Mesenchymal stem cells (MSCs) are a dynamic population of cells capable of self-renewal, differentiation, tumor and wound homing, and immunomodulation. Harvested from bone marrow, adipose tissue, cord blood, or a variety of other sites, MSCs play multiple roles in tumor progression, as previously reviewed(1
). Complications in comparing studies and drawing conclusions arise due to different stem cell isolation, characterization, and culture protocols, and the inherent variability in stem cells within and between donors. MSCs can have both tumor supportive (pro-tumor) and inhibitory (anti-tumor) effects(2
), but most myeloma-specific studies demonstrate a stimulatory, protective, and pro-tumor effect of MSCs on myeloma cells, suggesting that novel drugs could counteract these tumor-supporting effects in the bone marrow.
Local bone microenvironment activates many pathways leading to lesion growth and disease progression including the following: the PI-3K/Akt/mTOR/p70S6K cascade, the IKK-α/NF-κB pathway, Ras/Raf/MAPK, and JAK/STAT3, as reviewed extensively(3
). Many clinical and pre-clinical trials are aimed specifically at developing inhibitors of these pathways. Moreover, findings are emerging that alterations in local microenvironment may be not only supportive of tumor growth, but required for tumorigenesis. For example, deletion of DICER in osteoprogenitor mesenchymal cells can disrupt hematoposis and cause myelodysplasia and acute myelogenous leukemia in mice. This, among other studies, demonstrates the concept of microenvironment-induced oncogenesis (5
). MSCs can also increase multiple myeloma (MM) cell adhesion to bone marrow, protecting the cells from chemotherapy and helping them accumulate within the bone. Adhesion is mediated by molecules including CD44, Very Late Antigen (VLA)4, VLA5, leukocyte function-associated antigen 1 (LFA1), neuronal adhesion molecule (NCAM), intercellular adhesion molecule (ICAM1), syndecan 1, and MCP1 as reviewed previously(10
). Binding of CD40, located on MM cells, with its ligand (CD40L) on MSCs can further increase expression of adhesion molecules such as LFA1 and VLA4. Subsequently, MM cell adhesion is further increased, stimulating cytokine (IL6, [interleukin 6] and VEGF [vascular endothelial growth factor]) secretion by MSCs, creating a forward feedback loop for tumor growth(11
). In sum, stromal dysfunction is tied to neoplasia progression, implicating local stromal cells as coconspirators in tumor development.
Stromal cell-induced chemotherapy resistance in myeloma cells is well documented (13
), yet, many drug screens are still performed in the absence of stromal cells and therefore produce deceiving findings. Novel drug screens using stromal cell-myeloma cell co-cultures are now being developed to produce more clinically-relevant modeling tools (15
). Pharmaceutical developers are also now attacking tumor cells through stromal-affecting drugs, such as Bortezomib, Perifosine, and an array of bisphosphonates which target stromal cell-tumor cell interactions. Perifosine induces apoptosis even in MM cells attached to bone marrow stromal cells through the c-Jun N-terminal kinase (JNK) pathway(17
) and Bortezomib, a proteasome inhibitor, was recently found to directly induce osteoblastic differentiation in MSCs to combat osteolysis through the transcription factor RUNX-2(18
). As a last example, the CXCR4 inhibitor AMD3100 disrupts the interaction of MM cells and MSCs and enhances MM cell sensitivity to therapy(19
). This and other work demonstrates that CXCR4 inhibitors, or other therapies that detach tumor cells from the bone matrix, can increase chemosensitivity of MM cells. The discussed pharmaceuticals were developed based on in vitro
studies of healthy donor stroma cells and MM cells. We hypothesize that more effective and specific chemotherapeutic strategies will be identified using in vitro
models containing MM patient MSCs. The questions are then: are there differences between non-diseased (ND-MSCs) and myelomatous MSCs, those derived from multiple myeloma patients (MM-MSCs)? How do these relate to differing interactions with MM cells? Lastly, how can we target these interactions for a therapeutic effect? These questions are herein addressed. MM-MSCs discussed were from untreated MM patients unless otherwise noted; often the status of age-matching was not reported in the studies.