Harvard Stem Cell Institute Research Newsletter
| |
| | | |  | Research Commentary Stem cell maintenance factors represent potential therapeutic targets for cancer by Lisa Girard, PhD
HSCI Science Editor Cancer stem cells are capable of initiating and sustaining a tumor. Current cancer therapies may fail, leaving patients prone to recurrence because the cancer stem cells have not been eradicated. This problem has been likened to "pulling out a weed while leaving the roots." Cancer stem cells were first conclusively identified in association with hematological malignancies and our understanding of them continues to be derived largely from findings related to leukemic stem cells. In addition to their role in leukemias, cancer stem cells are being increasingly identified in solid tumors. Recent findings continue to underscore the importance of understanding the unique features of these cells in order to target them therapeutically. Stem cell quiescence is one feature of stem cells involving unique, and thus potentially targetable, factors. Quiescence, the slow cell cycling of a stem cells, makes cancer stem cells unresponsive to many chemotherapeutics that typically target rapidly proliferating cells. Understanding the factors involved in stem cell quiescence is critical since their mutation or deletion causes the cells to begin cycling more rapidly. This can result in tumor growth and metastasis but also render the cells more sensitive to chemotherapeutics and increase the likelihood of their progression to terminal differentiation and therefore departure from the stem cell pool. Recent papers exploring the potential of quiescence factors as therapeutic targets have yielded promising results. In a recent paper by Ito et al. (Ito et al., 2008), the researchers explore the role of PML as a hematopoietic stem cell (HSC) quiescence factor. PML is a protein that encodes a protein localizing to PML nuclear bodies in the cell and acts as a tumor suppressor, affecting a number of cellular processes including apoptosis, cellular proliferation, and senescence. The Pml gene is involved in the chromosomal translocation implicated in acute promyelocytic leukemia (APL). The researchers investigated the association between PML levels in Leukemia-initiating cells (LIC) and clinical outcome in patients with chronic myeloid leukemia (CML) and found that positive clinical outcomes were associated with low PML levels. This result prompted them to investigate the stem cell pool in mice lacking PML and they found, by examining marker expression, that there were fewer quiescent stem cells and more differentiating cells. This suggests that the PML mutant mice are defective in stem cell maintenance, which in turn suggests that PML acts to maintain HSCs in normal mice. Ito et al further found that PML is needed for LIC maintenance as well. In order to test whether down-regulation of PML in LICs facilitates their eradication by increasing their cell cycling and making them increasingly sensitive to chemotherapy, they treated the cells with arsenic trioxide. Arsenic trioxide is known to target PML and is a historic treatment for APL. Treatment with arsenic trioxide, which increases the rate of cell cycle entry by eliminating PML, significantly decreased the number of LICs in response to chemotherapy. These results highlight the role of PML in LIC quiescence and demonstrate the usefulness of compounds such as arsenic trioxide in promoting the eradication of LICs. PML's utility could be further expanded if its usefulness in cancer stem cells in solid tumors could be demonstrated. PML is not the only potential therapeutic target identified in leukemia stem cells (LSCs). Recent work by Guo et al. (Guo et al., 2008) has made significant progress toward defining the molecular mechanisms that PTEN uses to maintain quiescence in LSCs. PTEN, like PML, is a tumor suppressor protein. It is a phosphatase which functions in the PI(3)K-AKT pathway and previously found to be involved in development of human leukemia. The group showed that loss of PTEN in mice leads to defects in adult HSC self-renewal and eventually T-lymphoblastic leukemia (T-ALL). Further, they identify the players involved in LSC formation. They measure the levels of beta-catenin, a key component of the Wnt pathway, and examine the effects of its partial depletion, finding that lower beta catenin levels incompletely inhibits the PTEN caused T-ALL development and suggests that beta catenin may contribute to LSC formation and expansion. Additionally, the researchers find a chromosomal translocation overly represented in leukemia blast cells that causes overexpression of c-myc. These results suggest a multi-hit model of leukemia development, with PTEN activation as the first step activating the PI(3)K-AKT pathway, promoting proliferation and setting the stage for genomic instability caused by beta-catenin activation and c-myc overexpression. These factors may lead to LSC self renewal and T-ALL development in a Pten mutant background. The scenario elaborated in this work informs a number of potential therapeutic options whose goal would be to promote LSC cell cycling, thereby make them more susceptible the cytotoxic effects of chemotherapy. Therapeutic targeting of cancer stem cell quiescence factors, such as PML and PTEN, represent a means by which we may be able to get a specific handle on cancer stem cells. This has been an elusive goal because many of the standard chemotherapeutic approaches target rapidly proliferating cells. As we continue to identify factors involved in quiescence, and the pathways in which they act, additional targets will reveal themselves. Additionally, the solid footing gained in our understanding of leukemic stem cells will inform studies on cancer stem cells in solid tumors. References - Guo, W., Lasky, J.L., Chang, C.J., Mosessian, S., Lewis, X., Xiao, Y., Yeh, J.E., Chen, J.Y., Iruela-Arispe, M.L., Varella-Garcia, M., Wu, H. (2008) Multi-genetic events collaboratively contribute to Pten-null leukaemia stem-cell formation. Nature 453, 529-33.
- Ito, K., Bernardi, R., Morotti, A., Matsuoka, S., Saglio, G., Ikeda, Y., Rosenblatt, J., Avigan, D.E., Teruya-Feldstein, J., Pandolfi, P.P. (2008). PML targeting eradicates quiescent leukaemia-initiating cells. Nature May 11. [Epub ahead of print]
| | | Spotlight Article PML targeting eradicates quiescent leukaemia-initiating cells This month's spotlighted article, published online in the journal Nature, is by HSCI Principal Faculty member Pier Paolo Pandolfi, MD, PhD, of Beth Israel Deaconess Medical Center. Abstract: The existence of a small population of 'cancer-initiating cells' responsible for tumour maintenance has been firmly demonstrated in leukaemia. This concept is currently being tested in solid tumours. Leukaemia-initiating cells, particularly those that are in a quiescent state, are thought to be resistant to chemotherapy and targeted therapies, resulting in disease relapse. Chronic myeloid leukaemia is a paradigmatic haematopoietic stem cell disease in which the leukaemia-initiating-cell pool is not eradicated by current therapy, leading to disease relapse on drug discontinuation. Here we define the critical role of the promyelocytic leukaemia protein (PML) tumour suppressor in haematopoietic stem cell maintenance, and present a new therapeutic approach for targeting quiescent leukaemia-initiating cells and possibly cancer-initiating cells by pharmacological inhibition of PML. Ito K, Bernardi R, Morotti A, Matsuoka S, Saglio G, Ikeda Y, Rosenblatt J, Avigan DE, Teruya-Feldstein J, Pandolfi PP. PML targeting eradicates quiescent leukaemia-initiating cells. Nature. 2008 May 11. | Review and Commentary Articles - Bonventre JV. Dialysis in Acute Kidney Injury -- More Is Not Better. N Engl J Med. 2008 May 20. [Epub ahead of print] Read Abstract.
- Chien KR. Regenerative medicine and human models of human disease. Nature. 2008 May 15;453(7193):302-5. Read Abstract.
- Carracedo A, Salmena L, Pandolfi PP. SnapShot: PTEN signaling pathways. Cell. 2008 May 2;133(3):550.e1. Read Abstract.
- Salmena L, Carracedo A, Pandolfi PP. Tenets of PTEN tumor suppression. Cell. 2008 May 2;133(3):403-14. Read Abstract.
- Sadelain M, Williams DA. A "vector drain" in US gene therapy development? Mol Ther. 2008 May;16(5):801-2. No abstract available. Read Abstract.
- Monach PA, Mathis D, Benoist C. The K/BxN arthritis model. Curr Protoc Immunol. 2008 May;Chapter 15:Unit 15.22. Read Abstract.
- Zon LI. Intrinsic and extrinsic control of haematopoietic stem-cell self-renewal. Nature. 2008 May 15;453(7193):306-13. Read Abstract.
- Pfister O, Liao R. Pump to survive: novel cytoprotective strategies for cardiac progenitor cells. Circ Res. 2008 May 9;102(9):998-1001. Read Abstract.
- Hoganson DM, Pryor HI 2nd, Vacanti JP. Tissue engineering and organ structure: a vascularized approach to liver and lung. Pediatr Res.. 2008 May;63(5):520-6. Read Abstract.
| Scientific Papers
Blood - Wang Y, Yabuuchi A, McKinney-Freeman S, Ducharme DM, Ray MK, Chawengsaksophak K, Archer TK, Daley GQ. Cdx gene deficiency compromises embryonic hematopoiesis in the mouse. Proc Natl Acad Sci USA. 2008 Jun 3;105(22):7756-61. Epub 2008 May 29. Read Abstract.
- Cao YA, Wagers AJ, Karsunky H, Zhao H, Reeves R, Wong RJ, Stevenson DK, Weissman IL, Contag CH. Heme oxygenase-1 deficiency leads to disrupted response to acute stress in stem cells and progenitors. Blood. 2008 May 28. [Epub ahead of print] Read Abstract.
- Orford K, Kharchenko P, Lai W, Dao MC, Worhunsky DJ, Ferro A, Janzen V, Park PJ, Scadden DT.. Differential H3K4 methylation identifies developmentally poised hematopoietic genes. Dev Cell. 2008 May;14(5):798-809. Read Abstract.
- Mayack SR, Wagers AJ. Osteolineage niche cells initiate hematopoietic stem cell mobilization. Blood. 2008 May 2. [Epub ahead of print] Read Abstract.
- Fernandez L, Rodriguez S, Huang H, Chora A, Fernandes J, Mumaw C, Cruz E, Pollok K, Cristina F, Price JE, Ferkowicz MJ, Scadden DT, Clauss M, Cardoso AA, Carlesso N. Tumor necrosis factor-alpha and endothelial cells modulate Notch signaling in the bone marrow microenvironment during inflammation. Exp Hematol. 2008 May;36(5):545-558. Read Abstract.
| Cancer - Ito K, Bernardi R, Morotti A, Matsuoka S, Saglio G, Ikeda Y, Rosenblatt J, Avigan DE, Teruya-Feldstein J, Pandolfi PP. PML targeting eradicates quiescent leukaemia-initiating cells. Nature. 2008 May 11. [Epub ahead of print] Read Abstract.
- Wittner BS, Sgroi DC, Ryan PD, Bruinsma TJ, Glas AM, Male A, Dahiya S, Habin K, Bernards R, Haber DA, Van't Veer LJ, Ramaswamy S. Analysis of the MammaPrint Breast Cancer Assay in a Predominantly Postmenopausal Cohort. Clin Cancer Res. 2008 May 15;14(10):2988-2993. Read Abstract.
- Xu L, Shen SS, Hoshida Y, Subramanian A, Ross K, Brunet JP, Wagner SN, Ramaswamy S, Mesirov JP, Hynes RO. Gene expression changes in an animal melanoma model correlate with aggressiveness of human melanoma metastases. Mol Cancer Res. 2008 May;6(5):760-9. Read Abstract.
| Developmental Biology - Stadtfeld M, Brennand K, Hochedlinger K. Reprogramming of Pancreatic beta Cells into Induced Pluripotent Stem Cells. Curr Biol. 2008 May 21. [Epub ahead of print] Read Abstract.
- Damiani D, Alexander JJ, O'Rourke JR, McManus M, Jadhav AP, Cepko CL, Hauswirth WW, Harfe BD, Strettoi E. Dicer inactivation leads to progressive functional and structural degeneration of the mouse retina.. J Neurosci. 2008 May 7;28(19):4878-87. Read Abstract.
| Diabetes - Inada A, Kanamori H, Arai H, Akashi T, Araki M, Weir GC, Fukatsu A. A model for diabetic nephropathy: advantages of the inducible cAMP early repressor transgenic mouse over the streptozotocin-induced diabetic mouse. J Cell Physiol. 2008 May;215(2):383-91.. Read Abstract.
| Genetics and Genomics - Nygaard V, Liu F, Holden M, Kuo WP, Trimarchi J, Ohno-Machado L, Cepko C, Frigessi A, Glad IK, van de Wiel MA, Hovig E, Lyng H. Validation of oligoarrays for quantitative exploration of the transcriptome. BMC Genomics. 2008 May 30;9(1):258. [Epub ahead of print] Read Abstract.
- Pawlisz AS, Mutch C, Wynshaw-Boris A, Chenn A, Walsh CA, Feng Y. Lis1-Nde1 dependent neuronal fate control determines cerebral cortical size and lamination. Hum Mol Genet. 2008 May 10. [Epub ahead of print] Read Abstract.
| Imaging - Shaw SY, Westly EC, Pittet MJ, Subramanian A, Schreiber SL, Weissleder R. Perturbational profiling of nanomaterial biologic activity. Proc Natl Acad Sci USA. 2008 May 27;105(21):7387-92. Epub 2008 May 20. Read Abstract.
| Nervous System - Li S, Jin Z, Koirala S, Bu L, Xu L, Hynes RO, Walsh CA, Corfas G, Piao X. GPR56 regulates pial basement membrane integrity and cortical lamination. J Neurosci. 2008 May 28;28(22):5817-26. Read Abstract.
| Pulminary System - Yang Y, Iwanaga K, Raso MG, Wislez M, Hanna AE, Wieder ED, Molldrem JJ, Wistuba II, Powis G, Demayo FJ, Kim CF, Kurie JM. Phosphatidylinositol 3-kinase mediates bronchioalveolar stem cell expansion in mouse models of oncogenic K-ras-induced lung cancer. PLoS ONE. 2008 May 21;3(5):e2220. Read Abstract.
| Renal System - Ichimura T, Asseldonk EJ, Humphreys BD, Gunaratnam L, Duffield JS, Bonventre JV. Kidney injury molecule-1 is a phosphatidylserine receptor that confers a phagocytic phenotype on epithelial cells. J Clin Invest. 2008 May;118(5):1657-68. Read Abstract.
| Skeletal System - Shimada M, Greer PA, McMahon AP, Bouxsein ML, Schipani E. In vivo targeted deletion of calpain small subunit, Capn4, in cells of the osteoblast lineage impairs cell proliferation, differentiation, and bone formation. J Biol Chem. 2008 May 30. [Epub ahead of print] Read Abstract.
| Translational Medicine - Szentirmai O, Baker CH, Bullain SS, Lin N, Takahashi M, Folkman J, Mulligan RC, Carter BS. Successful inhibition of intracranial human glioblastoma multiforme xenograft growth via systemic adenoviral delivery of soluble endostatin and soluble vascular endothelial growth factor receptor-2: laboratory investigation. J Neurosurg. 2008 May;108(5):979-88. Read Abstract.
| The Harvard Stem Cell Institute is a scientific collaborative established to fulfill the promise of stem cell biology as the basis for cures and treatments for a wide range of chronic medical conditions. Visit our website at www.hsci.harvard.edu. If there is anything that you would like to see added to this email alert, please email maureen_lyons@harvard.edu. | |
| |
