Proangiogenic stimulation of bone marrow endothelium engages mTOR and is inhibited by simultaneous blockade of mTOR and NF-kappaB.
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 p27(kip1) and p21(cip1). 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-kappaB 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.
Costa
Lara F
LF
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Balcells
Mercedes
M
Edelman
Elazer R
ER
Nadler
Lee M
LM
Cardoso
Angelo A
AA
D000328:Adult; D001853:Bone Marrow / Q000098:blood supply*; D002453:Cell Cycle; D049109:Cell Proliferation; D002478:Cells, Cultured; D002648:Child; D019938:Cyclin D1 / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics; D004727:Endothelium / Q000166:cytology / Q000502:physiology*; D005786:Gene Expression Regulation; D006801:Humans; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D009389:Neovascularization, Pathologic / Q000209:etiology*; D010766:Phosphorylation; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000097:blood; D011494:Protein Kinases / Q000378:metabolism / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016328:NF-kappa B; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D051357:Cyclin-Dependent Kinase 2