Matrix metalloproteinase-10 promotes tumor progression through regulation of angiogenic and apoptotic pathways in cervical tumors

Abstract

BackgroundCancer invasion and metastasis develops through a series of steps that involve the loss of cell to cell and cell to matrix adhesion, degradation of extracellular matrix and induction of angiogenesis. Different protease systems (e.g., matrix metalloproteinases, MMPs) are involved in these steps. MMP-10, one of the lesser studied MMPs, is limited to epithelial cells and can facilitate tumor cell invasion by targeting collagen, elastin and laminin. Enhanced MMP-10 expression has been linked to poor clinical prognosis in some cancers, however, mechanisms underlying a role for MMP-10 in tumorigenesis and progression remain largely unknown. Here, we report that MMP-10 expression is positively correlated with the invasiveness of human cervical and bladder cancers.MethodsUsing commercial tissue microarray (TMA) of cervical and bladder tissues, MMP-10 immunohistochemical staining was performed. Furthermore using a panel of human cells (HeLa and UROtsa), in vitro and in vivo experiments were performed in which MMP-10 was overexpressed or silenced and we noted phenotypic and genotypic changes.ResultsExperimentally, we showed that MMP-10 can regulate tumor cell migration and invasion, and endothelial cell tube formation, and that MMP-10 effects are associated with a resistance to apoptosis. Further investigation revealed that increasing MMP-10 expression stimulates the expression of HIF-1α and MMP-2 (pro-angiogenic factors) and PAI-1 and CXCR2 (pro-metastatic factors), and accordingly, targeting MMP-10 with siRNA in vivo resulted in diminution of xenograft tumor growth with a concomitant reduction of angiogenesis and a stimulation of apoptosis.ConclusionTaken together, our findings show that MMP-10 can play a significant role in tumor growth and progression, and that MMP-10 perturbation may represent a rational strategy for cancer treatment.

Tumor angiogenesis: MMP-mediated induction of intravasation- and metastasis-sustaining neovasculature

“…The overall dependence of tumor angiogenesis on the expression of various MMPs is still in the spotlight of experimental and clinical cancer research, deeply focusing on unraveling the precise interrelations between different regulatory molecules and proteolytic activities of specific MMPs (Al Rawashdeh et al, 2014; Barillari et al, 2014; Depner et al, 2014; Gong et al, 2014; Kahlert et al, 2014; Zhang et al, 2014). In this review, however, we attempted to summarize the data on the mechanisms whereby various MMPs, characterized by different substrate specificities, e.g.…”

Semi-solid tumor model in Xenopus laevis/gilli cloned tadpoles for intravital study of neovascularization, immune cells and melanophore infiltration

“…For example, type I collagen produced by stromal fibroblast in the tumor microenvironment can promote tumor growth in breast cancer (Kim et al, 2014). In addition, tumor cells are known to secrete enzymes such as metalloproteases to degrade extracellular matrix including collagen to facilitate invasion (Zhang et al, 2014). Thus, using our model we can now study how collagen modification can modulate tumor growth.…”

Biochemical and Biological Attributes of Matrix Metalloproteinases

“…46 MMPs could break the cell to cell and cell to ECM adhesion, degrade ECM proteins, and promote angiogenesis, and thereby facilitate cancer invasion and metastasis. 54 …”

“…These findings suggest that MMP-10 can play a role in tumor growth and progression, and MMP-10 inhibition may represent a rational strategy for cancer treatment. 54 …”