Interplay Between Myeloma Cells and the Microenvironment

In the Multiple Myeloma: Mi-croenvironment Simultaneous Session on Monday afternoon, a series of eight very interesting papers were presented on different aspects of the biology and pathophysiology of multiple myeloma (MM), myeloma cells, and the microenvironment.

A group of scientists led by K. Anderson from the Dana-Farber Cancer Institute demonstrated that VEGF induces MM cells to proliferate and protects against apoptosis through Mcl-1, and suggested that targeting this pathway may lead to novel therapeutics in MM. The group of V. Rizzoli from Parma, Italy, showed that marrowderived osteoblast differentiation can be inhibited by myeloma cells through Runx2/Cbfa1 and that this inhibition requires cell-to-cell contact.

The group from the University of Arkansas contributed two papers to this session. In the first one they described the effect of osteoclasts on the reprogramming of primary myeloma cells when the two were co-cultured for six weeks. Following their retrieval from culture, mature MM cells acquired autonomous survival properties and were resistant to apoptosis suggesting that such transformation in vivo may generate apoptosis-resistant cells that may be responsible for relapse. In the second paper from this group, the interaction between MM cells and fibroblast activation protein (FAP) was examined. Again, using the osteoclast-MM co-culture system, inhibition of osteoclast-derived FAP with siRNA reduced the number of viable MM cells, and, in the presence of chemotherapeutic drugs, siRNA enhanced apoptosis of MM cells suggesting that FAP is a critical survival factor for myeloma plasma cells. Also from Little Rock, Dr. Yang used an experimental animal model to demonstrate that heparanase, an enzyme that may regulate heparan-binding growth factor activity, is a key molecule involved in the dissemination of myeloma cells to bone.

Dr. Nimmanapalli from Tampa examined the relationship between myeloma cells, the cellular stress-induced heat shock protein HSP70, and drug resistance. The findings of these studies indicate that HSP70, which can be over expressed after the adhesion of 8226 cells to fibronectin or stromal cells, enhances cell survival, whereas its inhibition reverses acquired drug resistance, therefore suggesting a potential role for anti-HSP70 inhibitors in myeloma therapy. Dr Hattori from Tokyo, Japan, introduced a mouse model for molecular targeting of angiogenic growth factor and demonstrated that signaling through the hepatocyte growth factor plays an important role in the progression of myeloma cells and that antagonists of HGF can inhibit the growth of MM cells.

The last presentation in this session belonged to the group of Dr. Munshi at the Dana-Farber Cancer Institute and illustrated that a potent new telomerase inhibitor, labeled GRN163L, targets the RNA component of telomerase and promotes telomerase inhibition, telomere shortening, and apoptosis in MM cells. Hematologists focusing on multiple myeloma found this session full of new and useful information on many potential therapeutic approaches that may not be far from clinical evaluation.