Neo-organoid of marrow mesenchymal stromal cells secreting interleukin-12 for breast cancer therapy.

Abstract

Bone marrow-derived mesenchymal stromal cells (MSCs), beneficial for regenerative medicine applications due to their wide differentiation capabilities, also hold promise as cellular vehicles for the delivery of therapeutic plasma-soluble gene products due to their ease of handling, expansion, and genetic engineering. We hypothesized that MSCs, gene enhanced to express interleukin-12 (IL-12) and then embedded in a matrix, may act as an anticancer neo-organoid when delivered s.c. in autologous/syngeneic hosts. We performed such experiments in mice and noted that primary murine MSCs retrovirally engineered to secrete murine IL-12 can significantly interfere with growth of 4T1 breast cancer cells in vivo, with a more substantial anticancer action achieved when these cells are embedded in a matrix. Plasma of mice that received the IL-12 MSC-containing neo-organoids showed increased levels of IL-12 and IFN-gamma. Histopathologic analysis revealed less tumor cells in implants of 4T1 cells with IL-12 MSCs, and the presence of necrotic tumor islets and necrotic capillaries, suggesting antiangiogenesis. We also showed that the anticancer effect exerted by the IL-12 MSCs is immune mediated because it is absent in immunodeficient mice, is not due to systemic IL-12 delivery, and also occurs in a B16 melanoma model. This study therefore establishes the feasibility of using gene-enhanced MSCs in a cell-based neo-organoid approach for cancer treatment.

• Authors: Nicoletta Eliopoulos, Moïra Francois, Marie-Noëlle Boivin, Daniel Martineau, Jacques Galipeau
• Journal: Cancer research (Cancer Res) Vol. 68 Issue 12 Pg. 4810-8 (Jun 15 2008) ISSN: 1538-7445 [Electronic] United States
• PMID: 18559528 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Interleukin-12

Topics

• Animals
• Bone Marrow Cells (metabolism)
• Cells, Cultured
• Female
• Immunotherapy
• Interleukin-12 (metabolism, therapeutic use)
• Mammary Neoplasms, Experimental (immunology, metabolism, therapy)
• Melanoma, Experimental (immunology, metabolism, therapy)
• Mesoderm (cytology, immunology, metabolism)
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Mice, Inbred NOD
• Mice, SCID
• Neovascularization, Physiologic
• Organoids
• Stromal Cells (immunology, metabolism, pathology)
• Survival Rate