Cancer cells manage to get away with a lot - they evade recognition by cells of the immune system, they hijack oxygen and nutrients from normal cells and tissues, and travel and successfully establish themselves into new parts of the body. The later, known as metastasis, is considered the main cause of death in cancer, and despite this the factors driving it have remained fairly enigmatic. But today I came across a slightly older study from Cell that identified a 'duel' between cancer cells and cells from the brain microenvironment involving the molecule plasmin.
Plasmin is an enzyme that is released by the body to break down naturally occurring blood clots, and in the brain is expressed in high levels by one type of cell known as an astrocyte. While looking for factors involved in metastasis, the authors of this study found that metastatic lung and breast cancer cells express high levels of molecules known as serpins, a subset of which (NS, serpin B2, serpin E1 and serpin E2) are known to inhibit the function of plasmin.
These proteins apparently act as a shield for metastatic cancer cells, helping them survive the hostile environment created by plasmin in the brain. Specifically, the authors found that plasmin kills cancer cells infiltrating the brain, which stop multiplying and die through a type of programmed cell 'suicide' known as apoptosis. Plasmin achieves this in two ways: by directly inducing the death of cancer cells by processing (and thus activating) the FAS ligand death signal, which can then instruct cells to die through apoptosis; and by inhibiting their adhesion and spreading on capillaries (required for metastasis) through processing of the adhesion molecule L1CAM.
Metastatic cells, however, survive and continue to multiply by increasing their expression and production of serpins. And so, removal of these proteins or blocking their function makes the cancer cells once again vulnerable to the effects of plasmin. In the case of the metastatic lung cancer cells (which increase the expression of just NS), blocking NS inhibited their metastatic behaviour, as did forcing them to express a form of NS that can no longer inhibit plasmin. Similarly, removing the three serpins that metastatic breast cancer cells upregulate prevented their metastatic behaviour.
With brain metastasis being one of the most common complications of cancer, the potential implications of these findings are evident, as they could lead to the development of therapeutics that specifically manipulate the plasmin-serpin interaction. But what is also intriguing is that the 'duel' between serpins and plasmin may apply more broadly in metastasis, as serpins are also expressed in other metastatic sites, and expression of plasmin, FAS ligand and L1CAM have been linked to poor cancer prognosis.
Plasmin is an enzyme that is released by the body to break down naturally occurring blood clots, and in the brain is expressed in high levels by one type of cell known as an astrocyte. While looking for factors involved in metastasis, the authors of this study found that metastatic lung and breast cancer cells express high levels of molecules known as serpins, a subset of which (NS, serpin B2, serpin E1 and serpin E2) are known to inhibit the function of plasmin.
 |
| The plasmin-serpin duel Image from https://www.flickr.com/photos/ahnmyrrh/3634171130 |
Metastatic cells, however, survive and continue to multiply by increasing their expression and production of serpins. And so, removal of these proteins or blocking their function makes the cancer cells once again vulnerable to the effects of plasmin. In the case of the metastatic lung cancer cells (which increase the expression of just NS), blocking NS inhibited their metastatic behaviour, as did forcing them to express a form of NS that can no longer inhibit plasmin. Similarly, removing the three serpins that metastatic breast cancer cells upregulate prevented their metastatic behaviour.
With brain metastasis being one of the most common complications of cancer, the potential implications of these findings are evident, as they could lead to the development of therapeutics that specifically manipulate the plasmin-serpin interaction. But what is also intriguing is that the 'duel' between serpins and plasmin may apply more broadly in metastasis, as serpins are also expressed in other metastatic sites, and expression of plasmin, FAS ligand and L1CAM have been linked to poor cancer prognosis.
No comments:
Post a Comment