Osteoclast-Derived Matrix Metalloproteinase-9 Directly Affects Angiogenesis in the Prostate Tumor–Bone Microenvironment

Abstract

In human prostate to bone metastases and in a novel rodent model that recapitulates prostate tumor-induced osteolytic and osteogenic responses, we found that osteoclasts are a major source of the proteinase, matrix metalloproteinase (MMP)-9. Because MMPs are important mediators of tumor-host communication, we tested the effect of host-derived MMP-9 on prostate tumor progression in the bone. To this end, immunocompromised mice that were wild-type or null for MMP-9 received transplants of osteolytic/osteogenic-inducing prostate adenocarcinoma tumor tissue to the calvaria. Surprisingly, we found that that host MMP-9 significantly contributed to prostate tumor growth without affecting prostate tumor-induced osteolytic or osteogenic change as determined by microcomputed tomography, microsingle-photon emission computed tomography, and histomorphometry. Subsequent studies aimed at delineating the mechanism of MMP-9 action on tumor growth focused on angiogenesis because MMP-9 and osteoclasts have been implicated in this process. We observed (a) significantly fewer and smaller blood vessels in the MMP-9 null group by CD-31 immunohistochemistry; (b) MMP-9 null osteoclasts had significantly lower levels of bioavailable vascular endothelial growth factor-A 164 ; and (c) using an aorta sprouting assay, conditioned media derived from wild-type osteoclasts was significantly more angiogenic than conditioned media derived from MMP-9 null osteoclasts. In conclusion, these studies show that osteoclast-derived MMP-9 affects prostate tumor growth in the bone microenvironment by contributing to angiogenesis without altering prostate tumor-induced osteolytic or osteogenic changes. Mol Cancer Res; 8(4); 459-70. ©2010 AACR.

Late SV40 Factor (LSF) Enhances Angiogenesis by Transcriptionally Up-regulating Matrix Metalloproteinase-9 (MMP-9)

“…The source of pro-angiogenic MMP-9 might be the tumor cells themselves. Studies from mouse models also suggest bone marrow-derived cells, neutrophils or osteoclasts as potential sources of MMP-9 facilitating tumor angiogenesis (25)(26)(27)(28). We document that the angiogenic properties of conditioned media (CM) from MMP-9 knockdown HCC cells in an LSF-overexpression background were significantly compromised suggesting that MMP-9 plays a key role in the angiogenic function of LSF.…”

The PCa Tumor Microenvironment

“…[ [151][152][153] Fibroblasts Fibroblasts produce the support structures, including the bulk of extracellular matrix, for the prostate. In cancer, they may differentiate into a myofibroblast (a cell with characteristics of both fibroblasts and smooth muscle cells).…”

How MMPs Impact Bone Responses to Metastatic Prostate Cancer

“…Again, MMP-9 was implicated in osteoclast migration, invasion and angiogenesis, presumably via an increase in the amount of bioavailable VEGF-A, as the mechanism mediating these effects. Our group has also defined osteoclast derived MMP-9 as mediating angiogenesis in the prostate tumor-bone microenvironment [130]. We observed that in human samples of prostate to bone metastasis, the osteoclasts are a major source of MMP-9 while surprisingly, the human cancer metastases were rarely positive for this MMP.…”

“…In the tumorbone microenvironment, the osteoclast has recently come under scrutiny as a major facilitator of angiogenesis and a number of studies point to MMP-9 being critical for mediating the release of VEGF-A 164 from the bone matrix [21,[130][131][132]. In development, MMP-9 expression by osteoclasts is critical for their invasion into developing long bones, and MMP-9 mediated release of VEGF-A (presumably the VEGF-A 164 isoform) is the principal molecular mechanism underlying this effect [54].…”