Role of intracellular transport, sorting and release of membrane type 1 matrix metalloproteinase (MT1-MMP) in tumor cell invasion and metastatic dissemination

Mazzone, Marco (2005). Role of intracellular transport, sorting and release of membrane type 1 matrix metalloproteinase (MT1-MMP) in tumor cell invasion and metastatic dissemination. PhD thesis The Open University.



The primary cause of death in cancer patients is the development of metastatic secondary tumours in distal organs. This is a complex process during which metastatic tumour cells need to overcome the natural barriers impeding access to vascular or lymphatic pathways: importantly they also need to alter the extracellular environment to allow ectopic cancer growth in distant locations. These events generally require the direct participation of released and exposed matrix metalloproteinases (MMPs), a family of related zinc-dependent proteases.

Regulation of MMP activity is known to occur by modulation of gene expression, via zymogen activation and inhibition by tissue inhibitors of metalloproteinases (TIMPs). It is now evident, however, that modulation of intracellular trafficking, membrane sorting and cell surface release can also regulate MMP activities. These latter topics are still not well understood and, for this reason, represent the main aims of the present study.

In particular, it has clearly emerged that MT1-MMP, a membrane-type MMP, is essential for the growth for human cancers, and acts by disrupting the three-dimensional matrix, which would otherwise impede cell proliferation. Ablation of the gene encoding MT1-MMP causes the most significant phenotype among the MMP knockout mice, and suggests that the activity of MT1-MMP cannot be substituted by any of the other members of the family. For this reason, the main focus of my PhD thesis is the regulation of MT1-MMP activity.

Here I show that, in a melanoma cell line, the majority (80%) of MT1-MMP is sorted to detergent-resistant membrane fractions; however, it is only the minor (20%) detergent-soluble fraction of MT1-MMP that undergoes intracellular processing to the mature form. Also, this processed MT1-MMP is the sole form responsible for ECM degradation in vitro. Finally, furin-dependent processing of MT1-MMP is shown to occur intracellularly after exit from the Golgi apparatus and prior to arrival at the plasma membrane. It is thus proposed that the association of MT1-MMP with different membrane subdomains might be crucial in the control of its different activities: for instance in cell migration and invasion and other less defined roles such as MTl-MMP-dependent signaling pathways.

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