Advances in cancer research in the past have led to an evolving understanding of cancer pathogenesis and the development of novel drugs that significantly improve patient outcomes. However, many patients still encounter treatment resistance, recurrence, or metastasis and eventually die from progressing disease. Experimental evidence indicates that a subpopulation of cancer cells, called cancer stem cells (CSCs), possess “stemness” properties similar to normal stem cells, including self-renewal, differentiation, and proliferative potential. These stemness properties are lost during differentiation and are governed by pathways such as STAT3, NANOG, NOTCH, WNT, and HEDGEHOG, which are highly dysregulated in CSCs due to genetic and epigenetic changes. Promising results have been observed in preclinical models targeting these CSCs through the disruption of stemness pathways in combination with current treatment modalities. This has led to anti-CSC–based clinical trials in multiple stages of development. In this review, we discuss the role of CSCs and stemness pathways in cancer treatment and how they relate to clinical observations. Because CSCs and the stemness pathways governing them may explain the negative clinical outcomes observed during treatment, it is important for oncologists to understand how they contribute to cancer progression and how they may be targeted to improve patient outcomes.
Julius Cohnheim: (1839-1884) experimental pathologist. JAMA. 1968;206:1561–2.
Mackillop WJ, Ciampi A, Till JE, Buick RN. A stem cell model of human tumor growth: implications for tumor cell clonogenic assays. J Natl Cancer Inst. 1983;70:9–16. PubMed
Pierce GB, Speers WC. Tumors as caricatures of the process of tissue renewal: prospects for therapy by directing differentiation. Cancer Res. 1988;48:1996–2004. PubMed
Ailles LE, Gerhard B, Kawagoe H, Hogge DE. Growth characteristics of acute myelogenous leukemia progenitors that initiate malignant hematopoiesis in non-obese diabetic/severe combined immunodeficient mice. Blood. 1999;94:1761–72. PubMed
Agliano A, Calvo A, Box C. The challenge of targeting cancer stem cells to halt metastasis. Semin Cancer Biol. 2017.
Machle AH. Ambiguous cells: the emergence of the stem cell concept in the nineteenth and twentieth centuries. Notes Rec R Soc Lond. 2011;65:359–78. CrossRef
Kummermehr J, Trott K-R. Stem Cells. In: Potten CS, editor. Tumor stem cells. London: Academic Press; 1997. p. 363–400. CrossRef
Potten CS. Stem cells in gastrointestinal epithelium: numbers, characteristics and death. Philos Trans R Soc Lond Ser B Biol Sci. 1998;353:821–30. CrossRef
Falzacappa MV, Ronchini C, Reavie LB, Pelicci PG. Regulation of self-renewal in normal and cancer stem cells. FEBS J. 2012;279:3559–72. CrossRef
National Institutes of Health. Stem cell basics. https://stemcells.nih.gov/sites/default/files/SCprimer2009.pdf. Accessed 15 March 2017.
Laplane L. Cancer stem cells: philosophy and therapies. Cambridge: Harvard University Press; 2016. CrossRef
Boman BM, Fields JZ, Cavanaugh KL, Gujetter A, Runquist OA. How dysregulated colonic crypt dynamics cause stem cell overpopulation and initiate colon cancer. Cancer Res. 2008;6:3304–13. CrossRef
Vathipadieka V, Saxena D, Mok SC, Hauschka PV, Ozbun L, Birrer MJ. Identification of a potential ovarian cancer stem cell gene expression profile from advanced stage papillary serous ovarian cancer. PLoS One. 2012;7:e29079. CrossRef
Boman BM, Wicha M, Fields JZ, Runquist O. Symmetric division of cancer stem cells: a key mechanism in tumor growth that should be targeted in future therapeutic approaches. J Clin Pharmacol Ther. 2007;81:893–8. CrossRef
Jarrar A, Chumakova A, Hitomi M, Lathia J. Enrichment and interrogation of cancer stem cells. In: Liu H, Lathia J, editors. Cancer stem cells: targeting the roots of cancer, seeds of metastasis, and sources of therapy resistance. 1st ed. London: Academic Press; 2016. p. 59–100. CrossRef
Ajani JA, Song S, Hochster HS, Steinberg IB. Cancer stem cells: the promise and the potential. Semin Oncol. 2015;(Suppl 1):S3–17.
Chen S, Fisher RC, Signs S, Molina LA, Shenoy AK, Lopez MC, et al. Inhibition of PI3K/Akt/mTOR signaling in PI3KR2-overexpressing colon cancer stem cells reduces tumor growth due to apoptosis. Oncotarget. 2016.
Dawood S, Austin L, Cristofanilli M. Cancer stem cells: implications for cancer therapy. Oncology. 2014;28:1101–7. PubMed
Habu N, Imanishi Y, Kameyama K, Shimoda M, Tokumaru Y, Sakamoto K, et al. Expression of Oct3/4 and Nanog in the head and neck squamous carcinoma cells and its clinical implications for delayed neck metastasis in stage I/II oral tongue squamous cell carcinoma. BMC Cancer. 2015;15:730. PubMedPubMedCentralCrossRef
Hoey T, Yen WC, Axelrod F, Basi J, Donigian L, Dylla S, et al. DLL4 blockade inhibits tumor growth and reduces tumor-initiating cell frequency. Cell Stem Cell. 2009;5:168–77.
Fabregat I, Malfettone A, Soukupova J. New insights into the crossroads between EMT and stemness in the context of cancer. J Clin Med. 2016;5:1–12. CrossRef
Liu S, Cong Y, Wang D, Sun Y, Deng L, Liu Y, et al. Breast cancer stem cells transition between epithelial and mesenchymal states reflective of their normal counterparts. Stem Cell Rep. 2013;2(1):78–91. CrossRef
Tu Z, Xie S, Xiong M, Liu Y, Yang X, Tembo KM, et al. CXCR4 is involved in CD133-induced EMT in non-small cell lung cancer. Int J Oncol. 2017;50(2):505–514.91. PubMed
Oliva CR, Zhang W, Langford C, Suto MJ, Griguer CE. Repositioning chlorpromazine for treating chemoresistant glioma through the inhibition of cytochrome c oxidase bearing the COX4–1 regulatory subunit. Oncotarget. 2017;8(23):37568–83.
Warmann S, Hunger M, Teichmann B, Flemming P, Gratz KF, Fuchs J. The role of the MDR1 gene in the development of multidrug resistance in human hepatoblastoma: clinical course and in vivo model. Cancer. 2002:951795–801.
Nishikawa S, Konno M, Hamabe A, Hasegawa S, Kano Y, Ohta K, et al. Aldehyde dehydrogenase high gastric cancer stem cells are resistant to chemotherapy. Int J Oncol. 2013;42:1437–42. PubMed
Rao CV, Mohammed A. New insights into pancreatic cancer stem cells. World J Gastroenterol. 2015;7:547–55.
Dallas NA, Xia L, Fan F, Gray MJ, Gaur P, van Buren G, et al. Chemoresistant colorectal cancer cells, the cancer stem cell phenotype, and increased sensitivity to insulin-like growth factor-I receptor inhibition. Cancer Res. 2009;69:1951–7.
Xie Q, Liang J, Rao Q, Xie X, Li R, Liu Y, et al. Aldehyde dehydrogenase 1 expression predicts chemoresistance and poor clinical outcomes in patients with locally advanced cervical cancer treated with neoadjuvant chemotherapy prior to radical hysterectomy. Ann Surg Oncol. 2016;23:163–70. PubMedCrossRef
Qu Q, Liu L, Zhang Y, Li X, Wu D. Increasing aclarubicin dosage of the conventional CAG (low-dose cytarabine and aclarubicin in combination with granulocyte colony-stimulating factor) regimen is more efficacious as a salvage therapy than CAG for relapsed/refractory acute myeloid leukemia. Leuk Res. 2015;39(12):1353–9. PubMedCrossRef
Pabst T, Vellenga E, van Putten W, Schouten HC, Graux C, Vekemans MC, et al. Dutch-Belgian Hemato-oncology cooperative Group (HOVON); German AML study Group (AMLSG); Swiss collaborative Group for Clinical Cancer Research (SAKK) favorable effect of priming with granulocyte colony-stimulating factor in remission induction of acute myeloid leukemia restricted to dose escalation of cytarabine. Blood. 2012;119:5367–73. PubMedCrossRef
Jia Y, Chen J, Zhu H, Jia ZH, Cui MH. Aberrantly elevated redox sensing factor Nrf2 promotes cancer stem cell survival via enhanced transcriptional regulation of ABCG2 and Bcl-2/Bmi-1 genes. Oncol Rep. 2015;34(5):2296–304. PubMed
Han L, Shi S, Gong T, Zhang Z, Sun X. Cancer stem cells: therapeutic implications and perspectives in cancer therapy. Acta Pharm Sin B. 2013;3:65–75. CrossRef
Eun K, Ham SW, Kim H. Cancer stem cell heterogeneity: origin and new perspectives on CSC targeting. BMB Rep. 2017;50(3):117–125.
Rimkus TK, Carpenter RL, Qasem S, Chan M, Lo HW. Targeting the sonic hedgehog signaling pathway: review of smoothened and GLI inhibitors. Cancers (Basel). 2016;8(2).
Iliopoulos D, Lindahl-Allen M, Polytarchou C, Hirsch HA, Tsichlis PN, Struhl K, et al. Loss of miR-200 inhibition of Suz12 leads to polycomb-mediated repression required for the formation and maintenance of cancer stem cells. Mol Cell. 2010;39:761–72.
- Overview of Cancer Stem Cells and Stemness for Community Oncologists
Justin D. Lathia
- Springer International Publishing
Neu im Fachgebiet Onkologie
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