Hallmarks of Immortality: Defining the Properties of Normal and Cancer-initiating Stem Cells
Posted August 10, 2007
Virtually all cancers are believed to arise from a single faulty cell. But the notion that any cell can be mutated to give rise to new tumors has been replaced by the idea that only a subset of cells, those with self-renewing properties, has the paradoxical effect of conferring immortality to the tumor at the same time they threaten the life of their host organism.
A March 29, 2007, meeting of the Academy's Cancer & Signaling Discussion Group addressed various aspects of the stem cell–cancer connection. John Dick, who hypothesized the existence of leukemia stem cells in the 1990s, looked at CD44 as a possible protein marker that could help identify and target cancer stem cells within a tumor cell population. Michael Clarke presented evidence that high CSC concentrations correlate with higher mortality, and described the role of Bmi-1 in regulating stem cell renewal. Erica Herzog discussed the mechanism for the emergence of marrow-derived epithelial cells, which could prove to be a fruitful target for cancer prevention or treatment. David Scadden explained how pharmacologically altering a cancer stem cell's niche, the microenvironment that supports it, might provide a novel therapeutic approach.
Use the tabs above to find a meeting report and multimedia from this event.
International Society for Stem Cell Research
The ISSCR is an independent, nonprofit organization established to promote and foster the exchange and dissemination of information and ideas relating to stem cells, to encourage the general field of research involving stem cells, and to promote professional and public education in all areas of stem cell research and application.
Krause Lab at Yale Medical School
The Krause lab Web site describes their research on characterizing hematopoietic stem and progenitor cells, and defining the molecular mechanisms that regulate the self-renewal and differentiation of these cells.
Leukemia and Lymphoma Society
The Leukemia and Lymphoma Society Web site has basic information about these diseases as well as information about clinical trials and information for researchers in the field.
Boman BM, Fields JZ, eds. 2007. Stem Cell Basis of Cancer: Tumorigenesis and Drug Development. Humana Press, Totowa, NJ.
Parsons DW, ed. 2007. Stem Cells and Cancer. Nova Science Publishers, Hauppauge, New York.
Wiestler OD, Haendler B, Mumberg D, eds. 2007. Cancer Stem Cells: Novel Concepts and Prospects for Tumor Therapy (Ernst Schering Foundation Symposium Proceedings). Springer, Berlin.
Cancer-initiating Cells: From Leukemia to Solid Tumors
Dick JE, Lapidot T. 2005. Biology of normal and acute myeloid leukemia stem cells.Int J Hematol. 82: 389-396.
Jin L, Hope KJ, Zhai Q, et al. 2006. Targeting of CD44 eradicates human acute myeloid leukemic stem cells. Nat. Med. 12: 1167-1174.
Ornatsky O, Baranov VI, Bandura DR, et al. 2006. Multiple cellular antigen detection by ICP-MS. J. Immunol. Methods 308: 68-76.
Wang JC, Warner JK, Erdmann N, et al. 2005. Dissociation of telomerase activity and telomere length maintenance in primitive human hematopoietic cells. Proc. Natl. Acad. Sci. USA 102: 14398-14403. Full Text
Warner JK, Wang JC, Takenaka K, et al. 2005. Direct evidence for cooperating genetic events in the leukemic transformation of normal human hematopoietic cells. Leukemia 19: 1794-1805.
Molecular Mechanisms Regulating Stem Cell Self-Renewal
Diehn M, Clarke MF. 2006. Cancer stem cells and radiotherapy: new insights into tumor radioresistance. J. Natl. Cancer Inst. 98: 1755-1757.
Hosen N, Yamane T, Muijtjens M, et al. 2007. Bmi-1-green fluorescent protein (GFP)-knock-in mice reveal the dynamic regulation of Bmi-1 expression in normal and leukemic hematopoietic cells. Stem Cells Mar 29; [Epub ahead of print]
Li C, Heidt DG, Dalerba P, et al. 2007. Identification of pancreatic cancer stem cells. Cancer Res. 67: 1030-1037.
Liu TX, Becker MW, Jelinek J, et al. 2007. Chromosome 5q deletion and epigenetic suppression of the gene encoding alpha-catenin (CTNNA1) in myeloid cell transformation. Nat. Med. 13: 78-83.
Prince ME, Sivanandan R, Kaczorowski A, et al. 2007. Identification of a subpopulation of cells with cancer stem cell properties in head and neck squamous cell carcinoma. Proc. Natl. Acad. Sci. USA 104: 973-978.
Bone Marrow Derived Lung Epithelium Following BMT and Pneumonitis
Harris RG, Herzog EL, Bruscia EM, et al. 2004. Lack of a fusion requirement for development of bone marrow-derived epithelia. Science 305: 90-93.
Herzog EL, Chai L, Krause DS. 2003. Plasticity of marrow-derived stem cells. Blood 102: 3483-3493. Full Text
Herzog EL, Krause DS. 2006. Engraftment of marrow-derived epithelial cells: the role of fusion. Proc. Am. Thorac. Soc. 3: 691-695. Full Text
Cancer and the Niche Hypothesis
Adams GB, Martin RP, Alley IR et al. 2007. Therapeutic targeting of a stem cell niche. Nat. Biotechnol. 25: 238-243.
Scadden DT. 2007. The stem cell niche in health and leukemic disease. Best Pract. Res. Clin. Haematol. 20: 19-27.
Wang ZZ, Au P, Chen T, et al. 2007. Endothelial cells derived from human embryonic stem cells form durable blood vessels in vivo. Nat. Biotechnol. 25: 317-318.
Zhang J, Scadden DT, Crumpacker CS. 2007. Primitive hematopoietic cells resist HIV-1 infection via p21. J. Clin. Invest. 117: 473-481.
John E. Dick, PhD
John Dick is the Canada Research Chair in Stem Cell Biology and director of the Program in Stem Cell Biology at Toronto General Research Institute at the University of Toronto. The long term objectives of his research program are to understand the organization and developmental program of human hematopoietic stem cells, and to characterize how expression of key regulatory genes leads to leukemic transformation. His lab has developed novel in vivo assays for normal human hematopoietic stem cells by transplantation of normal human bone marrow into immune deficient mice. In addition to normal cells, they have established an animal model of human leukemia that is analogous to the progression of the disease in humans. These advances lay the foundation for a novel approach to create animal models of many human diseases providing a unique alternative to transgenic mice. They have also developed a system to genetically manipulate the human hematopoietic cells with retrovirus vectors expressing human growth regulatory genes and oncogenes. This will enable the researchers to mark stem cells to follow their lineage development as well as to express a variety of growth regulatory genes to determine their role in the stem cell developmental program.
Michael F. Clarke, MD, PhD
Michael Clarke is the associate director of the Stanford Institute for Stem Cell and Regenerative Medicine. In addition to his clinical duties in the Division of Oncology, Clarke maintains a laboratory focused on two areas of research: i) the control of self-renewal of normal stem cells and their malignant counterparts; and ii) the identification and characterization of cancer stem cells. A central issue in stem cell biology is to understand the mechanisms that regulate self-renewal of hematopoietic stem cells, which are required for hematopoiesis to persist for the lifetime of the animal. Until recently, the molecular mechanisms that regulate adult stem cell self-renewal were not known. His laboratory recently found that the proto-oncogene Bmi-1 regulates stem cell self-renewal via an epigenetic mechanism. By investigating the pathways upstream and downstream of Bmi1, the laboratory is actively investigating the molecular pathways that regulate self-renewal.
Clarke received his MD from Indiana University in 1977.
Erica L. Herzog, MD
Erica Herzog is an assistant professor of pulmonary and critical care medicine at Yale University School of Medicine. Following medical school at the University of North Carolina, Chapel Hill, she completed residency in internal medicine at Mount Sinai Hospital in New York, where she received the Ira M. Goldstein Award for resident teaching. Herzog combined postgraduate training in pulmonary and critical care medicine with PhD training in investigative medicine at Yale University, completing both programs with distinction in 2005. She pursued her PhD in the laboratory of Diane Krause where she studied the role of heterokaryon formation in the development of bone marrow derived epithelial cells. She has received multiple honors and awards including the Parker B. Francis Fellowship in Pulmonary Medicine (2004), an NIH mentored clinical scientist research award (2005) and the Edward Mallinckrodt, Jr, Scholar Award (2006). Herzog has a clinical interest in pulmonary fibrosis and an active research program focusing on novel approaches to overcoming failure of epithelial proliferation and repair mechanisms in the injured mammalian lung.
David T. Scadden, MD
David Scadden is a professor of medicine at Harvard Medical School and director of the Center for Hematological Malignancies and the Center for Regenerative Medicine at Massachusetts General Hospital. He is also codirector of the Harvard Stem Cell Institute at Harvard University. The focus of his laboratory is stem cell biology, with a particular interest in the regulation of the cell cycle within the stem cell compartment. Scadden's lab has identified differentiation stage-specific roles for cyclin dependent kinase inhibitors. In addition, Scadden is interested in the microenvironmental niche as a physiologic regulator of stem cell behavior. In his lab, each of these is addressed with a particular emphasis on how they might be targeted to human health.
Scadden received his MD from Case Western Reserve University School of Medicine in 1980.
Angelo DePalma is a freelance science writer living in Newton, New Jersey.