Adult human mesenchymal stem cell as a target for neoplastic transformation
Abstract
The neoplastic process may involve a cancer stem cell. This concept has emerged largely from the careful analysis of tumour biopsy systems from haematological, breast and brain tumours. However, the experimental systems necessary to provide the cellular and molecular evidence to support this important concept have been lacking. We have used adult mesenchymal stem cells (hMSC) transduced with the telomerase hTERT gene to investigate the neoplastic potential of adult stem cells. The hTERT-transduced line, hMSC-TERT20 at population doubling level (PDL) 256 showed loss of contact inhibition, anchorage independence and formed tumours in 10/10 mice. hMSC-TERT4 showed loss of contact inhibition at PDL 95, but did not exhibit anchorage independence and did not form tumours in mice. Both lines had a normal karyotype but showed deletion of the Ink4a/ARF locus. At later passage, hMSC-TERT4 also acquired an activating mutation in KRAS. In hMSC-TERT20, expression of the cell cycle-associated gene, DBCCR1 was lost due to promoter hypermethylation. This epigenetic event correlated with acquisition of tumorigenicity. These data suggest that the adult hMSCs can be targets for neoplastic transformation and have implications for the development of novel anticancer therapeutics and for the use of hMSC in tissue engineering and transplantation protocols.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The ability of stem cells to undergo senescence (and apoptosis) appears to be an important mechanism for preventing cancer.
“Whatever the case, the ability of stem cells to undergo senescence (and apoptosis, for that matter) appears to be an important mechanism for preventing cancer (Boulanger and Smith, 2001; Serakinci et al., 2004).”
From Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors (2005) · cites this paper as Serakinci et al., 2004
Cites
1 retracted
RETRACTED ARTICLE: Pluripotency of mesenchymal stem cells derived from adult marrow
Jiang, Y., Jahagirdar, B., Reinhardt, R. L., Schwartz, R. E., Keene, C. D., Ortiz-Gonzalez, X. R., Reyes, M., Lenvik, T. R., Lund, T. C., Blackstad, M., et al. (2002) · Nature · doi:10.1038/nature00870 · Cited by 5,523 · see citing works
RetractedProspective identification of tumorigenic breast cancer cells
Al‐Hajj, M., Wicha, M. S., Benito‐Hernández, A., Morrison, S. J., & Clarke, M. F. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0530291100 · Cited by 10,388 · see citing works
Stem cells, cancer, and cancer stem cells
Reya, T., Morrison, S. J., Clarke, M. F., & Weissman, I. L. (2001) · Nature · doi:10.1038/35102167 · Cited by 9,738 · see citing works
Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells.
Park, I.-K., Qian, D., Kiel, M., Becker, M. W., Pihalja, M., Weissman, I. L., Morrison, S. J., & Clarke, M. F. (2003) · Nature · doi:10.1038/nature01587 · Cited by 1,871 · see citing works
Cancerous stem cells can arise from pediatric brain tumors
Hemmati, H. D., Nakano, I., Lazareff, J. A., Masterman-Smith, M. D., Geschwind, D. H., Bronner-Fraser, M. E., & Kornblum, H. I. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2036535100 · Cited by 1,801 · see citing works
Bmi-1 determines the proliferative capacity of normal and leukaemic stem cells.
Lessard, J., & Sauvageau, G. (2003) · Nature · doi:10.1038/nature01572 · Cited by 1,452 · see citing works
Kiyono, T., Foster, S. A., Koop, J. I., McDougall, J. K., Galloway, D. A., & Klingelhutz, A. J. (1998) · Nature · doi:10.1038/23962 · Cited by 1,206 · cited 1× · see citing works
“…suggest that ectopic expression of hTERT alone or in combination with inactivation of either the p53/p21CIP/WAF1 or the pRB/p16INK4a pathways will result in immortalization, without the acquisition of a tumorigenic phenotype (Kiyono et al., 1998; Hahn and Weinberg, 2002; Lundberg et al., 2002).”
BackgroundRules for Making Human Tumor Cells
Hahn, W. C., & Weinberg, R. A. (2002) · New England Journal of Medicine · doi:10.1056/nejmra021902 · Cited by 951 · see citing works
Simonsen, J. L., Rosada, C., Serakıncı, N., Justesen, J., Stenderup, K., Rattan, S. I. S., Jensen, T. G., & Kassem, M. S. (2002) · Nature Biotechnology · doi:10.1038/nbt0602-592 · Cited by 806 · see citing works
Self-citationAdult Stem Cells for Tissue Repair — A New Therapeutic Concept?
Korbling, M. J., & Estrov, Z. E. (2003) · New England Journal of Medicine · doi:10.1056/nejmra022361 · Cited by 798 · see citing works
Passegue, E. A., Jamieson, C. H. M., Ailles, L., & Weissman, I. L. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2034201100 · Cited by 685 · see citing works
Mechanisms of sarcoma development
Helman, L. J., & Meltzer, P. S. (2003) · Nature reviews. Cancer · doi:10.1038/nrc1168 · Cited by 460 · see citing works
Shi, S., Gronthos, S., Chen, S., Reddi, A. H., Counter, C. M., Robey, P. G., & Wang, C.-Y. (2002) · Nature Biotechnology · doi:10.1038/nbt0602-587 · Cited by 375 · see citing works
Contribution of stem cells and differentiated cells to epidermal tumours
Owens, D. M., & Watt, F. M. (2003) · Nature reviews. Cancer · doi:10.1038/nrc1096 · Cited by 346 · see citing works
Breast cancer stem cells revealed
Dick, J. E. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0830967100 · Cited by 320 · see citing works
Stem-cell hierarchy in skin cancer
Pérez‐Losada, J., & Balmain, A. (2003) · Nature reviews. Cancer · doi:10.1038/nrc1095 · Cited by 270 · see citing works
Immortalization and transformation of primary human airway epithelial cells by gene transfer
Lundberg, A., Randell, S., Stewart, S. A., Elenbaas, B., Hartwell, K. A., Brooks, M., Fleming, M., Olsen, J., Miller, S., Weinberg, R., et al. (2002) · Oncogene · doi:10.1038/sj.onc.1205550 · Cited by 267 · see citing works
The new stem cell biology: something for everyone
Preston, S. L., Alison, M. R., Forbes, S. J., Direkze, N. C., Poulsom, R., & Wright, N. A. (2003) · Molecular Pathology · doi:10.1136/mp.56.2.86 · Cited by 158 · see citing works
Telomerase activation, cellular immortalization and cancer
Hahn, W. C., & Meyerson, M. M. (2001) · Annals of Medicine · doi:10.3109/07853890109002067 · Cited by 141 · see citing works
Risky immortalization by telomerase
Wang, J., Hannon, G. J., & Beach, D. (2000) · Nature · doi:10.1038/35015674 · Cited by 133 · see citing works
Mackall, C. L., Meltzer, P. S., & Helman, L. J. (2002) · Cancer Cell · doi:10.1016/s1535-6108(02)00132-0 · Cited by 95 · see citing works
Grønbæk, K., Brown, P. D. N., Møller, M. B., Nedergaard, T., Ralfkiaer, E. M., Mӧller, P., Zeuthen, J., & Guldberg, P. (2000) · Leukemia · doi:10.1038/sj.leu.2401901 · Cited by 79 · see citing works
Self-citationNegative regulation of G1/S transition by the candidate bladder tumour suppressor gene DBCCR1
Nishiyama, H., Gill, J. H., Pitt, E., Kennedy, W., & Knowles, M. A. (2001) · Oncogene · doi:10.1038/sj.onc.1204432 · Cited by 59 · see citing works
Collas, P., & Håkelien, A.-M. (2003) · Trends in biotechnology · doi:10.1016/s0167-7799(03)00147-1 · Cited by 53 · see citing works
Hamad, N. M., Banik, S. S. R., & Counter, C. M. (2002) · Oncogene · doi:10.1038/sj.onc.1205860 · Cited by 28 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors
Campisi, J. (2005) · Cell · doi:10.1016/j.cell.2005.02.003 · Cited by 2,359 · see citing works
A tumorigenic subpopulation with stem cell properties in melanomas
Fang, D., Nguyen, T. K., Leishear, K., Finko, R., Kulp, A. N., Hotz, S., Van Belle, P. A., Xu, X., Elder, D. E., & Herlyn, M. (2005) · Cancer Research · doi:10.1158/0008-5472.can-05-1343 · Cited by 1,280 · see citing works
Human mesenchymal stem cells exert potent antitumorigenic effects in a model of Kaposi's sarcoma
Khakoo, A. Y., Pati, S., Anderson, S. A., Reid, W., Elshal, M. F., Rovira, I. I., Nguyen, A. T., Malide, D., Combs, C. A., Hall, G., et al. (2006) · The Journal of Experimental Medicine · doi:10.1084/jem.20051921 · Cited by 747 · see citing works
Tumor microenvironment: The role of the tumor stroma in cancer
Li, H., Fan, X., & Houghton, J. (2007) · Journal of Cellular Biochemistry · doi:10.1002/jcb.21159 · Cited by 646 · see citing works
Hypoxia enhances proliferation and tissue formation of human mesenchymal stem cells
Grayson, W. L., Zhao, F., Bunnell, B., & Ma, T. (2007) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2007.05.054 · Cited by 521 · see citing works
Ebert, R., Ulmer, M., Zeck, S., Meissner‐Weigl, J., Schneider, D., Stopper, H., Schupp, N., Kassem, M., & Jakob, F. (2006) · STEM CELLS · doi:10.1634/stemcells.2005-0117 · Cited by 200 · see citing works
Self-citationMesenchymal Stem Cells in Cancer: Tumor-Associated Fibroblasts and Cell-Based Delivery Vehicles
Hall, B., Dembinski, J., Sasser, A., Studeny, M., Andreeff, M., & Marini, F. (2007) · International Journal of Hematology · doi:10.1532/ijh97.06230 · Cited by 171 · see citing works
Armstrong, L., Saretzki, G., Peters, H., Wappler, I., Evans, J., Hole, N., von Zglinicki, T., & Lako, M. (2005) · Stem Cells · doi:10.1634/stemcells.2004-0269 · Cited by 153 · see citing works
Immune properties of mesenchymal stem cells
Sotiropoulou, P. A., & Papamichail, M. (2007) · Methods in Molecular Biology · doi:10.1007/978-1-59745-536-7_16 · Cited by 57 · see citing works
- Authors
- Serakinci, N., Guldberg, P., Burns, J. S., Abdallah, B., Schrødder, H., Jensen, T., & Kassem, M.
- Affiliations
- Danish Cancer Society (DK)
- Odense University Hospital (DK)
- Aarhus University (DK)
- Venue
- Oncogene
- Published
- 2004-04-26
- Volume
- 23
- Issue
- 29
- Pages
- 5095-5098
- ISSN
- 0950-9232 (ISSN-L)
- 1476-5594
- OpenAlex
- W2145099626
- Cited by
- 350
- References
- 25
- Citations by year
- 2026: 3 · 2025: 6 · 2024: 7 · 2023: 6 · 2022: 1 · 2021: 4 · 2020: 7 · 2019: 5 · 2018: 7 · 2017: 4 · 2016: 7 · 2015: 13 · 2014: 20 · 2013: 10 · 2012: 27
- FWCI
- 21.50
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Oncogene (publishedVersion)
- PubMed (publishedVersion)
- University of Southern Denmark Research Portal (University of Southern Denmark) (submittedVersion)
- Institutional Research Information System University of Ferrara (University of Ferrara) (submittedVersion)
- Funders
- Sundhed og Sygdom, Det Frie Forskningsråd
- Novo Nordisk Fonden
- Topics
- Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Keywords
- oncogenic transformation, cancer stem cells, tumorigenicity, anchorage-independent growth, KRAS mutation, promoter hypermethylation, epigenetic silencing
- MeSH terms
- Adult, Cell Line, Cell Transformation, Neoplastic, DNA-Binding Proteins, Humans, Mutation, Transduction, Genetic, Telomerase, Mesenchymal Stem Cells
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
