Mesenchymal stem cells inhibit proliferation and apoptosis of tumor cells: impact on in vivo tumor growth

Abstract

Mesenchymal stem cells (MSC) have received much attention in the field of hematopoietic stem cell transplantation because not only do they support hematopoiesis but also exhibit a profound immunosuppressive activity that can be exploited to prevent undesired alloreactivity. We have previously shown that their immunosuppressive activity is mainly exerted at the level of T-cell proliferation. Here, we show that MSC exhibit a similar antiproliferative activity on tumor cells of hematopoietic and non hematopoietic origin. In vitro, MSC produced the transient arrest of tumor cells in the G 1 phase of cell cycle; this was accompanied by a reduction in the apoptotic rate even when survival factors were limiting. However, when tumor cells were injected into non-obese diabetic-severe combined immunodeficient mice in conjunction with MSC, their growth was much faster as compared to the group receiving only tumor cells. To explain the discrepancy between the in vitro and in vivo behavior, we suggest that MSC have the ability to form a cancer stem cell niche in which tumor cells can preserve the potential to proliferate and sustain the malignant process. We conclude that the clinical use of MSC in conditions in which a malignant disease is involved should be handled with extreme caution.

Modeling sarcomagenesis using multipotent mesenchymal stem cells

“…Thus, human and mMSCs can home to tumor sites and inhibit the growth of neoplastic cells as shown in models of gliomas [103], Kaposi's sarcomas [104] and hepatoma [105,106]. Other study shows that hMSCs exhibit an antiproliferative activity on tumor cells, although in in-vivo experiments, the co-injection of MSCs caused an increase in tumor cell growth rate [107].…”

CXCR4 antagonists: targeting the microenvironment in leukemia and other cancers

“…However, the overall role of MSC in the tumor microenvironment remains controversial. Although on the one hand, MSC can provide survival, growth and drug resistance signals, 48,54 MSC can also induce cell cycle and growth arrest in epithelial cancer [55][56][57] and leukemia cells. 58 On the basis of these findings, the therapeutic use of MSC to decelerate tumor growth has been proposed.…”

Multipotent mesenchymal stromal cells for autoimmune diseases: teaching new dogs old tricks

“…However, apart from one publication reporting of MSC-induced apoptosis of proliferating lymphocytes, 36 most publications not only excluded the involvement of MSC-induced apoptosis of target cells but, in contrast, suggested that the arrest of apoptosis may be a major mechanism for MSCs imparting a survival signal to immune cells 28,37 as well as to other cells. 38 Clearly, a major mechanism leading to the inhibition of immune-cell effector functions is the arrest of the cell cycle in G0/G1, which results in the inhibition of cell proliferation. [26][27][28]38 Whether this effect is mediated by cell contact mechanisms or soluble factors is still not fully understood.…”

“…38 Clearly, a major mechanism leading to the inhibition of immune-cell effector functions is the arrest of the cell cycle in G0/G1, which results in the inhibition of cell proliferation. [26][27][28]38 Whether this effect is mediated by cell contact mechanisms or soluble factors is still not fully understood. However, transwell experiments have shown putative paracrine soluble factors (Table 1) including hepatocyte growth factor (HGF) and transforming growth factor-b1 (TGF-b1), 22 prostaglandin E 2 39,30 indoleamine 2,3-deoxygenase, 40 inducible NO synthetase resulting in Stat 5 inhibition in lymphocytes, 41 soluble HLA-G 42 and soluble IL-1 receptor.…”