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Blood, 1 January 2006, Vol. 107, No. 1, pp. 285-292.
Prepublished online as a Blood First Edition Paper on September 1, 2005; DOI 10.1182/blood-2005-06-2208.
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NEOPLASIA
Proangiogenic stimulation of bone marrow endothelium engages mTOR and is inhibited by simultaneous blockade of mTOR and NF- B
Lara F. Costa,
Mercedes Balcells,
Elazer R. Edelman,
Lee M. Nadler, and
Angelo A. Cardoso
From the Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA; the Institute of Molecular Medicine, University of Lisbon, Lisbon, Portugal; the Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School and Harvard-Massachusetts Institute of Technology (MIT) Division of Health Sciences and Technology, Cambridge, MA; and the Institut Químic de Sarrià, Barcelona, Spain.
Most bone marrow (BM) malignancies develop in association with an angiogenic phenotype and increased numbers of endothelial cells. The molecular mechanisms involved in the modulation and recruitment of BM endothelium are largely unknown and may provide novel therapeutic targets for neoplastic diseases. We observed that angiogenic stimulation of BM endothelial cells activates mTOR and engages its downstream pathways 4E-BP1 and S6K1, which are inhibited by the mTOR-specific blockers rapamycin and CCI-779. Both mTOR blockers significantly inhibit growth factor- and leukemia-induced proliferation of BM endothelium by inducing G0/G1 cell-cycle arrest. This effect is associated with down-regulation of cyclin D1 and cdk2 phosphorylation, and up-regulation of the cdk inhibitors p27kip1 and p21cip1. Under conditions that reproduce the biomechanical fluidic environment of the BM, CCI-779 is equally effective in inhibiting BM endothelial-cell proliferation. Finally, simultaneous blockade of mTOR and NF- B pathways synergize to significantly inhibit or abrogate the proliferative responses of BM endothelial cells to mitogenic stimuli. This study identifies mTOR as an important pathway for the proangiogenic stimulation of BM endothelium. Modulation of this pathway may serve as a valid therapeutic intervention in BM malignancies evolving in association with an angiogenic phenotype.
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