Matrix metalloproteinase‐1‐mediated mesenchymal stem cell tumor tropism is dependent on crosstalk with stromal derived growth factor 1/C‐X‐C chemokine receptor 4 axis

Abstract

Human bone marrow-derived mesenchymal stem cells (MSCs) have the unique ability to home toward injuries or tumor sites. We have previously shown that the tumor-tropic property is dependent on the intrinsic expression and activity of the matrix remodeling gene, matrix metalloproteinase 1 (MMP-1). Herein, crosstalk between MMP-1/protease activated receptor 1 (PAR-1) and the G-protein coupled receptor stromal-derived growth factor 1 (SDF-1)/C-X-C chemokine receptor 4 (CXCR-4) in facilitating cell migration was investigated. Gain-of-function and RNA interference (RNAi) technology were used to evaluate the interplay between the key players. The downstream effect on the tumor-tropic migration of MSCs was investigated using modified Boyden chamber assay. Neutralizing PAR-1 activation using monoclonal antibody and targeted knockdown of MMP-1 using RNAi resulted in decreased expression of SDF-1, which was not observed in control-RNAi-transfected cells. Overexpression of CXCR-4 failed to promote MSC migration; the percentage of migrated cells toward tumor cell conditioned medium was similar to the vector-transduced and the CXCR-4-transduced MSCs. Furthermore, inhibition of SDF-1/CXCR-4 signaling using AMD3100 reduced MSC migration through the deregulation of MMP-1 promoter activities, protein expression, and metalloproteinase activity.

Senescent tumor cells lead the collective invasion in thyroid cancer

“…We also found that MMPs expression was markedly downregulated in AMD3100 treated cells (Supplementary Fig. 16b), which was consistent with the results of previous reports4142. Collectively, these data suggested that senescent cells work as a ‘storming party' in the collective invasion of cancer through SASP, including MMPs and CXCL12/CXCR4 signalling.…”

Bone mesenchymal stem cells differentiate into myofibroblasts in the tumor microenvironment

“…In the present study, the cells of Test 1 group had increased migration compared with the control group, which demonstrated the tropism of MSCs to the tumor microenvironment, which was consistent with previous studies (39,40). Furthermore, it is notable that migrated cells were significantly increased in the 30% VX2 conditioned medium group compared with the 50% VX2 conditioned medium group, however, these results contradict the results of previous studies (39,40).…”

“…Furthermore, it is notable that migrated cells were significantly increased in the 30% VX2 conditioned medium group compared with the 50% VX2 conditioned medium group, however, these results contradict the results of previous studies (39,40). There may be various reasons for this result.…”

Mesenchymal stromal cells’ role in tumor microenvironment: involvement of signaling pathways

“…Specifically, experimental evidence has established the CXCL12/CXCR4 pathway as a pivotal pathway for MSC and malignant cell migration and homing. Examples include reports suggesting the following: ( i ) MSC tumor tropism is mediated by matrix metalloproteinase-1 via a mechanism dependent on cross-talk with CXCL12/CXCR4 axis 129 (129); ( ii ) CXCL12 is abundantly released by BM-MSCs and drives the homing of leukemic cells in the bone marrow stroma in pediatric precursor B-cell acute lymphoblastic leukemia 130 ; and ( iii ) CXCL12/CXCR4 signals the silencing results in the inhibition of MSC migration to the primary tumor and metastasis sites in solid cancers, such as breast carcinoma 119,120 . …”