Human umbilical cord mesenchymal stem cells delivering sTRAIL home to lung cancer mediated by MCP-1/CCR2 axis and exhibit antitumor effects

Abstract

Mesenchymal stem cells (MSCs) are believed to be a potential vehicle delivering antitumor agents for their tumor-homing capacity, while the underlying mechanism is yet to be explored. The apoptotic ligand TNF-related apoptosis-inducing ligand (TRAIL) has been suggested as a promising candidate for cancer gene therapy owing to its advantage of selectively inducing apoptosis in cancer cells while sparing normal cells. An isoleucine zipper (ISZ) added to the N-terminal of secretable soluble TRAIL (sTRAIL) can generate the trimeric form of TRAIL (ISZ-sTRAIL) and increase its antitumor potential. However, the inefficient delivery and toxicity are still obstacles for its use. In this study, the migration of human umbilical cord mesenchymal stem cells (HUMSCs) to lung cancer was observed through transwell migration assay and animal bioluminescent imaging both in vitro and in vivo. We found that the homing ability of HUMSCs was suppressed after either knocking down the expression of monocyte chemoattractant protein-1(MCP-1) in lung cancer cells or blocking CCR2 expressed on the surface of HUMSCs, indicating the important role of MCP-1/CCR2 axis in the tropism of HUMSCs to lung cancer. Furthermore, we genetically modified HUMSCs to deliver ISZ-sTRAIL to tumor sites specifically. This targeted therapeutic system exhibited promising apoptotic induction and antitumor potential in a xenograft mouse model without obvious side effects. In conclusion, HUMSCs expressing ISZ-sTRAIL might be an efficient therapeutic approach against lung cancer and MCP-1/CCR2 axis is essential for the tumor tropism of HUMSCs.

Antitumor Activity of a Mesenchymal Stem Cell Line Stably Secreting a Tumor-Targeted TNF-Related Apoptosis-Inducing Ligand Fusion Protein

“…The analysis showed for all MSC groups only slightly elevated serum ALT levels compared to PBS group (<50 U/l), but low compared to the Fas ligand treatment known to cause acute liver toxicity (Figure 5D). This result revealed that the applied treatment protocol (three MSC administrations with and without BZB) did not induce discernable acute hepatotoxic effects in vivo , in accordance with a recent study from Yan and colleagues (21). Additionally, all the other standard parameters, such as body weight, remained in the normal range for the entire period of treatment (data not shown).…”

Mesenchymal Stem Cells Promote Metastasis of Lung Cancer Cells by Downregulating Systemic Antitumor Immune Response

“…It is well known that MSCs are inherently tumor-homing cells that, few hours after systemic injection, migrate in the lungs [ 14 , 15 ]. Many receptors, extracellular matrix proteins, and soluble tumor-derived factors have been reported to effect tumor tropism of intravenously injected MSCs [ 15 , 16 ]. Most recently, it was shown that macrophage migration inhibitory factor (MIF)/CXCR4 and monocyte chemoattractant protein-1 (MCP-1)/CCR2 pathways are responsible for migration of MSCs in the tumor microenvironment of the lungs [ 15 , 16 ].…”

“…Many receptors, extracellular matrix proteins, and soluble tumor-derived factors have been reported to effect tumor tropism of intravenously injected MSCs [ 15 , 16 ]. Most recently, it was shown that macrophage migration inhibitory factor (MIF)/CXCR4 and monocyte chemoattractant protein-1 (MCP-1)/CCR2 pathways are responsible for migration of MSCs in the tumor microenvironment of the lungs [ 15 , 16 ]. MIF secreted from tumor cells attracts MSCs to the lungs in CXCR4-dependent manner.…”

“…Knockdown of either CXCR4 or MIF abrogates MSC homing to tumors in an in vivo pulmonary metastasis model [ 15 ]. Similarly, homing ability of MSCs was suppressed after either knocking down the expression of MCP-1 in lung cancer cells or blocking CCR2 expressed on the surface of MSCs, indicating the important role of MCP-1/CCR2 axis in the tropism of MSCs to lung tumors [ 16 ]. Immediately after their engraftment, MSCs interact with tumor-infiltrated immune cells, affecting antitumor immune response [ 17 ].…”

High expression of TRAIL by osteoblastic differentiated dental pulp stem cells affects myeloma cell viability

“…To date, it is evident that at least a hexavalent organization of TRAIL molecules bypass the pharmacokinetic problems, however not the trimeric form (18). In contrast, in order to manage the insufficient pharmacokinetic properties, several studies have examined the practice of in situ production of a standard soluble TRAIL molecule by different adult stem cells (19)(20)(21). Furthermore, two studies have reported the antitumor activity of human genetically modified MSCs expressing antibodies in a diabody format (22,23).…”