Impact of MMP-2 and MMP-9 enzyme activity on wound healing, tumor growth and RACPP cleavage

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.

Improved Antiglioblastoma Activity and BBB Permeability by Conjugation of Paclitaxel to a Cell‐Penetrative MMP‐2‐Cleavable Peptide

“…In recent years, numerous insightful studies have demonstrated that MMP‐2 is over‐expressed in GBM and has a characteristic ability to recognize and cleave peptides with specific sequences. [ 28,29,35 ] As such, various substrates of MMP‐2 were designed to enhance specificity for drug delivery, thus leading to a remarkable effort toward the investigation of drug‐targeted delivery systems. The present study aimed to conjugate PTX with the effective MMP‐2‐sensitive linker, PVGLIG to reduce off‐target binding and side effects.…”

“…Matrix metalloproteinases‐2 (MMP‐2; 72kD), a member of the MMP family, plays multiple roles in the progression of tumors. [ 28,29 ] Compared with almost no expression in normal brain tissue, it has been suggested that MMP‐2 is highly expressed in glioma tissues. [ 30,31 ] Furthermore, mRNA and protein levels of MMP‐2 increase along with the stage of glioma progression, closely associated with the invasion of glioma cells.…”

High expression of eIF4E regulates immune cell infiltration and leads to poor prognosis in breast cancer

“…The results of immunohistochemical analysis showed that there was signi cant difference in TNM staging between the high in ltration density group and the low in ltration density group in TS (P < 0.05), which indicated that TAM polarization and TS in ltration promoted the malignant progression of breast cancer,. Consistent studies have shown that TAM can secrete a variety of angiogenic factor, such as VEGF, MMP9, tumor necrosis factor (TNF), TGF-β, EGF, broblast growth factor (FGF) to promote angiogenesis (31,32).TAM is transformed into M2 to enhance tumor angiogenesis in advanced tumors (33). In breast cancer, TAM can also secrete matrix metalloproteinase 9 (MMP9) and matrix metalloproteinase 2 (MMP2) to degrade the extracellular matrix, M2 can produce high level of MMP, promote extracellular matrix (ECM) degradation, and stimulate tumorigenesis, cancer cell invasion and metastasis by activating Epithelial-mesenchymal transition (EMT) (31,34).…”

<p>Enhanced and Prolonged Antitumor Effect of Salinomycin-Loaded Gelatinase-Responsive Nanoparticles via Targeted Drug Delivery and Inhibition of Cervical Cancer Stem Cells</p>

“…53 Owing to their special structures, the NPs prepared from mPEG-peptide-PCL exhibit their own characteristics, such as prolonged circulation time and accumulation in the tumor site by the EPR effect. [54][55][56] MMPs are abundantly present in tumors, 57,58 and have been considered as tumorspecific stimuli for cancer imaging and drug delivery. 59,60 Following the accumulation of NPs in the tumors, the mPEG-peptide-PCL conjugates will be cleaved at a certain site of the MMP2/9 peptide by MMP2/9.…”