Abstract
Matrix metalloproteinases-2 and -9 (MMP-2/-9) are key tissue remodeling enzymes that have multiple overlapping activities critical for wound healing and tumor progression in vivo. To overcome issues of redundancy in studying their functions in vivo, we created MMP-2/-9 double knockout (DKO) mice in the C57BL/6 background to examine wound healing. We then bred the DKO mice into the polyomavirus middle T (PyVmT) model of breast cancer to analyze the role of these enzymes in tumorigenesis. Breeding analyses indicated that significantly fewer DKO mice were born than predicted by Mendelian genetics and weaned DKO mice were growth compromised compared with wild type (WT) cohorts. Epithelial wound healing was dramatically delayed in adult DKO mice and when the DKO was combined with the PyVmT oncogene, we found that the biologically related process of mammary tumorigenesis was inhibited in a site-specific manner. To further examine the role of MMP-2/-9 in tumor progression, tumor cells derived from WT or DKO PyVmT transgenic tumors were grown in WT or DKO mice. Ratiometric activatable cell penetrating peptides (RACPPs) previously used to image cancer based on MMP-2/-9 activity were used to understand differences in MMP activity in WT or knockout syngeneic tumors in WT and KO animals. Analysis of an MMP-2 selective RACPP in WT or DKO mice bearing WT and DKO PyVmT tumor cells indicated that the genotype of the tumor cells was more important than the host stromal genotype in promoting MMP-2/-9 activity in the tumors in this model system. Additional complexities were revealed as the recruitment of host macrophages by the tumor cells was found to be the source of the tumor MMP-2/-9 activity and it is evident that MMP-2/-9 from both host and tumor is required for maximum signal using RACPP imaging for detection. We conclude that in the PyVmT model, the majority of MMP-2/-9 activity in mammary tumors is associated with host macrophages recruited into the tumor rather than that produced by the tumor cells themselves. Thus therapies that target tumor-associated macrophage functions have the potential to slow tumor progression.
Highlights
Tissue matrix homeostasis is a complex process that is important in normal growth, development and wound healing
Reduced fecundity and compromised growth in double knockout (DKO) mice Given the fundamental roles that MMP-2/-9 play in tissue homeostasis, it is reasonable to hypothesize that a loss of both enzymes could result in reduced fertility and offspring viability
Since MMP-2/-9 have long been associated with cancer progression either through their effects on matrix degradation or as regulators of growth factor and cytokine bioactivity [36], we examined their role in tumor growth in the polyomavirus middle T (PyVmT) transgenic mouse model of breast cancer [16, 37]
Summary
Tissue matrix homeostasis is a complex process that is important in normal growth, development and wound healing. Proteolysis is regulated at multiple levels, including transcription, secretion, and conversion of the zymogen (pro-MMP) into an active protease as well as by the presence of cell type specific tissue inhibitors of metalloproteinases (TIMPs) [1, 2]. Efforts to develop therapeutic inhibitors were met with disappointment. This was due to side effects from insufficiently specific inhibitors as well as an inadequate understanding of the normal functions of these enzymes and the complex interactions taking place in vivo [6, 7]. Evidence suggests that MMPs act as key nodal components of an interconnected protease web and they can have opposing effects on the same biological process depending on factors present in the local microenvironment [8]. Regardless of the function of MMPs in cancer, fluorescence activatable probes that rely on MMP activity have been developed to visualize tumor margins and improve surgical outcomes [9,10,11]
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