Cancer stem cells are cells within a tumor that can renew themselves and also produce the other, more differentiated cancer cells that make up the tumor, much as normal tissue stem cells renew a healthy tissue.[1] The term is defined by what a cell does in an experiment, not by how it looks: a cancer stem cell is one that can regrow the whole, mixed tumor, which is usually tested by transplanting sorted human cancer cells into immunodeficient mice and passing the resulting tumors on to further mice.[2] The name does not mean the cancer began in a stem cell. Cancer stem cells can arise from normal tissue stem cells or from more mature cells that have taken on stem-like properties.[3]
Cancer stem cells share the capability of self-renewal with normal stem cells, such as neural and other adult stem cells, but they sustain a tumor instead of maintaining a healthy tissue.[4] The idea matters for treatment: if a therapy shrinks a tumor but spares the cells able to regrow it, the cancer can come back, so removing cancer stem cells has been proposed as necessary for lasting remission.[4]
Stem Cells and Cancer – VIDEO
Two sets of experiments started the field. In 1997, researchers transplanted cells from people with acute myeloid leukemia into immunodeficient (NOD/SCID) mice. In every subtype they studied, the cells able to start the leukemia carried the marker CD34 and lacked CD38, the profile of primitive blood-forming cells, and they went on to produce the leukemic blasts, so the leukemia was organized as a hierarchy.[5] In 2003, the same approach was applied to breast cancer. In tumors from eight of nine patients, as few as 100 cells marked CD44-positive and CD24-negative or low formed new tumors in mice, while tens of thousands of cells with other markers did not. The new tumors again contained both tumor-forming cells and the mixed, non-tumor-forming cells of the original.[2] Since then, cancer stem cells have been reported in many tumor types.[1]
How Strong the Evidence Is
How many tumor-forming cells a cancer appears to contain depends on the test. Studies in standard NOD/SCID mice had suggested that only 0.1% to 0.0001% of human cancer cells could form tumors. In more severely immunodeficient mice, about 25% of unselected melanoma cells from 12 patients formed tumors, and in single-cell transplants an average of 27% of cells from four patients did so.[6] In melanoma under these conditions, tumor-forming cells are common rather than a rare subset.
Transplants take cells out of their natural setting, so researchers also label cells genetically and follow them inside tumors growing in their normal place in mice, a method called lineage tracing. In mouse intestinal adenomas, a precursor of bowel cancer, cells carrying the intestinal stem cell marker Lgr5 made up about 5% to 10% of the tumor and produced more Lgr5-positive cells as well as all the other adenoma cell types.[7] In a mouse model of glioblastoma, a relatively quiescent group of tumor cells regrew the tumor after the chemotherapy drug temozolomide had paused its growth, and removing those cells held tumor growth back.[8]
The same kind of experiment showed that the stem-like state can change. When Lgr5-positive cells were selectively removed from mouse colon tumors, the tumors stopped growing but did not shrink: Lgr5-negative cells kept replacing the lost stem cells, and growth restarted quickly once the treatment stopped. Lgr5-positive cells were needed to form and maintain liver metastases.[9] In human breast epithelial cells made cancerous in the laboratory, non-stem cancer cells converted on their own into stem-like cells, both in culture and in mice.[10] This plasticity is one reason cancer stem cells have proved harder to identify and eliminate than first hoped.[1]
Treatment Resistance and Recurrence
Most cancer drugs work by triggering apoptosis, the cell’s built-in program of self-destruction, and cancer stem cells are characteristically resistant to it.[4] Radiation gives a measured example. In glioblastoma cells from patients and from tumors grown in mice, studied in culture and in the brains of immunodeficient mice, cells carrying the marker CD133 survived radiation in greater proportions than other tumor cells, switched on their DNA damage checkpoints more strongly and repaired DNA damage more effectively. A drug that blocks the checkpoint kinases Chk1 and Chk2 reversed this resistance in those experiments.[11] The mouse glioblastoma study above showed a similar pattern after chemotherapy.[8]
Most of this evidence comes from laboratory and animal work. A 2025 systematic review of 23 experimental studies, covering glioblastoma and breast, pancreatic, liver, colorectal, lung, thyroid and blood cancers, found that cancer stem cells resisted chemotherapy and regrew tumors after treatment. Most of the studies were preclinical, they defined cancer stem cells in different ways, and few checked their findings in patients. The reviewers concluded that drugs aimed at a single target are unlikely to remove cancer stem cells for good, and that reliable markers of how many cancer stem cells a tumor contains are still needed.[12]
Cancer Stem Cell Metabolism
Many cancer cells take up large amounts of glucose and turn it into lactate even when oxygen is available, a pattern called aerobic glycolysis or the Warburg effect; intermediates of this pathway feed the building of new cell material.[13] Cancer stem cells follow no single rule. Their main energy pathway differs between tumor types, between patients and even between subclones of one tumor: some rely more on glycolysis, others on oxidative phosphorylation in the mitochondria,[13] and some can shift between the two.[14]
Two examples studied in human cells show why this matters. Human pancreatic cancer stem cells, studied in the laboratory and as tumors grown in mice, depended on mitochondrial respiration, while their more differentiated descendants were highly glycolytic. Blocking the mitochondria, for example with the diabetes drug metformin, killed the stem cells, but resistant clones with an intermediate metabolism eventually emerged.[15] In samples from people with acute myeloid leukemia, most leukemia stem cells had low levels of reactive oxygen species, made too much of the survival protein BCL-2 and depended on oxidative phosphorylation; blocking BCL-2 reduced their respiration and killed the quiescent stem cells in the laboratory.[16]
Other fuels are involved too. Glutamine can feed the mitochondrial energy cycle and supply building blocks for fatty acids and nucleotides.[13] Increased synthesis of lipids is a long-recognized feature of cancer tissue and has been linked to cancer cell migration, invasion and the growth of new blood vessels.[17]
A treatment used in leukemia shows what an effect on stem cell metabolism can look like in patients. In leukemia stem cells taken from older people with acute myeloid leukemia during treatment with venetoclax (a BCL-2 inhibitor) plus azacitidine, the combination disrupted the cells’ energy metabolism and suppressed oxidative phosphorylation, and the researchers proposed that this explains part of the clinical benefit.[18] In the phase III VIALE-A trial, 431 previously untreated patients who could not have intensive chemotherapy, because they were 75 or older or had other illnesses, were randomized. Median overall survival was 14.7 months with azacitidine plus venetoclax and 9.6 months with azacitidine plus placebo; febrile neutropenia and infections were more common with the combination.[19] Venetoclax is approved in the United States, with azacitidine, decitabine or low-dose cytarabine, for newly diagnosed acute myeloid leukemia in adults aged 75 or older or with other illnesses that rule out intensive chemotherapy.[20] Other metabolism-based approaches to cancer stem cells, including metformin and other mitochondrial inhibitors, are still being tested in laboratories and early clinical studies.[13]
Drugs Designed Against Cancer Stem Cells
Napabucasin, an oral drug first developed as a “cancer stemness inhibitor” acting on the STAT3 pathway and later described as a generator of reactive oxygen species, has been tested in several large randomized trials.[21][22] It did not improve survival in any of these phase III trials:
| Trial | Cancer | Patients | Median overall survival | Result |
|---|---|---|---|---|
| CanStem303C, napabucasin plus FOLFIRI chemotherapy or FOLFIRI alone | Metastatic colorectal cancer, after first-line treatment | 1,253 | 14.3 vs 13.8 months | No improvement[22] |
| CanStem111P, napabucasin plus nab-paclitaxel and gemcitabine, or the chemotherapy alone | Untreated metastatic pancreatic cancer | 1,134 | 11.4 vs 11.7 months | Stopped for futility[23] |
| BRIGHTER, napabucasin or placebo, both with paclitaxel | Advanced gastric or gastroesophageal junction cancer, after earlier treatment | 714 | 6.93 vs 7.36 months | No difference[24] |
| Napabucasin or placebo, with supportive care | Advanced colorectal cancer after all standard treatments | 282 | 4.4 vs 4.8 months | Stopped for futility[21] |
In each trial, severe diarrhea was more common with napabucasin than without it.[22][23][24][21] Cancer stem cell research has not produced a treatment that replaces standard cancer care. Treatment is chosen with an oncologist according to the type of cancer, its stage and its molecular features, and a clinical trial is the way to receive an experimental approach.
Published Clinical Citations
[1] ^ Batlle E, Clevers H. Cancer stem cells revisited. Nature Medicine. 2017;23(10):1124-1134. https://doi.org/10.1038/nm.4409
[2] ^ Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF. Prospective identification of tumorigenic breast cancer cells. Proceedings of the National Academy of Sciences of the United States of America. 2003;100(7):3983-3988. https://doi.org/10.1073/pnas.0530291100
[3] ^ Walcher L, Kistenmacher AK, Suo H, et al. Cancer stem cells: origins and biomarkers. Perspectives for targeted personalized therapies. Frontiers in Immunology. 2020;11:1280. https://doi.org/10.3389/fimmu.2020.01280
[4] ^ Fulda S. Regulation of apoptosis pathways in cancer stem cells. Cancer Letters. 2013;338(1):168-173. https://doi.org/10.1016/j.canlet.2012.03.014
[5] ^ Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nature Medicine. 1997;3(7):730-737. https://doi.org/10.1038/nm0797-730
[6] ^ Quintana E, Shackleton M, Sabel MS, Fullen DR, Johnson TM, Morrison SJ. Efficient tumour formation by single human melanoma cells. Nature. 2008;456(7222):593-598. https://doi.org/10.1038/nature07567
[7] ^ Schepers AG, Snippert HJ, Stange DE, et al. Lineage tracing reveals Lgr5+ stem cell activity in mouse intestinal adenomas. Science. 2012;337(6095):730-735. https://doi.org/10.1126/science.1224676
[8] ^ Chen J, Li Y, Yu TS, et al. A restricted cell population propagates glioblastoma growth after chemotherapy. Nature. 2012;488(7412):522-526. https://doi.org/10.1038/nature11287
[9] ^ de Sousa e Melo F, Kurtova AV, Harnoss JM, et al. A distinct role for Lgr5+ stem cells in primary and metastatic colon cancer. Nature. 2017;543(7647):676-680. https://doi.org/10.1038/nature21713
[10] ^ Chaffer CL, Brueckmann I, Scheel C, et al. Normal and neoplastic nonstem cells can spontaneously convert to a stem-like state. Proceedings of the National Academy of Sciences of the United States of America. 2011;108(19):7950-7955. https://doi.org/10.1073/pnas.1102454108
[11] ^ Bao S, Wu Q, McLendon RE, et al. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature. 2006;444(7120):756-760. https://doi.org/10.1038/nature05236
[12] ^ Barjij I, Meliani M. Cancer stem cells and post-therapy tumour recurrence: a systematic review of mechanistic pathways and translational gaps. ecancermedicalscience. 2025;19:2016. https://doi.org/10.3332/ecancer.2025.2016
[13] ^ Jagust P, de Luxán-Delgado B, Parejo-Alonso B, Sancho P. Metabolism-based therapeutic strategies targeting cancer stem cells. Frontiers in Pharmacology. 2019;10:203. https://doi.org/10.3389/fphar.2019.00203
[14] ^ Zhu X, Chen HH, Gao CY, et al. Energy metabolism in cancer stem cells. World Journal of Stem Cells. 2020;12(6):448-461. https://doi.org/10.4252/wjsc.v12.i6.448
[15] ^ Sancho P, Burgos-Ramos E, Tavera A, et al. MYC/PGC-1α balance determines the metabolic phenotype and plasticity of pancreatic cancer stem cells. Cell Metabolism. 2015;22(4):590-605. https://doi.org/10.1016/j.cmet.2015.08.015
[16] ^ Lagadinou ED, Sach A, Callahan K, et al. BCL-2 inhibition targets oxidative phosphorylation and selectively eradicates quiescent human leukemia stem cells. Cell Stem Cell. 2013;12(3):329-341. https://doi.org/10.1016/j.stem.2012.12.013
[17] ^ Baenke F, Peck B, Miess H, Schulze A. Hooked on fat: the role of lipid synthesis in cancer metabolism and tumour development. Disease Models & Mechanisms. 2013;6(6):1353-1363. https://doi.org/10.1242/dmm.011338
[18] ^ Pollyea DA, Stevens BM, Jones CL, et al. Venetoclax with azacitidine disrupts energy metabolism and targets leukemia stem cells in patients with acute myeloid leukemia. Nature Medicine. 2018;24(12):1859-1866. https://doi.org/10.1038/s41591-018-0233-1
[19] ^ DiNardo CD, Jonas BA, Pullarkat V, et al. Azacitidine and venetoclax in previously untreated acute myeloid leukemia. New England Journal of Medicine. 2020;383(7):617-629. https://doi.org/10.1056/NEJMoa2012971
[20] ^ US Food and Drug Administration. VENCLEXTA (venetoclax) prescribing information, indications and usage (label effective 20 May 2026); Drugs@FDA application NDA208573. https://www.accessdata.fda.gov/scripts/cder/daf/
[21] ^ Jonker DJ, Nott L, Yoshino T, et al. Napabucasin versus placebo in refractory advanced colorectal cancer: a randomised phase 3 trial. The Lancet Gastroenterology & Hepatology. 2018;3(4):263-270. https://doi.org/10.1016/S2468-1253(18)30009-8
[22] ^ Shah MA, Yoshino T, Tebbutt NC, et al. Napabucasin plus FOLFIRI in patients with previously treated metastatic colorectal cancer: results from the open-label, randomized phase III CanStem303C study. Clinical Colorectal Cancer. 2023;22(1):100-110. https://doi.org/10.1016/j.clcc.2022.11.002
[23] ^ Bekaii-Saab T, Okusaka T, Goldstein D, et al. Napabucasin plus nab-paclitaxel with gemcitabine versus nab-paclitaxel with gemcitabine in previously untreated metastatic pancreatic adenocarcinoma: an adaptive multicentre, randomised, open-label, phase 3, superiority trial. eClinicalMedicine. 2023;58:101897. https://doi.org/10.1016/j.eclinm.2023.101897
[24] ^ Shah MA, Shitara K, Lordick F, et al. Randomized, double-blind, placebo-controlled phase III study of paclitaxel with or without napabucasin in pretreated advanced gastric or gastroesophageal junction adenocarcinoma. Clinical Cancer Research. 2022;28(17):3686-3694. https://doi.org/10.1158/1078-0432.CCR-21-4021