Host matrix metalloproteinase-9 contributes to tumor vascularization without affecting tumor growth in a model of prostate cancer bone metastasis

  • Sanaa M. Nabha
  • R. Daniel Bonfil
  • Hamilto A. Yamamoto
  • Abdelfettah Belizi
  • Christoph Wiesner
  • Zhong Dong
  • Michael L. Cher
Original Research
First Online:
Received:
Accepted:

Abstract

Matrix metalloproteinases (MMPs) have been associated with initiation, progression and vascularization of a number of tumors. However, clinical trials using MMP inhibitors failed to meet expectations. Previously, we demonstrated the potential importance of MMP-9 activity in experimental prostate cancer bone tumor tissue. However, the particular roles of host- and tumor-derived MMP-9 remains to be defined. Herein, we examined the role of host MMP-9 in subcutaneous and intraosseous growth of the human androgen independent prostate cancer cell line PC3 in MMP-9 deficient mice. In the subcutaneous model, the tumor incidence in the control (RAG-1 ko/ko ) and experimental (RAG-1 ko/ko /MMP-9 ko/ko ) group was 100%, with similar tumor growth kinetics and microvascular densities. In the intraosseous tumor model, the tumor incidence was higher in RAG-1 ko/ko /MMP-9 ko/ko mice than in RAG-1 ko/ko mice (67% and 39%, respectively), though no statistical differences were found. The intraosseous tumor areas were similar in both groups, and the number of tumor-associated osteoclasts did not differ significantly. However, the microvascular density of intraosseous tumors was higher in RAG-1 ko/ko than in RAG-1 ko/ko /MMP-9 ko/ko mice, though no changes in tumor growth could be detected. In an in vitro assay, we found that bone marrow (BM) cells increased the invasiveness of PC3 cells, and that this enhancement was independent of MMP-9 expression by marrow cells. Our results with the RAG-1 model suggest that host-derived MMP-9 is neither necessary nor sufficient for subcutaneous or intraosseous PC3 tumor growth, osteoclastic response, or in vitro invasiveness of tumor cells.

Keywords

MMP-9 Prostate cancer Vascularization 

Abbreviations

BM

bone marrow

EA

endothelial area

ECM

extracellular matrix

EDTA

ethylenediaminetetraacetic acid

FBS

fetal bovine serum

MMP

matrix metalloproteinase

MT-MMPs

membrane-type MMPs

MVD

microvascular density

SCF

stem cell factor

VEGF

vascular endothelial growth factor

TRAcP

tartrate-resistant acid phosphatase

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Notes

Acknowledgements

We thank Allen D. Saliganan and Hong Meng for their expert technical assistance. This work was supported by NIDDK Grant 067687 (MC). We thank Dr. Lisa Coussens (Comprehensive Cancer Center, University of California, San Francisco, CA) for providing RAG-1 ko/ko and RAG-1 ko/ko /MMP-9 ko/ko mice. The initial derivation of the mice was supported by grants P01 CA72006 and R01 CA94168 to Dr. Coussens.

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Copyright information

© Springer Science + Business Media B.V. 2006

Authors and Affiliations

  • Sanaa M. Nabha
    • 1
  • R. Daniel Bonfil
    • 1
    • 2
  • Hamilto A. Yamamoto
    • 1
  • Abdelfettah Belizi
    • 1
  • Christoph Wiesner
    • 1
  • Zhong Dong
    • 1
  • Michael L. Cher
    • 1
    • 2
  1. 1.Department of UrologyWayne State University School of Medicine, The Barbara Ann Karmanos Cancer InstituteDetroitUSA
  2. 2.Department of PathologyWayne State University School of Medicine, The Barbara Ann Karmanos Cancer InstituteDetroitUSA

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