| Budget Amount *help |
¥4,010,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥510,000)
Fiscal Year 2007: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Fiscal Year 2006: ¥1,800,000 (Direct Cost: ¥1,800,000)
|
|---|
| Research Abstract |
The bone marrow (BM) microenvironment confers growth, survival, and drug resistance to multiple myeloma (MM) cells via both direct cell contact and soluble factors. Adhesion of MM cells to extracellular matrix proteins, such as fibronectin, inhibits apoptosis through up-regulation of both p27kip1 and c-Fas-associated death domain-like interleukin (IL)-1-converting enzyme-like inhibitory protein-long (c-FLIP). Adhesion of MM cells to BM stromal cells (BMSCs) triggers secretion of cytokines, such as IL-6 and vascular endothelial growth factor (VEGF), which play a critical role in pathogenesis of MM IL-6 induces growth, survival, and drug resistance in MM cells, and VEGF triggers growth and migration of MM cells, stimulates BM angiogenesis, and augments IL-6 production in BMSCs. In addition, 1L-6 and VEGF contribute to immune deficits characteristic of MM. Conversely, abrogating adhesion of MM cells to BMSCs and associated IL-6 and VEGF secretion diminishes the growth advantage and drug r
… More
esistance of MM cells in the BM milieu. For example, we have demonstrated previously that thalidomide and immunomodulatory derivatives, as well as the proteasome inhibitor bortezomib, which can overcome clinical drug resistance, act not only directly on MM cells but also in the BM microenvironment to inhibit the up-regulation of IL-6 and VEGF secretion triggered by the binding of MM cells-to BMSCs.
In this study, I have clearly shown that coculture of MM cells and BMSCs augments production of IL-6 and VEGF which was abrogated by the inhibition of TGF-β. TGF-β1 inhibitor significantly inhibits not only transcription but also secretion of both IL-6 and VEGF from BMSCs triggered by either TGF-β1 or adhesion of MM cells to BMSCs. Moreover, inhibition of action of TGF-β1 decreased tumor cell growth triggered by MM cell adhesion to BMSCs. TGF-β works, at least in part, by nuclear accumulation of Smad2/3 and hypoxia-inducible factor 1a, as well as related production of IL-6 and VEGF, respectively.
These studies indicate that inhibition of TGF-β abrogates production of cytokines mediating MM cell growth, survival, drug resistance, and migration in the BM milieu, thereby providing the preclinical rationale for clinical evaluation of TGF-β inhibitor to improve patient outcome in MM. Less
|
