The tumor microenvironment contains many distinct cell types, including endothelial cells and their precursors, pericytes, smooth muscle cells, fibroblasts, carcinoma-associated fibroblasts, myofibroblasts, neutrophils/eosinophils/basophils/mast cells, T/B lymphocytes, natural killer cells and antigen-presenting cells, such as macrophages and dendritic cells . The microenvironment of a solid tumor closely resembles the environment of wound healing and tissue repair sites of an injured tissue. On tissue injury, platelets are activated. These activated platelets release vasoactive mediators for vascular permeability, serum fibrinogen for fibrin clot formation and growth factors/cytokines/matricellular proteins to initiate granulation tissue formation, activate fibroblasts, and induce and activate MMPs necessary for ECM remodeling. Epithelial and stromal cell types engage in a reciprocal signaling cross-talk to assist healing. The reciprocal signaling collapses after the wound is healed. In the case of tumorigenesis, the invasive inflammatory tumor cells produce an array of cytokines/chemokines that are mitogenic for granulocytes/monocytes/macrophages/fibroblasts/endothelial cells. These factors (cytokines/chemokines) potentiate tumor growth, stimulate angiogenesis, induce fibroblast migration and enable metastatic spread. During this process, nonhematopoietic mesenchymal stem cells (MSCs) originating from bone marrow localize to the sites of hematopoiesis, sites of inflammation and sites of injury, as well as to solid tumors [88–90]. Inactivated MSCs have been shown to inhibit tumor growth by inhibiting a PI3K/AKT pathway in an E-cadherin-dependent manner, prompting the use of these cells as tumor inhibitory cells in vivo , whereas activated MSCs within the solid tumors are the source of carcinoma-associated fibroblasts that contribute to tumor growth in several ways [92,93]. Tissue injury and inflammation are accompanied by increased production of stromal HA, which, in addition to cell–cell and cell–matrix adhesion [94,95], and cell proliferation and survival [10,83,87,96], helps to create highly hydrated ECM that may facilitate local cellular trafficking [97,98]. In the bone marrow, HA is also abundantly produced by both stromal and hematopoietic cells. CD44, in addition to its function to regulate cell proliferation/differentiation/survival/migration into tissues, is implicated in hematopoietic progenitor trafficking to the bone marrow and spleen [99–101]. The concept of the use of MSCs as delivery vehicles originates from the fact that tumors, similar to wounds, produce chemoattractants, such as cytokines/chemokines (e.g. vascular endothelial growth factor, transforming growth factor-β), to recruit MSCs to form the supporting stroma of the tumor, and also pericytes for angiogenesis. MSCs transfected with the interferon-β gene can increase the production of interferon-β at the local site [102,103]. Likewise, Herrera et al.  presented a convincing case indicating that interactions between CD44 and HA influence the homing of exogenous MSCs that localize to the kidneys during acute renal failure, i.e. CD44 on exogenous cells is important in helping MSCs to localize to the damaged renal tissue in vivo. However, this in vivo function of MSCs depends partly on signals from the target tissue microenvironment, i.e. endothelial progenitor cells were used as gene delivery vehicles to the site of angiogenesis rather than to the quiescent vasculature . On the basis of these observations, it is possible to deliver immune-activating cytokines/secreted proteins to the site of tumors through MSCs . As human MSCs can be easily expanded in vitro and retain an extensive multipotent capacity for differentiation [106,107], in a recent study, we found that genetically engineered human MSCs which secrete soluble CD44v that acts as an antagonist to HA–CD44v signaling inhibit malignant properties in cancer cells (S. Misra et al., unpublished results). These studies and co-implantation models combining tumor cells and MSCs [102,103,108] hold great promise for therapeutic strategies , in which the interaction between tumor and stroma can be manipulated and studied (the concept of using MSCs for tumor therapy is depicted in the model in Fig. 3).
Figure 3. Bone marrow-derived nonhematopoietic human mesenchymal stem cells (hMSCs) are pluripotent cells that are capable of differentiating into various tissue lineages, including osteoblasts, adipocytes, chondrocytes, myoblasts, hepatocytes and possibly even neural cells . After systemic injection, hMSCs can selectively migrate to solid tumors, where they proliferate and become cancer-associated stromal myofibroblasts . As hMSCs can be easily expanded in vitro and possess an extensive multipotent capacity for differentiation, they have been explored as vehicles for tissue repair and gene therapy , when they are appropriately engineered for therapy. We established that tissue-specific floxed plasmid/nanoparticle delivery is efficient for the activation of a gene of interest . In a pilot study (S. Misra et al., unpublished results) using genetically modified hMSCs in nanoparticles, the tropism was altered, because the secreted proteins from transduced hMSCs interacted with stromal hyaluronan, and thus inhibited the malignant properties of cancer cells by more than 20-fold by perturbing hyaluronan–CD44v interaction.
Download figure to PowerPoint