Macrophage Migration Inhibitory Factor–CXCR4 Is the Dominant Chemotactic Axis in Human Mesenchymal Stem Cell Recruitment to Tumors

Abstract

Mesenchymal stromal cells (MSCs) are inherently tumor-homing and can be isolated, expanded and transduced, making them viable candidates for cell therapy. This tumor-tropism has been used to deliver anti-cancer therapies to various tumor models. In this study we sought to discover which molecules are the key effectors of human MSC tumor homing in vitro and using an in vivo murine model. Here we discover for the first time that Macrophage Migration Inhibitory Factor (MIF) is the key director of MSC migration and infiltration towards tumor cells. We have shown this major role for MIF using in vitro migration and invasion assays, in presence of different receptor inhibitors and achieving a drastic decrease in both processes using MIF inhibitor. Additionally, we demonstrate physical interaction between MIF and three receptors: CXCR2, CXCR4 and CD74. CXCR4 is the dominant receptor used by MIF in the homing tumor context, although some signaling is observed through CXCR2. We demonstrate downstream activation of the MAPK pathway necessary for tumor homing. Importantly we show that knock down of either CXCR4 or MIF abrogates MSC homing to tumors in an in vivo pulmonary metastasis model, confirming the in vitro 2D and 3D assays. This improved understanding of MSC tumor tropism will further enable development of novel cellular therapies for cancers.

Skin-derived mesenchymal stem cells as quantum dot vehicles to tumors

“…We successfully simulated directional migration of MSCs toward human breast cancer cells and their conditioned medium in vitro. Our results complement the evidence that MSCs tend to migrate toward cancer cells, 13,18 cancer cell-conditioned medium, 61 and growth medium, supplemented with recombinant proteins found in cancer cell-conditioned medium, 62 verifying that cancer cells secrete molecules promoting MSC migration. The key molecules inducing MSC migration toward tumors supposedly are vascular endothelial growth factor, 63 fibroblast growth factor 2, 64 stromal cell derived factor 1 (SDF-1), 65 chemokine (C-C motif) ligand 2, also known as monocyte chemotactic protein-1, 66 and macrophage migration inhibitory factor.…”

“…10 MSCs have chemokine receptors 11 and a tendency to migrate through the chemokine gradient toward the tumor. 12,13 Owing to these tumor-tropic properties, MSCs could be used to transport therapeutic molecules directly to cancerous tissues. MSC-mediated transportation of different signaling molecules (interleukins, interferons, chemokines), 14,15 genetically modified viruses, 16 gene therapy components, 17 chemotherapeutic drugs and prodrugs 18,19 are already topics of research.…”

“…The key molecules inducing MSC migration toward tumors supposedly are vascular endothelial growth factor, 63 fibroblast growth factor 2, 64 stromal cell derived factor 1 (SDF-1), 65 chemokine (C-C motif) ligand 2, also known as monocyte chemotactic protein-1, 66 and macrophage migration inhibitory factor. 13 MSC migration is suppressed by antibodies against chemokine (C-X-C motif) receptor 4 (CXCR4) 67 or by receptor antagonists, 13 proving SDF-1/ CXCR4 to be the main axis mediating MSC migration to cancerous tissue. 51 Our research shows that in comparison to the chemotaxis toward highly potent chemoattractant (growth medium supplemented with 20% serum), the migration induced by cancer cells was mediocre ( Figures 5C and 6).…”

Combined cell-gene therapy for lung cancer: rationale, challenges and prospects

“…Similar to leucocytes, MSCs may undergo both passive and active homing and chemotaxis is thought to be largely dependent on CXCR4, which binds to CXCL12, which is known to be overexpressed at tumour sites. In lung cancer we have demonstrated overexpression of macrophage inhibitory factor (MIF), which also binds CXCR4 maybe a key modulator of MSC tumour tropism [8].…”

The analysis of estrogen receptor-α positive breast cancer stem-like cells unveils a high expression of the serpin proteinase inhibitor PI-9: Possible regulatory mechanisms

“…In this regard, we focused particular attention on CXCR4, the chemokine receptor specific for the stromal-derived-factor-1 (29). This receptor represents a prognostic factor in different types of cancer and plays a role in chemotaxis, stemness and drug resistance (30,31). Moreover, recent data have also described this factor as a key regulator of breast cancer invasion, directing homing of BC cells to particular sites of metastases (32).…”