Cancer gene therapy using mesenchymal stem cells
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Cellular and gene therapies represent promising treatment strategies at the frontier of medicine. Hematopoietic stem cells, lymphocytes, and mesenchymal stem cells (MSCs) can all serve as sources of cells for use in such therapies. Strategies for gene therapy are often based on those of cell therapy, and it is anticipated that some examples will be put to practical use in the near future. Given their ability to support hematopoiesis, MSCs may be useful for the enhancement of stem cell engraftment, and the acceleration of hematopoietic reconstitution. Furthermore, MSCs may advance the treatment of severe graft-versus-host disease, based on their immunosuppressive ability. This application is also based on the homing behavior of MSCs to sites of injury and inflammation. Interestingly, MSCs possess tumor-homing ability, opening up the possibility of applications in the targeted delivery of anti-cancer genes to tumors. Many reports have indicated that MSCs can be utilized to target tumors and to deliver anti-cancer molecules locally, as tumors are recognized as non-healing wounds with inflammatory tissue. Here, we review both the potential of MSCs as cellular vehicles for targeted cancer therapy and the molecular mechanisms underlying MSC accumulation at tumor sites.
KeywordsMesenchymal stem (stromal) cell Cell and gene therapy TNF-α Adhesion molecules
Applications of genetically engineered MSCs for cancer therapy
An early application of MSCs to targeted cancer therapy was directed delivery of interferon beta (IFN-β). MSCs were transduced with the IFN-β gene, followed by their infusion into mice carrying melanoma xenografts. MSC treatment resulted in reduced tumor growth and prolonged survival of tumor-bearing mice . Based on this observation, genetically modified MSCs from various tissues have since been evaluated for their therapeutic efficacy and their ability to act as cellular vehicles [3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23].
Interleukins (ILs) that regulate inflammatory and immune responses are often used as therapeutic agents. IL-12-expressing MSCs (MSC-IL-12) have been used to improve tumor immunological surveillance by activating cytotoxic lymphocytes and natural killer (NK) cells. Administration of MSC-IL-12 was shown to suppress metastasis and increase tumor cell apoptosis in mice bearing melanoma, lung cancer and hepatoma. Other immunomodulatory cytokines have also been examined for anti-tumor activities, including the T cell attractant CX3CL1. For example, MSC-CX3CL1 inhibited lung metastasis of melanoma and prolonged survival of tumor-bearing mice.
Studies of cell and gene therapy for cancer that utilize genetically modified MSCs
Immunostimulatory, apoptosis inducing and anti-angiogenic
Metastasis (prostate, breast, melanoma)
S-phase accumulation and apoptosis
Immunostimulatory and apoptosis inducing
In vitro (leukemia)
Activates CTLs and NK cells and produces IFN-γ
Subcutaneous (melanoma, hepatoma, lung)
Activates CTLs and NK cells
Metastasis (melanoma, colon)
Subcutaneous, orthotopic (glioma)
Prodrug conversion (5-FC → 5-FU)
Subcutaneous (melanoma, colon)
Inhibits angiogenesis and promotes apoptosis
Destroys tumors by viral replication
Orthotopic (breast, lung, ovarian)
Interactions between tumors and MSCs
As detailed above, the use of MSCs to deliver anti-cancer agents is an attractive novel cancer therapeutic strategy. Endothelial cells (ECs), pericytes, and stromal cells are all known to support tumor growth and contribute to the tumor microenvironment by producing various growth factors including vascular endothelial growth factor (VEGF)-A, IL-8, transforming growth factor (TGF)-β, epidermal growth factor (EGF), and platelet-derived growth factor (PDGF) [24, 25, 26, 27, 28, 29]. MSCs can also act in such a supportive fashion. It is speculated that when MSCs accumulate at tumor sites, they differentiate into pericytes or cancer-associated fibroblasts (CAFs) and are involved in facilitating tumor growth by providing structural support to the tumor microenvironment [3, 30, 31]. Interestingly, breast cancer cells stimulate MSCs and MSCs in turn support cancer cell invasion and metastasis by secreting CCL5 . Conversely, MSCs can also induce apoptosis in tumor cells by blocking phosphorylation of AKT or preventing cell cycle progression . Moreover, MSCs can produce DKK-1 to attenuate the potential for growth and malignancy of tumor cells . As MSCs have dual and opposing effects with respect to tumor growth, modification with anti-tumor genes is required for MSC-based cancer-targeted therapy. Furthermore, it is also necessary to promote more efficient MSC accumulation at tumor sites.
Molecular mechanisms of MSC accumulation at tumors
If it becomes possible to increase the accumulation efficiency of MSCs at tumor sites, MSCs can effectively target not only primary tumors but also metastatic lesions. It is thought that MSCs are mobilized to damaged tissues, such as in injury or inflammation, by the release of inflammatory cytokines. Tumors possess a microenvironment consisting of a large number of inflammatory cells . This microenvironment promotes the recruitment of MSCs via various soluble factors secreted by both tumor and inflammatory cells, including EGF, VEGF-A, PDGF, IL-8, IL-6, fibroblast growth factor, stromal cell-derived factor, granulocyte colony-stimulating factor, granulocyte–macrophage colony-stimulating factor, monocyte chemoattractant protein-1 (MCP-1), hepatocyte growth factor, TGF-β1, and urokinase-type plasminogen activator [36, 37, 38, 39, 40, 41, 42]. However, our own work found that while systemically injected MSCs accumulated at tumor sites, subcutaneously injected MSCs did not. We also compared the migration capacity of MSCs and fibroblasts (FBs) toward growth factors and chemokines in vitro, and found that FBs were more strongly attracted to these factors than MSCs . These results suggest that the mechanism of MSC accumulation cannot be explained solely by cytokine-mediated migration.
Considerations for the use of genetically modified MSCs in cancer therapy
Although we focused on the function of TNF-α in the above study, other inflammatory cytokines including IL-1β and IFN-γ have the ability to induce VCAM-1 expression on target cells, and may also be involved in MSC accumulation. TNF-α is a major inflammatory cytokine that has important roles in diverse cellular events including cell survival, proliferation, differentiation, and death. Numerous reports have demonstrated elevated TNF-α levels in the serum of cancer patients, and TNF-α correlates closely with tumor progression and metastasis [44, 45]. For example, TNF-α readily induces IL-6 and MCP-1 secretion by CAFs and normal FBs and has an indirect influence on the generation of a prometastatic microenvironment. Furthermore, TNF-α is released in cardiac infarction  and graft-versus-host disease [47, 48]; MSCs accumulate at the site of cardiac infarction [49, 50]. These results indicate that pro-inflammatory cytokines also promote homing of MSCs in the heart and that these cytokines have a positive effect on cardiac regeneration. Therefore, MSC-based tissue-targeting strategies could be adapted for various inflammatory diseases, and activation with TNF-α may be one of the critically important steps for MSC accumulation.
For MSC-based cancer-targeted gene therapies, it is thought that therapeutic efficacy is directly coupled with the efficiency of MSC accumulation at tumor sites. Results from our laboratory suggest that the combined use of NF-κB inhibitors, including bortezomib, or TNF-α blocking agents, such as infliximab, reduces the therapeutic efficacy of genetically modified MSCs because of inhibition of MSC accumulation at the tumor. In contrast, tumor-specific TNF-α-inducing agents would be useful in enhancing therapeutic efficacy, thus further investigation is required for identifying such agents to establish more effective therapeutic strategies.
The application of anti-cancer gene-expressing MSCs for targeted cancer therapy is a novel and promising strategy. Here, we propose that suicide cancer gene therapy may be improved using vector-producing MSCs. This strategy is likely to generate vectors in situ, leading to the killing of solid tumors. This could be achieved using MSCs to initiate virus production near tumor cells in situ. These viruses are then transduced into tumor cells, which themselves produce virus progeny, thereby amplifying the transgene expression at tumor sites. While the therapeutic benefit and safety of this approach requires further examination, it holds great potential for the eradication of tumors.
MSC accumulation at tumor sites is related to migratory capacity toward growth factors and chemokines and also MSC-EC adhesion following activation by TNF-α. Furthermore, NF-κB activity regulates MSC accumulation at tumor sites through the induction of VCAM-1 expression and the resultant interaction with tumor blood vessel ECs. Although MSCs are useful as cellular vehicles for cancer-targeted gene therapy, previous studies have shown that increased MSC accumulation is required to enhance therapeutic efficacy. Thus, mechanisms of enhancing MSC accumulation should be developed, and the TNF-α-NF-κB-VCAM-1 axis may represent a solution to this problem.
Conflict of interest
The authors declare that they have no conflict of interest.