The ultimate goal of this area of research is for the development of a cellular therapy for humans. MSC-directed anticancer treatment has definite potential for translation to clinical medicine. The specific targeting is likely to produce significantly less host toxicity than traditional agents and will allow much higher local concentrations of antitumour agents. Other tumour-directed therapies such as monoclonal antibodies rely on the detection and expression of specific tumour antigens which are likely to change between patients, cancers and time. Conversely, MSCs appear to be able to localise specifically in a range of different tumours and their metastases.
The most likely position for MSC-delivered therapy in cancer treatment would be in combination with present radiotherapy and chemotherapy agents. Our study demonstrated an elimination of metastases with TRAIL-expressing MSCs,7
and others have also described a reduced metastatic load with MSC-delivered therapies (). This effect on metastases is extremely important as secondary spread is the main cause of mortality and morbidity in patients with cancer. Many patients with solid organ tumours progress to metastatic disease despite primary tumour resection, chemotherapy and radiotherapy. The recurrence rate following surgery of curative intent, despite tumour negative lymph nodes, is up to 40% in non-small cell lung cancer, 30% in colon cancer, 25% in breast cancer and 15–50% in prostate cancer.94
The use of new molecular and cytological techniques to detect small numbers of circulating malignant cells makes the identification of patients at significant risk of future metastatic disease a possibility.94
The detection of these cells, presumably resistant to the host’s endogenous immune surveillance, is related to metastatic recurrence and poorer prognosis and could be amenable to MSC-directed therapy.
There may also be an increased synergism of a combination therapy approach which is greater than the sum of its parts (). The homing of MSCs to tumours has been shown to increase significantly with the use of radiation. This has been demonstrated with irradiated glioma, breast and colon cancer xenograft models, in addition to a syngeneic murine breast carcinoma model, and to be secondary to the increased inflammation and expression of cytokines from the irradiated tissue in addition to the upregulation of chemokine receptors on the MSCs.96
Chemotherapeutic agents and radiotherapy have also been shown to increase the cancer-killing effects of some of the MSC-delivered therapies. The apoptotic effects of TRAIL are significantly increased in vitro and in in vivo xenograft studies with chemotherapy or radiotherapy. A number of possible mechanisms have been postulated for this synergism, including the upregulation of TRAIL receptors,98
the clustering of TRAIL receptors into lipid rafts,100
the downregulation of apoptotic pathway inhibitors101
or the enhanced cleavage of caspases.102
Figure 4 Synergy of chemotherapy and radiotherapy with mesenchymal stem cell (MSC)-delivered anticancer agents. Chemotherapy and radiotherapy cause DNA damage and cancer cell apoptosis by the intrinsic apoptosis pathway, whereas TRAIL leads to cancer cell apoptosis (more ...)
As described above, there are some concerns for MSC-based therapies. Despite these, however, phase 1 and 2 clinical trials have now been performed or are ongoing, with exogenous MSCs for the promotion of haematopoietic recovery,104
for GvHD following bone marrow transplantation,70
ischaemic cardiac disease,74
and chronic obstructive pulmonary disease,106
and so far neither acute nor long-term adverse effects have been reported following their infusion.