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

Cecilia Melani, Sabina Sangaletti, Francesca M. Barazzetta, Zena Werb, Mario P. Colombo

Research output: Contribution to journalArticle

221 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)11438-11446
Number of pages9
JournalCancer Research
Volume67
Issue number23
DOIs
Publication statusPublished - Dec 1 2007

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Matrix Metalloproteinase 9
Bone Marrow
Macrophages
Neoplasms
Vascular Endothelial Growth Factor A
Myeloid-Derived Suppressor Cells
Myelopoiesis
Mouse mammary tumor virus
Bone Matrix
Terminal Repeat Sequences
Hematopoiesis
Myeloid Cells
Stromal Cells
Growth
Serum
Transgenes
Knockout Mice
Immunosuppression
Immunization
Leukocytes

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

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. / Melani, Cecilia; Sangaletti, Sabina; Barazzetta, Francesca M.; Werb, Zena; Colombo, Mario P.

In: Cancer Research, Vol. 67, No. 23, 01.12.2007, p. 11438-11446.

Research output: Contribution to journalArticle

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