Increased plasma MMP9 in integrin α1‐null mice enhances lung metastasis of colon carcinoma cells

Abstract

Inhibitors of matrix metalloproteinases (MMPs) were developed as anticancer agents based on the observation that MMPs facilitate local tumor spread and metastasis by promoting matrix degradation and cell migration. Unfortunately, these inhibitors were unsuccessful in the clinical treatment of several cancers, including lung cancer. A possible reason contributing to their failure is that MMP activity is critical for the generation of inhibitors of tumor angiogenesis, including angiostatin. Thus, MMPs might play opposing roles in tumor vascularization and invasion. To determine which effect of elevated MMP levels dominates in the progression of metastatic cancer, experimental lung metastasis assays were performed in integrin a1-null mice, a genetic model for increased plasma levels of MMP9 and MMP9-generated angiostatin (Pozzi et al., Proc. Natl. Acad. Sci. USA 2000;97:2202-7). We show that while the number of lung colonies in integrin a1-null mice was significantly increased compared to their wild-type counterparts, tumor volume was markedly reduced. In vivo treatment with the MMP inhibitor doxycycline resulted in a significant decrease in the number of lung colonies in both genotypes, but the tumors that formed were bigger and more vascularized. Increased tumor vascularization paralleled decreased plasma levels of MMP9 and consequent decreased angiostatin synthesis. These results demonstrate that while inhibition of MMPs prevents and/ or reduces tumor invasion and lung metastasis, it has the paradoxical effect of increasing the size and vascularization of metastatic tumors due to decreased generation of inhibitors of endothelial cell proliferation. The continued growth of these large well-vascularized tumors may explain the poor efficacy of MMP inhibitors in lung cancer clinical trials. ' 2005 Wiley-Liss, Inc.Key words: angiostatin; matrix metalloproteinase inhibitor; angiogenesis; CT26 MMPs are proteolytic enzymes involved in the degradation of ECM components. They belong to a multigenic family of more than 20 members 1 and are critical for both physiologic and pathologic events, such as wound healing, tissue remodeling, tumor growth, vascularization and metastasis. MMPs can promote tumor progression by degrading ECM and thus facilitating cell migration, invasion and neovascularization. In this context, synthesis of MMP9 by tumor cells and/or host stromal cells plays a pivotal role in promoting local tumor progression 4 and invasion, with a subsequent increase in distant metastasis. 5,6 Moreover, stroma-derived MMP9 contributes to tumor angiogenesis by promoting blood vessel morphogenesis and pericyte recruitment.7 Consistent with these observations, treatment with MMPIs decreases metastatic lung colonization following tail vein injection of lung carcinoma cells.8 Furthermore, reduced pericyte recruitment with consequent inhibition of tumor angiogenesis is observed in MMP9-deficient mice orthotopically implanted with neuroblastoma cells.7 Together these results suggest that increasing MMP activity and/or expres...

Macrophage Migration Inhibitory Factor Promotes Colorectal Cancer

“…Thus, high expression of MMP-2 and MMP-9 may be used to characterize the behaviors of colorectal carcinoma (38,39). Moreover, high colorectal MMP-9 expression has been implicated in lung metastases (40) and tumor cell resistance to proapoptotic and p53 effects, as well as poor efficacy in postoperative adjuvant chemotherapy (41). In vitro, MIF also was shown to promote cell invasiveness through macrophage secretion of MMP (42).…”

MMP-9 from sublethally irradiated tumor promotes Lewis lung carcinoma cell invasiveness and pulmonary metastasis

“…MMPs have been correlated with cancer prognosis clinically and histopathologically (Leeman et al, 2003). One, in particular, MMP-9 (a 92-kDa type IV collagenase or gelatinase B) has a role in tumor invasion, angiogenesis and metastasis (Bernhard et al, 1994), and its level is related to angiostatin synthesis and systemic metastasis in animal models (Basile et al, 2004;Chen et al, 2005).…”

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

“…Chen, et al, showed that treatment of CT26 (colon carcinoma cells) inoculated mice with 40 mg/kg/day of doxycyclin starting immediately or 2-weeks after tumor cell injections resulted in fewer but larger and more vascularized lung tumors. On the other hand, when therapy started at the time of tumor injections, mice had fewer lung tumors than mice treated 2-weeks after injection of colon carcinoma cells [83]. This suggests that the time and/or the frequency of the treatment have significant effect on development of lung experimental metastasis.…”

“…The increased vascularization was attributed to decreased production of angiostatin by MMP-9 [83]. Thus, MMP-9 inhibitors may have a null or pro-tumorigenic effect when administered intravenously.…”

“…Thus, PKD1 regulates breast cancer cell invasion through regulation of the expression of MMP-9. Furthermore, Chen et al provided evidence that the presence of increased levels of MMP-9 in integrin alpha1-null mice enhanced the number of tumors on lung but these tumors were smaller compared to lung tumors in WT counterparts [83]. They also showed that inhibition of MMP-9 by doxycyclin in these alpha1-null mice led to reduced number of lung colonies but bigger tumors were observed.…”