Amino-biphosphonate-mediated MMP-9 inhibition breaks the tumor-bone marrow axis responsible for myeloid-derived suppressor cell expansion and macrophage infiltration in tumor stroma.

Abstract

BALB-neuT mice expressing an activated rat c-erbB-2/neu transgene under the mouse mammary tumor virus long terminal repeat show enhanced hematopoiesis with hyperproduction of myeloid-derived suppressor cells (MDSC) because of vascular endothelial growth factor (VEGF) secreted by the tumor. Here, we show that both tumor and stromal cells express matrix metalloproteinase-9 (MMP-9), thereby increasing the levels of pro-MMP-9 in the sera of tumor-bearing mice. Treatment with amino-biphosphonates impaired tumor growth, significantly decreased MMP-9 expression and the number of macrophages in tumor stroma, and reduced MDSC expansion both in bone marrow and peripheral blood by dropping serum pro-MMP-9 and VEGF. We dissected the role of tumor-derived MMP-9 from that secreted by stromal leukocytes by transplanting bone marrow from MMP-9 knockout mice into BALB-neuT mice. Although bone marrow progenitor-derived MMP-9 had a major role in driving MDSC expansion, amino-biphosphonate treatment of bone marrow chimeras further reduced both myelopoiesis and the supportive tumor stroma, thus enhancing tumor necrosis. Moreover, by reducing MDSC, amino-biphosphonates overcome the tumor-induced immune suppression and improved the generation and maintenance of antitumor immune response induced by immunization against the p185/HER-2. Our data reveal that suppression of MMP-9 activity breaks the vicious loop linking tumor growth and myeloid cell expansion, thus reducing immunosuppression. Amino-biphosphonates disclose a specific MMP-9 inhibitory activity that may broaden their application above their current usage.

• Authors: Cecilia Melani, Sabina Sangaletti, Francesca M Barazzetta, Zena Werb, Mario P Colombo
• Journal: Cancer research (Cancer Res) Vol. 67 Issue 23 Pg. 11438-46 (Dec 01 2007) ISSN: 1538-7445 [Electronic] United States
• PMID: 18056472 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Diphosphonates
• Imidazoles
• Vascular Endothelial Growth Factor A
• Zoledronic Acid
• Receptor, ErbB-2
• Matrix Metalloproteinase 9

Topics

• Animals
• Bone Marrow Cells (enzymology, pathology)
• Bone Marrow Transplantation
• Colony-Forming Units Assay
• Diphosphonates (pharmacology)
• Female
• Hematopoiesis
• Imidazoles
• Immune Tolerance
• Immunotherapy
• Macrophages (drug effects, metabolism, pathology)
• Male
• Mammary Neoplasms, Experimental (blood supply, enzymology, pathology)
• Matrix Metalloproteinase 9 (biosynthesis, deficiency, genetics)
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Mice, Transgenic
• Myeloid Cells (drug effects, metabolism, pathology)
• Neovascularization, Pathologic (enzymology, pathology)
• Receptor, ErbB-2 (metabolism)
• Stromal Cells (drug effects, metabolism, pathology)
• Vascular Endothelial Growth Factor A
• Zoledronic Acid