Harvard Stem Cell Institute Research Newsletter
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| | | |  | Research Commentary Cell signaling pathways and cancer stem cells-targeting the source by Lisa Girard, PhD
HSCI Science Editor Disruptions in cell signaling pathways, the messenger systems of the cells, are found in a large number of cancers. These changes are often the result of alterations in the regulatory regions or structure of the genes that alter their level of expression. Additionally, cancer-causing changes may result from mutations in the gene itself that don't change the level at which it is expressed, but rather change the properties of the final protein-for example creating a receptor that is always "on" independent of whether or not the appropriate "on" signal is present. Cancer promoting disruptions can be broadly classified into three categories. These include inappropriately activated signaling cascades involving mutant tyrosine kinases and phosphatases such as the Ras pathway and overactive growth factors and receptors that excessively drive cell proliferation including the EGF, PDGF, and FGF growth factor receptors. Another category includes abnormal changes in gene expression effected by proteins in the cell's nucleus or chromatin effects. Chromatin proteins wrap around and help condense DNA and can also influence gene regulation by affecting access to the gene by regulatory proteins. Cancer stem cells are a self-renewing source of cancer cells. They are difficult to target therapeutically and contribute to the high relapse rate for many cancers. There is great interest in identifying signaling factors that go awry in stem and multipotent progenitor cells because they may represent a point of origin for these cancer stem cells. Recently published findings reported from Gary Gilliland's lab of the Harvard Stem Cell Institute (Lee et al., 2007) describe significant progress toward understanding one such instance of signaling gone awry involving altered expression of the FMS-like tyrosine kinase 3 (FLT3), a receptor protein involved in hematopoiesis, or blood cell formation. FLT3 overactivation is found in many patients with acute myelogenous leukemia and is associated with a poor prognosis. Lee and coworkers used a range of molecular tools to create a mouse that constitutively expressed FLT3, allowing them to clearly examine the effects on hematopoietic stem and progenitor cells. These mice developed a leukemia that correlated with overproliferation of hematopoietic stem and progenitor cells. Creating this mouse model opens the door for exciting possibilities, including using these mice as a means for identifying additional factors promoting leukemia along with FLT3, and a platform for testing potential therapeutics. Elaborating the signaling pathways that go awry during the development of cancer provides a bevy of potential drug targets. Prior attempts to mine this approach have been met with some success. Trastuzumab, better known as Herceptin, is perhaps the most well known example. Herceptin is an antibody that targets the tyrosine kinase growth factor ErbB2 receptor. ErbB2 is overexpressed in a significant percentage of breast cancer patients, and Herceptin downregulates the pathway it stimulates. The ability to target specific cancer-causing alterations, coupled with advancing approaches in pharmacogenomics, allowing clinicians to tailor a patient's treatment to target alterations identified through genomic profiling, is moving us further toward less toxic, more specific, chemotherapeutic approaches. The ability to target these alterations right in the cancer stem cells propagating the disease will advance along with our understanding of their unique properties and serve to decrease relapse rates allowing us to speak of cancer treatment in terms of cure, rather than remission. Lee BH, Tothova Z, Levine RL, Anderson K, Buza-Vidas N, Cullen DE, McDowell EP, Adelsperger J, Frohling S, Huntly BJ, Beran M, Jacobsen SE, Gilliland DG. FLT3 mutations confer enhanced proliferation and survival properties to multipotent progenitors in a murine model of chronic myelomonocytic leukemia. Cancer Cell. 2007 Oct;12(4):367-80. Read Abstract. | | | Spotlight Article The cdx Genes and Retinoic Acid Control the Positioning and Segmentation of the Zebrafish Pronephros This month's spotlighted article is by HSCI Principal Faculty Member Alan Davidson of Massachusetts General Hospital, and HSCI Executive Committee Member Andrew McMahon of Harvard University Department of Molecular and Cellular Biolgy. Using zebrafish, a versatile model for studying organ formation during embryonic development, Wingert et al. have made two important discoveries: firstly, they demonstrate that the embryonic zebrafish kidney is far more complex than previously thought and in fact shares many attributes with the human kidney. Secondly, they reveal that the vitamin A derivative, retinoic acid (RA), plays a critical role in determining the identities of renal cell progenitors-- too much or too little RA results in a loss or expansion of certain kidney cell types at the expense of others. This study provides valuable insights into how the kidney forms during embryonic development and is pivotal to our understanding of how it undergoes repair and regeneration following injury or disease. In addition, this knowledge will be useful for approaches that aim to convert embryonic stem cells into therapeutically useful renal cell types. Model for How the cdx Genes and RA Establish Pronephros Position and Segmentation  (A) At the end of gastrulation, the IM is located lateral to the PM. The production of RA in the PM is localized to the anterior-most region (purple). RA is proposed to diffuse as a gradient across to the adjacent IM such that the anterior IM is exposed to high RA levels, which induce proximal fates and suppress expansion of distal fates. (B) In wild-type embryos, cdx1a and cdx4 set the expression boundaries of raldh2 (and potentially other putative raldh-like genes, 'raldhX') and cyp26a1, thereby restricting RA production to the anterior PM. The absence of cdx4 function (C) and cdx1a/4 function (D) causes posterior shifts in the RA source, due to the combined posterior shifts of both the raldh2 and cyp26a1 expression domains. These shifts in the presumptive RA zone lead to pronephros formation at a more posterior location, and an expansion of anterior intermediate mesodermal fates (indicated by an asterisk). In cdx1a/4-deficient embryos, the posterior shift of the pronephros, together with the body truncation, results in an abrogation of distal nephron segments.
Wingert RA, Selleck R, Yu J, Song HD, Chen Z, Song A, Zhou Y, Thisse B, Thisse C, McMahon AP, Davidson AJ. The cdx genes and retinoic acid control the positioning and segmentation of the zebrafish pronephros. PLoS Genet. 2007 Oct 19;3(10):1922-38. Read Article. | Review and Commentary Articles - Hyun I, Hochedlinger K, Jaenisch R, Yamanaka S. New Advances in iPS Cell Research Do Not Obviate the Need for Human Embryonic Stem Cells. Cell Stem Cell. 2007 Oct 11;1(4):367-368. Read Abstract.
- Hedlund E, Hefferan MP, Marsala M, Isacson O. Cell therapy and stem cells in animal models of motor neuron disorders. Eur J Neurosci. 2007 Oct;26(7):1721-37. Read Abstract.
- Arnaout MA, Goodman SL, Xiong JP. Structure and mechanics of integrin-based cell adhesion. Curr Opin Cell Biol. 2007 Oct;19(5):495-507. Read Abstract.
- Morgan KJ, Gilliland DG. A Role for JAK2 Mutations in Myeloproliferative Diseases. Annu Rev Med. 2007 Oct 5 - Epub ahead of print. Read Abstract.
- Humphreys BD, Bonventre JV. Mesenchymal Stem Cells in Acute Kidney Injury. Annu Rev Med. 2007 Oct 3 - Epub ahead of print. Read Abstract.
- Mathis D, Benoist C. Yes, it does. Nat Rev Immunol. 2007 Oct 12;7(10):1 - Epub ahead of print. Read Abstract.
- Vaidya VS, Ferguson MA, Bonventre JV. Biomarkers of Acute Kidney Injury. Annu Rev Pharmacol Toxicol. 2007 Oct 15 - Epub ahead of print. Read Abstract.
| Scientific Papers
Cancer - Lee BH, Tothova Z, Levine RL, Anderson K, Buza-Vidas N, Cullen DE, McDowell EP, Adelsperger J, Frohling S, Huntly BJ, Beran M, Jacobsen SE, Gilliland DG. FLT3 mutations confer enhanced proliferation and survival properties to multipotent progenitors in a murine model of chronic myelomonocytic leukemia. Cancer Cell. 2007 Oct;12(4):367-80. Read Abstract.
- Costa DB, Halmos B, Kumar A, Schumer ST, Huberman MS, Boggon TJ, Tenen DG, Kobayashi S. BIM mediates EGFR tyrosine kinase inhibitor-induced apoptosis in lung cancers with oncogenic EGFR mutations. PLoS Med. 2007 Oct 30;4(10):1669-79. Read Abstract.
- Renlund N, Pieretti-Vanmarcke R, O'Neill FH, Zhang L, Donahoe PK, Teixeira J. JNK inhibitor II (SP600125) activates Mullerian Inhibiting Substance type II receptor-mediated signal transduction. Endocrinology. 2007 Oct 18 - Epub ahead of print. Read Abstract.
| Developmental Biology - Aidlen JT, Nazarey PP, Kinane TB, Donahoe PK, Schnitzer JJ, Kling DE. Retinoic acid-mediated differentiation protects against nitrofen-induced apoptosis. Birth Defects Res B Dev Reprod Toxicol. 2007 Oct;80(5):406-16. Read Abstract.
- Zhou Q, Chipperfield H, Melton DA, Wong WH. A gene regulatory network in mouse embryonic stem cells. Proc Natl Acad Sci USA. 2007 Oct 16;104(42):16438-43. Read Abstract.
- Burket CT, Montgomery JE, Thummel R, Kassen SC, Lafave MC, Langenau DM, Zon LI, Hyde DR. Generation and characterization of transgenic zebrafish lines using different ubiquitous promoters. Transgenic Res. 2007 Oct 30 - Epub ahead of print. Read Abstract.
| Imaging - Tam JM, Upadhyay R, Pittet MJ, Weissleder R, Mahmood U. Improved in vivo whole-animal detection limits of green fluorescent protein-expressing tumor lines by spectral fluorescence imaging. Mol Imaging. 2007 Oct-Dec;6(4):269-76. Read Abstract.
- Law B, Weissleder R, Tung CH. Protease-Sensitive Fluorescent Nanofibers. Bioconjug Chem. 2007 Oct 5 - Epub ahead of print. Read Abstract.
- Farrar CT, Dai G, Novikov M, Rosenzweig A, Weissleder R, Rosen BR, Sosnovik DE. Impact of field strength and iron oxide nanoparticle concentration on the linearity and diagnostic accuracy of off-resonance imaging. NMR Biomed. 2007 Oct 8 - Epub ahead of print. Read Abstract.
- Swirski FK, Berger CR, Figueiredo JL, Mempel TR, von Andrian UH, Pittet MJ, Weissleder R. A near-infrared cell tracker reagent for multiscopic in vivo imaging and quantification of leukocyte immune responses. PLoS ONE. 2007 Oct 24;2(10):e1075. Read Abstract.
| Immunology - Sarantopoulos S, Stevenson KE, Kim HT, Bhuiya NS, Cutler CS, Soiffer RJ, Antin JH, Ritz J. High Levels of B-Cell Activating Factor in Patients with Active Chronic Graft-Versus-Host Disease. Clin Cancer Res. 2007 Oct 15;13(20):6107-6114. Read Abstract.
- Munoz NM, Meliton AY, Arm JP, Bonventre JV, Cho W, Leff AR. Deletion of secretory group v phospholipase A2 attenuates cell migration and airway hyperresponsiveness in immunosensitized mice. J Immunol. 2007 Oct 1;179(7):4800-7. Read Abstract.
- Gray D, Abramson J, Benoist C, Mathis D. Proliferative arrest and rapid turnover of thymic epithelial cells expressing Aire. J Exp Med. 2007 Oct 29;204(11):2521-8. Read Abstract.
| Muscular System - Eisenberg I, Eran A, Nishino I, Moggio M, Lamperti C, Amato AA, Lidov HG, Kang PB, North KN, Mitrani-Rosenbaum S, Flanigan KM, Neely LA, Whitney D, Beggs AH, Kohane IS, Kunkel LM. Distinctive patterns of microRNA expression in primary muscular disorders. Proc Natl Acad Sci USA. 2007 Oct 23;104(43):17016-21. Read Abstract.
| Nervous System - Hong S, Kang UJ, Isacson O, Kim KS. Neural precursors derived from human embryonic stem cells maintain long-term proliferation without losing the potential to differentiate into all three neural lineages, including dopaminergic neurons. J Neurochem. 2007 Oct 18 - Epub ahead of print. Read Abstract.
- Mizuno Y, Guyon JR, Okamoto K, Kunkel LM. Synemin expression in brain. Muscle Nerve. 2007 Oct;36(4):497-504. Read Abstract.
| Renal System - Zhou Y, Vaidya VS, Brown RP, Zhang J, Rosenzweig BA, Thompson KL, Miller TJ, Bonventre JV, Goering PL. Comparison of Kidney Injury Molecule-1 and Other Nephrotoxicity Biomarkers in Urine and Kidney Following Acute Exposure to Gentamicin, Mercury, and Chromium. Toxicol Sci. 2007 Oct 13 - Epub ahead of print. Read Abstract.
- Zhang Z, Humphreys BD, Bonventre JV. Shedding of the urinary biomarker kidney injury molecule-1 (KIM-1) is regulated by MAP kinases and juxtamembrane region. J Am Soc Nephrol. 2007 Oct;18(10):2704-14. Read Abstract.
- Wingert RA, Selleck R, Yu J, Song HD, Chen Z, Song A, Zhou Y, Thisse B, Thisse C, McMahon AP, Davidson AJ. The cdx genes and retinoic acid control the positioning and segmentation of the zebrafish pronephros. PLoS Genet. 2007 Oct 19;3(10):1922-38. 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. | |
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