Development
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Research Article
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Christine Fritsch, Elzbieta A. Swietlicki, Olivier Lefebvre, Michele Kedinger, Hristo Iordanov, Marc S. Levin, Deborah C. Rubin
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Research Article
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Lydie Cassard, Joël F.G. Cohen-Solal, Annie Galinha, Xavier Sastre-Garau, Claire Mathiot, Jérôme Galon, Thierry Dorval, Alain Bernheim, Wolf H. Fridman, Catherine Sautès-Fridman
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Research Article
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Wolfgang E. Gallwitz, Theresa A. Guise, Gregory R. Mundy
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Research Article
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Dipak Panigrahy, Samuel Singer, Lucy Q. Shen, Catherine E. Butterfield, Deborah A. Freedman, Emy J. Chen, Marsha A. Moses, Susan Kilroy, Stefan Duensing, Christopher Fletcher, Jonathan A. Fletcher, Lynn Hlatky, Philip Hahnfeldt, Judah Folkman, Arja Kaipainen
UV-induction of keratinocyte endothelin-1 downregulates E-cadherin in melanocytes and melanoma cells
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Research Article
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Sumayah Jamal, Robert J. Schneider
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Research Article
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Flavio Curnis, Angelina Sacchi, Angelo Corti
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Dinesh S. Rao, Teresa S. Hyun, Priti D. Kumar, Ikuko F. Mizukami, Mark A. Rubin, Peter C. Lucas, Martin G. Sanda, Theodora S. Ross
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Research Article
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April L. Blajeski, Vy A. Phan, Timothy J. Kottke, Scott H. Kaufmann
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TGF-βs are potent inhibitors of epithelial cell proliferation. However, in established carcinomas, autocrine/paracrine TGF-β interactions can enhance tumor cell viability and progression. Thus, we studied the effect of a soluble Fc:TGF-β type II receptor fusion protein (Fc:TβRII) on transgenic and transplantable models of breast cancer metastases. Systemic administration of Fc:TβRII did not alter primary mammary tumor latency in MMTV-Polyomavirus middle T antigen transgenic mice. However, Fc:TβRII increased apoptosis in primary tumors, while reducing tumor cell motility, intravasation, and lung metastases. These effects correlated with inhibition of Akt activity and FKHRL1 phosphorylation. Fc:TβRII also inhibited metastases from transplanted 4T1 and EMT-6 mammary tumors in syngeneic BALB/c mice. Tumor microvessel density in a mouse dorsal skin window chamber was unaffected by Fc:TβRII. Therefore, blockade of TGF-β signaling may reduce tumor cell viability and migratory potential and represents a testable therapeutic approach against metastatic carcinomas.
Authors
Rebecca S. Muraoka, Nancy Dumont, Christoph A. Ritter, Teresa C. Dugger, Dana M. Brantley, Jin Chen, Evangeline Easterly, L. Renee Roebuck, Sarah Ryan, Philip J. Gotwals, Victor Koteliansky, Carlos L. Arteaga
Abstract
Whole-body irradiation at the minimal lethal dose causes bone marrow failure and death within 12–18 days. To identify the principal components of the hematopoietic system that are radioprotective, we transplanted lethally irradiated mice with purified progenitors: common myeloid progenitors (CMPs), megakaryocyte/erythrocyte-restricted progenitors (MEPs), or granulocyte/monocyte-restricted progenitors (GMPs). Transplanted CMPs gave rise to cells both of the granulocyte/monocyte (GM) series and the megakaryocyte/erythrocyte series, whereas GMPs or MEPs showed reconstitution of only GM or ME cells, respectively. CMPs and MEPs but not GMPs protected mice in a dose-dependent manner, suggesting that erythrocytes, platelets, or both are the critical effectors of radioprotection. Accordingly, CMPs and MEPs formed robust colonies in recipient bone marrow and spleen, whereas GMPs formed small colonies that rapidly disappeared. Direct comparisons of spleen CFU (CFU-S) potentials among each progenitor subset showed that MEPs contain the vast majority of day 8 CFU-S activity, suggesting that day 8 CFU-S are the precursors of radioprotective cell subsets. All animals radioprotected for 30 days subsequently survived for at least 6 months post-transplant, and showed only host-derived hematopoiesis after 30 days. These findings suggest that rare hematopoietic stem cells survive myeloablation that can eventually repopulate irradiated hosts if myeloerythroid-restricted progenitors transiently rescue ablated animals through the critical window of bone marrow failure.
Authors
Thanyaphong Na Nakorn, David Traver, Irving L. Weissman, Koichi Akashi
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Copyright © 2018 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)