Study sheds light on cancer-spreading enzymes produced by the immune-system.
As a part of the human immune system, white blood cells create a number of enzymes that help fight disease. Sometimes, these enzymes can malfunction, causing damage to the body or increasing cancer growth. Now, a study from researchers at the University of Missouri has mapped the structure of one of these enzymes, called MMP7, as it binds to the surface of cancer cells. The team state that understanding the structure of this enzyme and how it works with partners will help create future treatments for cancer. The opensource study is published in the journal Structure.
Previous studies show that matrix metalloproteinase-7 (MMP-7) sheds signaling proteins from cell surfaces to activate bacterial killing, wound healing, and tumourigenesis. MMP7 has been shown to make cancer cells more aggressive and likely to spread throughout the body. Several instances of its shedding of the soluble transmembrane proteins from cell surfaces promote tumourigenesis or other key tumour cell behaviours. For example, MMP-7 shedding of HB-EGF stimulates EGF receptor signaling and the proliferation of squamous cell carcinoma cells. Its shedding of a domain from the ErbB4 receptor boosts the proliferation of mammary tumour cells. Its release of E-cadherin increases tumour cell invasiveness and MMP-7 shedding of Fas ligand and syndecan-1 are each associated with resistance to chemotherapy. Therefore, understanding how MMP-7 can catalyze these pivotal shedding events will benefit from insight into the structural basis of its pericellular positioning. The current study shows how MMP7 signals to cancer cells to become more aggressive when the enzyme cuts off specific proteins as it binds to those cancer cells.
The current study used Nuclear Magnetic Resonance (NMR) to map the structure of assemblies containing MMP7. NMR examined membrane-binding orientations and allostery in MMP-7, from linings of organs and tumour cells. Results show that cholesterol sulfate partially inserts and reorients MMP-7 in bilayers and the auto-inhibitory conformation is released by remote binding of bicelles, implicating a possible cancer path of allosteric transmission.
The lab also investigated a sister enzyme, known as MMP14, using NMR to determine how it helps cancer spread throughout the body. The group explain that MMP14 is the most important protein-cutting enzyme in terms of how cancer cells migrate throughout the body. They go on to add that these enzymes essentially cut paths through the collagen mesh of tissues in the body to enable cancer cells to move and spread.
The team surmise that understanding the structures of how these enzymes attack collagen and other proteins, the global medical community can find ways to block them from allowing cancer to spread. For the future, the researchers state that mapping the structures will hopefully lead to ways to prevent these enzymes from binding and signaling to cancer cells in the first place. They go on to conclude that the end result could be a way to prevent cancer cells from spreading so rapidly.
Source: University of Missouri