Effect of Ablation or Inhibition of Stromal Matrix Metalloproteinase-9 on Lung Metastasis in a Breast Cancer Model Is Dependent on Genetic Background

Abstract

Matrix metalloproteinases (MMP) are a family of enzymes with a myriad of functions. Lately, we have come to realize that broad-spectrum inhibition of these enzymes, as was tried unsuccessfully in multiple phase III trials in cancer patients, is likely unwise given the protumorigenic and antitumorigenic functions of various family members. Here, we used the multistage mammary tumor model MMTV-PyVT to investigate roles for either MMP7 or MMP9 in tumor progression. We found no effect of genetic ablation of MMP7 or MMP9 on the multifocal tumors that developed in the mammary glands. Lack of MMP7 also had no effect on the development of lung metastases, suggesting that MMP7 is irrelevant in this model. In contrast, MMP9 deficiency was associated with an 80% decrease in lung tumor burden. The predominant cellular source of MMP9 was myeloid cells, with neutrophils being the largest contributor in tumor-bearing lungs. Experimental metastasis assays corroborated the role of host-derived MMP9 in lung metastasis and also facilitated determination of a time frame most relevant for the MMP9-mediated effect. The lung tumors from MMP9-deficient mice showed decreased angiogenesis. Surprisingly, the antimetastatic outcome of MMP9 ablation seemed to be dependent on strain. Only mice that had genetic background derived from C57BL/6 showed reduced metastasis, whereas mice fully of the FVB/N background showed no significant effect. These strain-specific responses were also observed in a study using a highly selective pharmacologic inhibitor of MMP9 and thus suggest that responses to MMP inhibition are controlled by genetic differences. [Cancer Res 2008;68(15):6251-9]

Raf-induced MMP9 disrupts tissue architecture of human breast cells in three-dimensional culture and is necessary for tumor growth in vivo

“…Whereas MMTV-PyMT mice deficient for MMP9 did not show a change in the occurrence of multifocal mammary tumors, formation of lung metastases was reduced significantly (Martin et al 2008). Increased MMP9 levels correlate also with an increase in metastatic disease and reduced relapse-free survival in patients with breast cancer (Li et al 2004;Vizoso et al 2007;Wu et al 2008).…”

Understanding the Effects of Cytotoxic Chemotherapeutics on the Innate Immune System

“…Although MMP9 does not influence primary tumor growth in the transgenic MMTV-PyMT model (Martin et al, 2008), we found that the growth of grafted tumors was reduced in Mmp9 À/À hosts compared to FVB/n hosts ( Figure S4A). Interestingly, tumors in Mmp9 À/À hosts responded better to doxorubicin than those in FVB/n hosts ( Figure S4B).…”

The Treatment of Breast Cancer Tumor Growth and Metastasis With an Anti-MMP9 DNAzyme

“…Martin et al [68] have demonstrated that spontaneous lung metastases decreased by 80% in MMTV-PyMT MMP-9 null mice compared to MMTV-PyMT MMP-9 wild type mice. In addition, the lung tumors developed in MMTV-PyMT MMP-9 wild type mice are larger in size and are more highly vascular compared to those tumors that developed in MMTV-PyMT MMP-9 null mice.…”

“…They found that SB-3CT therapy resulted in a significant decrease in tumor growth in C57BL/6 mice, while mice on a FVB/N background showed enhanced tumor growth according to luciferase signal upon treatment. The mice utilized in our experimental metastasis model are FVB/N, the same strain that showed enhanced tumor growth when treated with a gelatinase inhibitor in the Martin, et al publication [68]. These data suggest that the mice with different genetic backgrounds should be used to assess the significance of genetics on efficacy of AM9D in experimental metastasis.…”

“…Martin et al showed that the treatment outcome of a gelatinase inhibitor, SB-3CT, on experimental metastasis is strain dependent [68]. In their experiments, luciferase-labeled 17L3C cells (MTEC from MMTV-PyMT mice) were injected via tail vein into C57BL/6 and FVB/N mice followed by daily injections of 50 mg/kg of the drug SB-3CT or vehicle for 14 days.…”