A Specific Subpopulation of Mesenchymal Stromal Cell Carriers Overrides Melanoma Resistance to an Oncolytic Adenovirus

Abstract

The homing properties of mesenchymal stromal c'ells (MSCs) toward tumors turn them into attractive tools for combining cell and gene therapy. The aim of this study was to select in a feasible way a human bone marrowderived MSC subpopulation that might exhibit a selective ability to target the tumor mass. Using differential in vitro adhesive capacities during cells isolation, we selected a specific MSC subpopulation (termed MO-MSCs) that exhibited enhanced multipotent capacity and increased cell surface expression of specific integrins (integrins a2, a3, and a5), which correlated with an enhanced MO-MSCs adhesiveness toward their specific ligands. Moreover, MO-MSCs exhibited a higher migration toward conditioned media from different cancer cell lines and fresh human breast cancer samples in the presence or not of a human microendothelium monolayer. Further in vivo studies demonstrated increased tumor homing of MO-MSCs toward established 578T and MD-MBA-231 breast cancer and A375N melanoma tumor xenografts. Tumor penetration by MO-MSCs was highly dependent on metallopeptidases production as it was inhibited by the specific inhibitor 1,10 phenantroline. Finally, systemically administered MO-MSCs preloaded with an oncolytic adenovirus significantly inhibited tumor growth in mice harboring established A375N melanomas, overcoming the natural resistance of the tumor to in situ administration of the oncolytic adenovirus. In summary, this work characterizes a novel MSC subpopulation with increased tumor homing capacity that can be used to transport therapeutic compounds.

Polysome Profiling Shows the Identity of Human Adipose-Derived Stromal/Stem Cells in Detail and Clearly Distinguishes Them from Dermal Fibroblasts

“…Indeed, a subpopulation of MSCs derived from human bone marrow cells that exhibited enhanced adhesive and multipotent capacities has been recently identified by Bolontrade et al [38]. It would be interesting to determine whether a subpopulation of this type also exists in ADSCs and whether it is responsible for the difference to fibroblasts in adherence.…”

A Novel CDC25B Promoter–Based Oncolytic Adenovirus Inhibited Growth of Orthotopic Human Pancreatic Tumors in Different Preclinical Models

“…For systemic administration, it will be necessary to circumvent liver uptake and preexisting immunity elicited by neutralizing antibodies, adenovirus-specific T cells and NK response. One possibility relies on varying the administration routes (39); in addition, the use of carrier cells might act as shields to protect the virus from the immune attack (40). AV25CDC seems to have the capacity to eliminate also colon cancer and gastric cancer cells with clear biosafety parameters.…”

Oncolytic Adenovirus-Loaded Menstrual Blood Stem Cells Overcome the Blockade of Viral Activity Exerted by Ovarian Cancer Ascites

“…disseminated ovarian cancer with reduced hepatotoxicity 25, 42. Systemically administered MSCs preloaded with an oncolytic Ad significantly inhibited tumor growth in mice harboring established A375N melanomas, overcoming the natural resistance of the tumor to intratumor administration of the CRAd 23 . Among MSCs obtained from different sources, menstrual stem cells exhibited properties that make them likely candidates for future clinical trials.…”

“…In this regard, mesenchymal stem cells (MSCs) were isolated from the bone marrow, adipose tissue, umbilical cord, and other tissues 22 . Different studies, including from our group, showed clear evidence that MSCs obtained from different sources can be used as carriers of oncolytic viruses to deliver the virus deeply inside the tumor mass 23, 24. MSCs might eventually hide the virus from immune attack and may reduce hepatic uptake, increasing viral availability 25 …”