application of metabolomics technologies toward cancer prognosis and therapy. International Review of Cell and Molecular Biology, 347, 191–223. doi: 10.1016/bs.ircmb.2019.07.003. [DOI] [PubMed]
